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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Alport Syndrome - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="Alport Syndrome">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2025/02/27">
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<meta name="citation_author" content="Kandai Nozu">
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<meta name="citation_author" content="Tomohiko Yamamura">
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<meta name="citation_author" content="Tomoko Horinouchi">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1207/">
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<meta name="citation_keywords" content="Familial Nephritis">
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<meta name="citation_keywords" content="Hereditary Nephritis">
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<meta name="citation_keywords" content="Familial Nephritis">
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<meta name="citation_keywords" content="Hereditary Nephritis">
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<meta name="citation_keywords" content="Thin Basement Membrane Disease">
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<meta name="citation_keywords" content="Thin Basement Membrane Nephropathy">
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<meta name="citation_keywords" content="Collagen alpha-3(IV) chain">
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<meta name="citation_keywords" content="Alport Syndrome">
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<meta name="DC.Title" content="Alport Syndrome">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Kandai Nozu">
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<meta name="DC.Contributor" content="Tomohiko Yamamura">
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<meta name="DC.Contributor" content="Tomoko Horinouchi">
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<meta name="DC.Date" content="2025/02/27">
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<meta name="description" content="Alport syndrome is characterized by kidney manifestations, sensorineural hearing loss (SNHL), and ocular manifestations. In the absence of treatment, kidney disease progresses from microhematuria to proteinuria, progressive kidney insufficiency, and end-stage kidney disease (ESKD) in most males with X-linked Alport syndrome (XLAS), and in most males and females with autosomal recessive Alport syndrome (ARAS). Progressive SNHL is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In females with XLAS and individuals with autosomal dominant Alport syndrome (ADAS), ESKD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare.">
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<meta name="og:title" content="Alport Syndrome">
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<meta name="og:description" content="Alport syndrome is characterized by kidney manifestations, sensorineural hearing loss (SNHL), and ocular manifestations. In the absence of treatment, kidney disease progresses from microhematuria to proteinuria, progressive kidney insufficiency, and end-stage kidney disease (ESKD) in most males with X-linked Alport syndrome (XLAS), and in most males and females with autosomal recessive Alport syndrome (ARAS). Progressive SNHL is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In females with XLAS and individuals with autosomal dominant Alport syndrome (ADAS), ESKD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare.">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK1207_"><span class="title" itemprop="name">Alport Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Familial Nephritis, Hereditary Nephritis</div><p class="contribs">Nozu K, Yamamura T, Horinouchi T.</p><p class="fm-aai"><a href="#_NBK1207_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 42 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="alport.Summary" itemprop="description"><h2 id="_alport_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Alport syndrome is characterized by kidney manifestations, sensorineural hearing loss (SNHL), and ocular manifestations. In the absence of treatment, kidney disease progresses from microhematuria to proteinuria, progressive kidney insufficiency, and end-stage kidney disease (ESKD) in most males with X-linked Alport syndrome (XLAS), and in most males and females with autosomal recessive Alport syndrome (ARAS). Progressive SNHL is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In females with XLAS and individuals with autosomal dominant Alport syndrome (ADAS), ESKD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The molecular diagnosis of Alport syndrome is established in a proband with suggestive findings and a pathogenic variant(s) in <i>COL4A3</i>, <i>COL4A4</i>, or <i>COL4A5</i> identified by molecular genetic testing. Kidney biopsy, skin biopsy (in some individuals with XLAS), or clinical diagnostic criteria may be used to establish the diagnosis in those without access to genetic testing or those with uninformative results.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to delay onset of ESKD; standard treatment of hypertension; kidney transplantation for ESKD. Potential living related donors must be evaluated carefully to avoid nephrectomy in an affected individual. Hearing aids as needed for SNHL; cataract removal as needed; in those with deletions of <i>COL4A5</i> extending into intron 2 of <i>COL4A6</i>, surgical intervention for symptomatic leiomyomas as needed.</p><p><i>Surveillance:</i> Evaluation by a nephrologist including urinalysis, assessment of kidney function, and blood pressure every six to 12 months; monthly monitoring of at-risk transplant recipients for development of anti-glomerular basement membrane antibody-mediated glomerulonephritis for the first year post transplant; audiologic evaluation every one to two years beginning at age six to seven years; ophthalmology evaluation for ocular abnormalities every one to two years beginning in adolescence in males with a <i>COL4A5</i> truncating pathogenic variant and in persons with ARAS.</p><p><i>Agents/circumstances to avoid:</i> Drink adequate fluids as dehydration may accelerate the progression of nephropathy. Protection of corneas from minor trauma in those with recurrent corneal erosions. Minimize exposure to loud noise.</p><p><i>Evaluation of relatives at risk:</i> Evaluate at-risk family members in order to identify as early as possible those who would benefit from initiation of treatment either by molecular genetic testing if the pathogenic variant(s) in the family are known or urinalysis and blood pressure if the pathogenic variant(s) in the family are not known.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>COL4A5</i>-related Alport syndrome is inherited in an X-linked manner (XLAS)<i>.</i>
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<i>COL4A3-</i> and <i>COL4A4-</i>related Alport syndrome are inherited in an autosomal dominant (ADAS) or autosomal recessive (ARAS) manner. Digenic Alport syndrome is caused by pathogenic variants in more than one Alport syndrome-related gene: typically pathogenic variants in both <i>COL4A3</i> and <i>COL4A4</i> (in <i>cis</i> or in <i>trans)</i> or, more rarely, a pathogenic variant in <i>COL4A5</i> in addition to a pathogenic variant in <i>COL4A3</i> or <i>COL4A4</i>.</p><p><i>XLAS:</i> The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has a <i>COL4A5</i> pathogenic variant, the chance of transmitting it in each pregnancy is 50%. The risk to the sibs of a female proband depends on the genetic status of the parents: if the mother of the proband has a <i>COL4A5</i> pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a <i>COL4A5</i> pathogenic variant, he will transmit it to all of his daughters and none of his sons. Males and females who inherit the pathogenic variant will be affected.</p><p><i>ARAS:</i> If both parents are known to be heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants (and having ARAS), a 50% chance of being heterozygous (and at risk for ADAS), and a 25% chance of inheriting neither of the familial pathogenic variants.</p><p><i>ADAS:</i> If a parent of the proband is affected and/or is known to have the <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. The severity of clinical manifestations may vary greatly among heterozygous family members; some heterozygotes may be asymptomatic and some may develop ESKD.</p><p><i>Digenic Alport syndrome:</i> The risk to sibs depends on the involved genes, the location of the pathogenic variants (i.e., in <i>cis</i> or in <i>trans</i>) in families segregating pathogenic variants in <i>COL4A3</i> and <i>COL4A4</i>, and the sex of the proband (in families segregating pathogenic variants in <i>COL4A5</i> and <i>COL4A3</i> or <i>COL4A4</i>).</p><p>Once the Alport syndrome-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p></div></div><div id="alport.Diagnosis"><h2 id="_alport_Diagnosis_">Diagnosis</h2><p>Diagnostic criteria for Alport syndrome have been published [<a class="bibr" href="#alport.REF.nozu.2019.158" rid="alport.REF.nozu.2019.158">Nozu et al 2019</a>].</p><div id="alport.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Molecular genetic testing for Alport syndrome <b>should be considered</b> in an individual with <b>persistent glomerular hematuria</b>, plus one or more of the following clinical findings, family history, pathology, or other findings [<a class="bibr" href="#alport.REF.kashtan.2021.272" rid="alport.REF.kashtan.2021.272">Kashtan 2021</a>].</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Sensorineural deafness</div></li><li class="half_rhythm"><div>Anterior lenticonus and/or characteristic retinopathy</div></li><li class="half_rhythm"><div>Diffuse leiomyomatosis</div></li></ul><p>
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<b>Family history findings</b>
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</p><ul><li class="half_rhythm"><div>Hematuria</div></li><li class="half_rhythm"><div>Chronic kidney disease / kidney failure</div></li><li class="half_rhythm"><div>Deafness associated with chronic kidney disease</div></li></ul><p>
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<b>Pathologic findings on kidney biopsy</b>
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</p><ul><li class="half_rhythm"><div>Negative or nonspecific routine immunofluorescence</div></li><li class="half_rhythm"><div>Type IV collagen abnormal expression</div></li><li class="half_rhythm"><div>Thin glomerular basement membranes</div></li><li class="half_rhythm"><div>Characteristic glomerular basement membrane thickening, lamellation, and scalloping</div></li></ul><p><b>Note:</b> Molecular genetic testing for Alport syndrome can also be considered in those with <b>hematuria</b> and either:</p><ul><li class="half_rhythm"><div>Family history of hematuria, chronic kidney disease, kidney failure, or deafness associated with chronic kidney disease; OR</div></li><li class="half_rhythm"><div>Diagnoses of immunoglobulin A nephropathy, membranous nephropathy, and membranoproliferative glomerular glomerulonephritis (C3 nephropathy) have been ruled out.</div></li></ul></div><div id="alport.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><div id="alport.Molecular_Diagnosis"><h4>Molecular Diagnosis</h4><p>The molecular diagnosis of Alport syndrome <b>is established</b> in a proband with suggestive findings and <b>one of the following</b> identified by molecular genetic testing (see <a href="/books/NBK1207/table/alport.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobalportTmoleculargenetictestingused">Table 1</a>):</p><ul><li class="half_rhythm"><div>Biallelic pathogenic (or likely pathogenic) variants involving <i>COL4A3</i> or <i>COL4A4</i> (ARAS)</div></li><li class="half_rhythm"><div>A hemizygous pathogenic (or likely pathogenic) variant involving <i>COL4A5</i> in a male proband or a heterozygous pathogenic (or likely pathogenic) variant involving <i>COL4A5</i> in a female proband (XLAS)</div></li><li class="half_rhythm"><div>A heterozygous pathogenic (or likely pathogenic) variant involving <i>COL4A3</i> or <i>COL4A4</i> (ADAS)</div></li></ul><p>Note: Digenic inheritance has been described, typically due to pathogenic variants in both <i>COL4A3</i> and <i>COL4A4</i> (in <i>cis</i> or in <i>trans)</i> or, more rarely, a pathogenic variant in <i>COL4A5</i> in addition to a pathogenic variant in <i>COL4A3</i> or <i>COL4A4</i>.</p><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#alport.REF.richards.2015.405" rid="alport.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis. (3) Modified ACMG variant interpretation guidelines have been published [<a class="bibr" href="#alport.REF.savige.2022.143" rid="alport.REF.savige.2022.143">Savige et al 2022</a>].</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#alport.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#alport.Option_2">Option 2</a>).</p><div id="alport.Option_1"><h5>
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<b>Option 1</b>
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</h5><p>When the phenotypic and laboratory findings suggest the diagnosis of Alport syndrome, the recommended molecular genetic testing approach is the use of a <b>multigene panel</b>.</p><p><b>A multigene panel</b> that includes <i>COL4A3</i>, <i>COL4A4</i>, <i>COL4A5</i>, and other genes of interest (see <a href="#alport.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p><p>Note: (1) Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish ancestry. (2) Some laboratories may offer targeted analysis for pathogenic variants particularly common in the United States, including p.Cys1564Ser, p.Leu1649Arg, and p.Arg1677Gln (see <a href="/books/NBK1207/table/alport.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobalportTpathogenicvariantsreferenced">Table 8</a>).</p></div><div id="alport.Option_2"><h5>
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<b>Option 2</b>
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</h5><p>When the diagnosis of Alport syndrome has not been considered because an individual has atypical phenotypic features, <b>comprehensive genomic testing</b> does not require the clinician to determine which gene(s) are likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportTmoleculargenetictestingused"><a href="/books/NBK1207/table/alport.T.molecular_genetic_testing_used/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobalportTmoleculargenetictestingused"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.T.molecular_genetic_testing_used"><a href="/books/NBK1207/table/alport.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobalportTmoleculargenetictestingused">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Alport Syndrome </p></div></div></div></div><div id="alport.Other_Testing"><h4>Other Testing</h4><div id="alport.Kidney_Biopsy"><h5>
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<b>Kidney Biopsy</b>
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</h5><p>
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<b>Immunohistochemical analysis</b>
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</p><ul><li class="half_rhythm"><div><b>Males with XLAS</b> typically show complete absence of immunostaining for collagen IV alpha (α) 3, α4, and α5 chains. Note: Approximately 30%-40% of males with XLAS show positive staining of renal basement membranes for collagen IV α3, α4, and α5 chains [<a class="bibr" href="#alport.REF.hashimura.2014.1208" rid="alport.REF.hashimura.2014.1208">Hashimura et al 2014</a>]. A <i>COL4A5</i> missense pathogenic variant is detected in almost all individuals with normal immunostaining.</div></li><li class="half_rhythm"><div><b>Females heterozygous for XLAS</b> typically exhibit patchy loss of staining for collagen IV α3, α4, and α5 chains in glomerular basement membranes and tubular basement membranes, a so-called mosaic pattern [<a class="bibr" href="#alport.REF.kashtan.1996.142" rid="alport.REF.kashtan.1996.142">Kashtan et al 1996</a>]. Some heterozygous females exhibit normal staining for collagen IV α3, α4, and α5 chains in renal basement membranes.</div></li><li class="half_rhythm"><div><b>Individuals with ARAS</b> typically exhibit complete absence of staining for collagen IV α3 and α4 chains on glomerular basement membranes and show no staining for collagen IV α5 chains; however, staining of Bowman capsules and tubular basement membranes for collagen IV α5 chains is positive [<a class="bibr" href="#alport.REF.gubler.1995.1142" rid="alport.REF.gubler.1995.1142">Gubler et al 1995</a>]. Some individuals with ARAS exhibit normal renal basement membrane staining for collagen IV α3, α4, and α5 chains [<a class="bibr" href="#alport.REF.oka.2014.1535" rid="alport.REF.oka.2014.1535">Oka et al 2014</a>].</div></li><li class="half_rhythm"><div><b>Individuals with ADAS</b> exhibit normal glomerular basement membrane staining for collagen IV α3, α4, and α5 chains.</div></li></ul><p>
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<b>Electron microscopy</b>
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</p><ul><li class="half_rhythm"><div>The earliest finding is diffuse thinning of the glomerular basement membrane. Children with XLAS and ARAS frequently exhibit only glomerular basement membrane thinning on kidney biopsy. Women with XLAS and individuals with ADAS also may exhibit only glomerular basement membrane thinning. Marked variability in glomerular basement membrane width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome.</div></li><li class="half_rhythm"><div>Pathognomonic findings of Alport syndrome when diffusely present are:</div><ul><li class="half_rhythm"><div>Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting);</div></li><li class="half_rhythm"><div>Lacunae between these strands, sometimes with findings of podocyte infolding;</div></li><li class="half_rhythm"><div>Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years).</div></li></ul></li></ul></div><div id="alport.Skin_Biopsy"><h5>
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<b>Skin Biopsy</b>
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</h5><p>When kidney biopsy is contraindicated (and molecular genetic testing is not possible), a skin biopsy with monoclonal antibody staining for collagen IV α5 chains could be performed in place of the kidney biopsy.</p><p>Note: Diagnostic findings on skin biopsy are only informative in some individuals with XLAS. Individuals with ARAS and ADAS have normal skin immunostaining for collagen IV α5 chains.</p><ul><li class="half_rhythm"><div><b>Males with XLAS.</b> In about 80% of males, incubation of a skin biopsy specimen with a monoclonal antibody directed against collagen IV α5 chains shows complete absence of staining of epidermal basement membranes. Approximately 20% of males show normal staining.</div></li><li class="half_rhythm"><div><b>Females heterozygous for XLAS.</b> Approximately 60%-70% of heterozygous females exhibit discontinuous staining of collagen IV α5 chains [<a class="bibr" href="#alport.REF.van_der_loop.1999.1217" rid="alport.REF.van_der_loop.1999.1217">van der Loop et al 1999</a>]. This is attributed to X-chromosome inactivation, by which it would be expected that one half of the basilar keratinocytes would express normal COL4A5.</div></li><li class="half_rhythm"><div><b>Individuals with ARAS.</b> All individuals have normal skin immunostaining for collagen IV α5 chains.</div></li><li class="half_rhythm"><div><b>Individuals with ADAS.</b> All individuals have normal skin immunostaining for collagen IV α5 chains.</div></li></ul></div></div><div id="alport.Clinical_Diagnosis"><h4>Clinical Diagnosis</h4><p>In rare circumstances, if there is no access to molecular genetic testing or kidney biopsy, or if genetic testing fails to detect a pathogenic variant(s), the diagnosis is established in a proband with <b>persistent hematuria</b> and two or more of the following criteria:</p><ul><li class="half_rhythm"><div>Family history of kidney disease</div></li><li class="half_rhythm"><div>Bilateral sensorineural deafness</div></li><li class="half_rhythm"><div>Characteristic ocular abnormalities including anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion</div></li><li class="half_rhythm"><div>Diffuse leiomyomatosis</div></li></ul></div></div></div><div id="alport.Clinical_Characteristics"><h2 id="_alport_Clinical_Characteristics_">Clinical Characteristics</h2><div id="alport.Clinical_Description"><h3>Clinical Description</h3><p>Alport syndrome is characterized by kidney manifestations (ranging from isolated hematuria to progressive kidney disease), sensorineural hearing loss (SNHL), and ocular manifestations. Kidney insufficiency and SNHL may not develop until relatively late in life.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportTalportsyndromefrequencyofse"><a href="/books/NBK1207/table/alport.T.alport_syndrome_frequency_of_se/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobalportTalportsyndromefrequencyofse"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.T.alport_syndrome_frequency_of_se"><a href="/books/NBK1207/table/alport.T.alport_syndrome_frequency_of_se/?report=objectonly" target="object" rid-ob="figobalportTalportsyndromefrequencyofse">Table 2. </a></h4><p class="float-caption no_bottom_margin">Alport Syndrome: Frequency of Select Features </p></div></div><div id="alport.Kidney_Manifestations"><h4>Kidney Manifestations</h4><p>The hallmark of Alport syndrome is microhematuria. All males with XLAS and males and females with ARAS have persistent microhematuria from early in life. Episodic gross hematuria can occur, especially during childhood. Microhematuria is also very common in females with XLAS. Individuals with a heterozygous <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant have an estimated 50% incidence of persistent or intermittent microhematuria.</p><p>All males with XLAS develop proteinuria and most develop progressive kidney insufficiency, which leads to end-stage kidney disease (ESKD). Overall, an estimated 50% of males with XLAS reach ESKD by age 35 years [<a class="bibr" href="#alport.REF.yamamura.2020.1605" rid="alport.REF.yamamura.2020.1605">Yamamura et al 2020</a>]. The rate of progression to ESKD is influenced by the type of <i>COL4A5</i> pathogenic variant (see <a href="#alport.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>). In females with XLAS, median age for developing ESKD is 65 years [<a class="bibr" href="#alport.REF.yamamura.2017.850" rid="alport.REF.yamamura.2017.850">Yamamura et al 2017</a>]. Most individuals with ARAS develop significant proteinuria in childhood and ESKD before age 30 years [<a class="bibr" href="#alport.REF.storey.2013.1945" rid="alport.REF.storey.2013.1945">Storey et al 2013</a>, <a class="bibr" href="#alport.REF.oka.2014.1535" rid="alport.REF.oka.2014.1535">Oka et al 2014</a>]. Proteinuria is frequent in ADAS, especially with advancing age. Progression to ESKD occurs at a slower pace in individuals with ADAS (frequently delayed until later adulthood) than in males with XLAS or individuals with ARAS.</p></div><div id="alport.Cochlear_Manifestations"><h4>Cochlear Manifestations</h4><p>SNHL in individuals with Alport syndrome is never congenital. Diminished hearing is frequently detected in late childhood or early adolescence in boys with XLAS. In its early stages, the hearing deficit is detectable only by audiometry, with bilateral reduction in sensitivity to tones in the range of 2,000-8,000 Hz. In affected males, the hearing loss is progressive and eventually extends to other frequencies, including those of conversational speech. Hearing loss is frequently identifiable by formal assessment of hearing in late childhood, but in some families hearing loss is not detectable until relatively late in life. SNHL develops in 50%-60% of males with XLAS [<a class="bibr" href="#alport.REF.zhang.2018.229" rid="alport.REF.zhang.2018.229">Zhang et al 2018</a>]. In females with XLAS, hearing loss is less frequent and tends to occur later in life. There do not appear to be differences between males and females in the incidence or course of hearing loss in ARAS. In individuals with ARAS, 50%-60% typically exhibit hearing loss [<a class="bibr" href="#alport.REF.zhang.2021.2719" rid="alport.REF.zhang.2021.2719">Zhang et al 2021</a>]. If it occurs in individuals with ADAS, hearing loss may be a very late development.</p><p>The course of the hearing loss depends on the pathogenic variant (see <a href="#alport.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>). Hearing impairment in individuals with Alport syndrome is always accompanied by evidence of kidney involvement.</p><p>A histologic study of cochleas in individuals with Alport syndrome suggests that defective adhesion of the organ of Corti to the basilar membrane may underlie the hearing deficit [<a class="bibr" href="#alport.REF.merchant.2004.1609" rid="alport.REF.merchant.2004.1609">Merchant et al 2004</a>].</p></div><div id="alport.Ocular_Manifestations"><h4>Ocular Manifestations</h4><p>Ocular lesions are common in Alport syndrome, occurring in up to 70% of individuals with Alport syndrome [<a class="bibr" href="#alport.REF.savige.2009.356" rid="alport.REF.savige.2009.356">Savige & Colville 2009</a>, <a class="bibr" href="#alport.REF.savige.2015.703" rid="alport.REF.savige.2015.703">Savige et al 2015</a>]. The spectrum of ocular lesions appears to be similar in males with XLAS and in individuals with ARAS. Ocular lesions appear to be relatively uncommon in ADAS.</p><p>Anterior lenticonus, in which the central portion of the lens protrudes into the anterior chamber, is virtually pathognomonic of Alport syndrome. When present, anterior lenticonus is bilateral in approximately 75% of individuals. It is absent at birth, usually appearing during the second to third decade of life. Progressive distortion of the lens may occur, accompanied by increasing myopia. Lens opacities may be seen in conjunction with lenticonus, occasionally resulting from rupture of the anterior lens capsule.</p><p>All reported individuals with anterior lenticonus who have been adequately examined have exhibited evidence of chronic nephritis and SNHL. It is far more common in affected males but can occur in females with XLAS. The frequency of lenticonus in males with XLAS is 50% [<a class="bibr" href="#alport.REF.savige.2015.703" rid="alport.REF.savige.2015.703">Savige et al 2015</a>]; its occurrence is related to the type of pathogenic variant (see <a href="#alport.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>).</p><p>Maculopathy consisting of whitish or yellowish flecks or granulations in the perimacular region can be observed in males with XLAS and individuals with ARAS. While the maculopathy is usually not associated with any visual abnormalities, some individuals have developed macular holes associated with severe thinning of the retina.</p><p>Central or perimacular fleck retinopathy, characterized by asymmetric patches of confluent flecks, is observed in 70% of males with XLAS and in 20% of females with XLAS, making it a valuable diagnostic clue for Alport syndrome [<a class="bibr" href="#alport.REF.savige.2015.703" rid="alport.REF.savige.2015.703">Savige et al 2015</a>].</p><p>Corneal endothelial vesicles (posterior polymorphous dystrophy) and recurrent corneal erosion may also be seen in individuals with Alport syndrome.</p><p>Bilateral posterior subcapsular cataracts also occur frequently in individuals with Alport syndrome with diffuse leiomyomatosis (see <a href="#alport.Other">Other</a>). The frequency of other ocular complications in those with Alport syndrome with diffuse leiomyomatosis is unknown.</p></div><div id="alport.Other"><h4>Other</h4><p><b>Diffuse leiomyomatosis.</b> The association of XLAS with diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in several dozen families [<a class="bibr" href="#alport.REF.antignac.1996.172" rid="alport.REF.antignac.1996.172">Antignac & Heidet 1996</a>, <a class="bibr" href="#alport.REF.mothes.2002.70" rid="alport.REF.mothes.2002.70">Mothes et al 2002</a>, <a class="bibr" href="#alport.REF.nozu.2017.733" rid="alport.REF.nozu.2017.733">Nozu et al 2017</a>]. This results from large deletions that span the adjacent 5' ends of <i>COL4A5</i> and <i>COL4A6</i>, and the breakpoint in <i>COL4A6</i> is always located in intron 2 [<a class="bibr" href="#alport.REF.zhou.1993.1167" rid="alport.REF.zhou.1993.1167">Zhou et al 1993</a>, <a class="bibr" href="#alport.REF.nozu.2017.733" rid="alport.REF.nozu.2017.733">Nozu et al 2017</a>] (see <a href="#alport.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>). Symptoms usually appear in late childhood and include dysphagia, postprandial vomiting, retrosternal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor. Affected females in these kindreds typically exhibit genital leiomyomas as well, causing clitoral hypertrophy with variable involvement of the labia majora and uterus. In individuals with these deletions, kidney disease is severe in males and mild in females. However, leiomyomatosis occurs in all individuals, male and female.</p></div></div><div id="alport.Phenotype_Correlations_by_Gene"><h3>Phenotype Correlations by Gene</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportTphenotypecorrelationsbygene"><a href="/books/NBK1207/table/alport.T.phenotype_correlations_by_gene/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobalportTphenotypecorrelationsbygene"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.T.phenotype_correlations_by_gene"><a href="/books/NBK1207/table/alport.T.phenotype_correlations_by_gene/?report=objectonly" target="object" rid-ob="figobalportTphenotypecorrelationsbygene">Table 3. </a></h4><p class="float-caption no_bottom_margin">Phenotype Correlations by Gene </p></div></div></div><div id="alport.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><div id="alport.COL4A5_XLAS"><h4><i>COL4A5</i> (XLAS)</h4><p>
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<b>Risk for ESKD</b>
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</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Males.</b> Large rearrangements and pathogenic nonsense and frameshift variants confer a 50% probability of ESKD before age 20 years [<a class="bibr" href="#alport.REF.yamamura.2020.1605" rid="alport.REF.yamamura.2020.1605">Yamamura et al 2020</a>].</div><div class="half_rhythm">In affected males with splice site variants, the probability of ESKD before age 30 years is around 65%, with 50% of males reaching ESKD by age 25 years [<a class="bibr" href="#alport.REF.yamamura.2020.1605" rid="alport.REF.yamamura.2020.1605">Yamamura et al 2020</a>]. In individuals with splice variants, kidney prognosis differs significantly for those with truncating versus nontruncating variants at the transcript levels; ESKD occurs on average nine years earlier in those with truncating variants [<a class="bibr" href="#alport.REF.horinouchi.2018.2244" rid="alport.REF.horinouchi.2018.2244">Horinouchi et al 2018</a>].</div><div class="half_rhythm">Missense variants are associated with only a 30% probability of ESKD before age 30 years and a 50% probability of ESKD by age 40 years [<a class="bibr" href="#alport.REF.yamamura.2020.1605" rid="alport.REF.yamamura.2020.1605">Yamamura et al 2020</a>].</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Females.</b> Both genotype and unbalanced X-chromosome inactivation pattern might affect the severity of kidney disease [<a class="bibr" href="#alport.REF.suzuki.2024" rid="alport.REF.suzuki.2024">Suzuki et al 2024</a>].</div></li></ul><p>
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<b>Risk for deafness</b>
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</p><ul><li class="half_rhythm"><div>In males with large rearrangements of <i>COL4A5</i> or nonsense, frameshift, or splice site variants, the risk for deafness is 50% at age ten years [<a class="bibr" href="#alport.REF.jais.2000.649" rid="alport.REF.jais.2000.649">Jais et al 2000</a>].</div></li><li class="half_rhythm"><div>In males with missense variants, the risk for deafness does not reach 50% until age 20 years [<a class="bibr" href="#alport.REF.jais.2000.649" rid="alport.REF.jais.2000.649">Jais et al 2000</a>].</div></li></ul><p>
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<b>Risk for anterior lenticonus</b>
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</p><ul><li class="half_rhythm"><div>Anterior lenticonus occurs in approximately 50% of males with XLAS [<a class="bibr" href="#alport.REF.savige.2015.703" rid="alport.REF.savige.2015.703">Savige et al 2015</a>].</div></li><li class="half_rhythm"><div>Anterior lenticonus and central retinopathy typically indicate the onset of kidney failure before age 30 years in males with XLAS. Additionally, these features are more commonly observed in individuals with a <i>COL4A5</i> deletion or a pathogenic variant resulting in a premature stop codon [<a class="bibr" href="#alport.REF.savige.2015.703" rid="alport.REF.savige.2015.703">Savige et al 2015</a>].</div></li><li class="half_rhythm"><div>Note: Lenticonus and central retinopathy also seem to be more common in individuals with ARAS caused by nonsense pathogenic variants [<a class="bibr" href="#alport.REF.savige.2015.703" rid="alport.REF.savige.2015.703">Savige et al 2015</a>].</div></li></ul><p>
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<b>Risk for diffuse leiomyomatosis</b>
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</p><ul><li class="half_rhythm"><div>All families in which XLAS cosegregates with diffuse leiomyomatosis exhibit large deletions that span the adjacent 5' ends of <i>COL4A5</i> and <i>COL4A6</i>. These deletions involve varying lengths of <i>COL4A5</i>, but the <i>COL4A6</i> breakpoint is always located in the second intron of the gene [<a class="bibr" href="#alport.REF.antignac.1996.172" rid="alport.REF.antignac.1996.172">Antignac & Heidet 1996</a>].</div></li><li class="half_rhythm"><div>Leiomyomatosis does not occur in individuals with deletions of <i>COL4A5</i> and <i>COL4A6</i> that extend beyond intron 2 of <i>COL4A6</i>.</div></li><li class="half_rhythm"><div>Pathogenic variants of <i>COL4A6</i> alone do not appear to cause Alport syndrome, a finding consistent with the absence of collagen IV α6 chains from normal glomerular basement membranes.</div></li><li class="half_rhythm"><div>In individuals with these deletions, kidney disease is severe in males and mild in females. However, leiomyomatosis is 100% penetrant, occurring equally in both males and females.</div></li></ul></div></div><div id="alport.Penetrance"><h3>Penetrance</h3><p>The presence of <i>COL4A3</i> or <i>COL4A4</i> pathogenic variants is relatively common in the general population, with an overall prevalence of 0.94% according to gnomAD data, although this varies by ethnicity [<a class="bibr" href="#alport.REF.gibson.2021.2273" rid="alport.REF.gibson.2021.2273">Gibson et al 2021</a>]. The penetrance of ADAS is reduced. The severity of clinical manifestations varies greatly even within the same family; some heterozygotes may be asymptomatic, and some develop ESKD. The absolute risk of ESKD due to a heterozygous <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant is estimated to be significantly lower than 3% [<a class="bibr" href="#alport.REF.torra.2024" rid="alport.REF.torra.2024">Torra et al 2024</a>].</p></div><div id="alport.Nomenclature"><h3>Nomenclature</h3><p>Other terms used to refer to individuals with <i>COL4A3-</i>, <i>COL4A4-</i>, or <i>COL4A5-</i>related kidney manifestations include:</p><ul><li class="half_rhythm"><div>Thin basement membrane nephropathy</div></li><li class="half_rhythm"><div>Type IV collagen-associated kidney disease</div></li><li class="half_rhythm"><div>Alport spectrum nephropathy</div></li></ul><p>The variation in these terms reflects differences in diagnostic methods and criteria.</p><p>There is a strong consensus that the term "benign familial hematuria" should no longer be used to refer to individuals with <i>COL4A3-</i>, <i>COL4A4-</i>, or <i>COL4A5-</i>related hematuria as the risk of ESKD in these individuals is significantly higher than the risk of ESKD in the general population [<a class="bibr" href="#alport.REF.torra.2024" rid="alport.REF.torra.2024">Torra et al 2024</a>].</p></div><div id="alport.Prevalence"><h3>Prevalence</h3><p>The combined phenotype-based prevalence of XLAS and ARAS estimated from historical literature ranges from 1:5,000 to 1:50,000 [<a class="bibr" href="#alport.REF.torra.2024" rid="alport.REF.torra.2024">Torra et al 2024</a>]. Analysis of population-based genome sequencing data in gnomAD revealed that predicted pathogenic <i>COL4A5</i> variants occur in at least one in 2,320 individuals, while heterozygous <i>COL4A3</i> or <i>COL4A4</i> pathogenic variants are found in one in 106 individuals, with variations across ethnic groups [<a class="bibr" href="#alport.REF.gibson.2021.2273" rid="alport.REF.gibson.2021.2273">Gibson et al 2021</a>]. Note: These frequencies are calculated from a database of healthy individuals, and the incidence of Alport syndrome is likely lower, as some individuals heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant are asymptomatic.</p></div></div><div id="alport.Genetically_Related_Allelic_Disor"><h2 id="_alport_Genetically_Related_Allelic_Disor_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>COL4A3</i>, <i>COL4A4</i>, or <i>COL4A5</i>.</p><p><b>Contiguous gene deletions</b> in the Xq22.3 region involving all of <i>COL4A5</i> and extending beyond its 3' end have been reported in individuals with AMME complex (<i>A</i>lport syndrome, intellectual disability [<i>m</i>ental retardation], <i>m</i>idface hypoplasia, and <i>e</i>lliptocytosis) (OMIM <a href="https://omim.org/entry/300194" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">300194</a>).</p></div><div id="alport.Differential_Diagnosis"><h2 id="_alport_Differential_Diagnosis_">Differential Diagnosis</h2><p>Alport syndrome must be distinguished from other genetic disorders associated with persistent (>6 months in duration) hematuria and/or combined nephritis and hearing loss (see <a href="/books/NBK1207/table/alport.T.genetic_disorders_of_interest_i/?report=objectonly" target="object" rid-ob="figobalportTgeneticdisordersofinteresti">Table 4</a>).</p><p>Of note, in a child with no known family history of hematuria, the most likely diagnoses are immunoglobin A nephropathy, Alport syndrome, and <a href="/books/n/gene/mpgn/?report=reader">C3 glomerulopathy</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportTgeneticdisordersofinteresti"><a href="/books/NBK1207/table/alport.T.genetic_disorders_of_interest_i/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobalportTgeneticdisordersofinteresti"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.T.genetic_disorders_of_interest_i"><a href="/books/NBK1207/table/alport.T.genetic_disorders_of_interest_i/?report=objectonly" target="object" rid-ob="figobalportTgeneticdisordersofinteresti">Table 4. </a></h4><p class="float-caption no_bottom_margin">Genetic Disorders of Interest in the Differential Diagnosis of Alport Syndrome </p></div></div></div><div id="alport.Management"><h2 id="_alport_Management_">Management</h2><div id="alport.Evaluations_Following_Initial_Dia"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with Alport syndrome, the evaluations summarized in <a href="/books/NBK1207/table/alport.T.alport_syndrome_recommended_eva/?report=objectonly" target="object" rid-ob="figobalportTalportsyndromerecommendedeva">Table 5</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportTalportsyndromerecommendedeva"><a href="/books/NBK1207/table/alport.T.alport_syndrome_recommended_eva/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobalportTalportsyndromerecommendedeva"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.T.alport_syndrome_recommended_eva"><a href="/books/NBK1207/table/alport.T.alport_syndrome_recommended_eva/?report=objectonly" target="object" rid-ob="figobalportTalportsyndromerecommendedeva">Table 5. </a></h4><p class="float-caption no_bottom_margin">Alport Syndrome: Recommended Evaluations Following Initial Diagnosis </p></div></div></div><div id="alport.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Clinical practice recommendations for the treatment of individuals with Alport syndrome have been published [<a class="bibr" href="#alport.REF.nozu.2019.158" rid="alport.REF.nozu.2019.158">Nozu et al 2019</a>, <a class="bibr" href="#alport.REF.kashtan.2021.711" rid="alport.REF.kashtan.2021.711">Kashtan & Gross 2021</a>]. Early intervention is aimed at suppressing proteinuria using angiotensin antagonists.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportTalportsyndrometreatmentofma"><a href="/books/NBK1207/table/alport.T.alport_syndrome_treatment_of_ma/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobalportTalportsyndrometreatmentofma"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.T.alport_syndrome_treatment_of_ma"><a href="/books/NBK1207/table/alport.T.alport_syndrome_treatment_of_ma/?report=objectonly" target="object" rid-ob="figobalportTalportsyndrometreatmentofma">Table 6. </a></h4><p class="float-caption no_bottom_margin">Alport Syndrome: Treatment of Manifestations </p></div></div><p><b>Note on selection of kidney donors.</b> The following discussion considers potential donors [<a class="bibr" href="#alport.REF.torra.2024" rid="alport.REF.torra.2024">Torra et al 2024</a>].</p><ul><li class="half_rhythm"><div>It is recommended to determine the exact genotype in all potential donors.</div></li><li class="half_rhythm"><div>Heterozygous relatives (males or females with pathogenic variants in <i>COL4A3</i> or <i>COL4A4</i> or females with a <i>COL4A5</i> pathogenic variant) should only be considered as a last-resort option for living kidney donation.</div></li><li class="half_rhythm"><div>Living kidney donation is not advisable for individuals younger than age 40 years with a heterozygous pathogenic variant in <i>COL4A3</i>, <i>COL4A4</i>, or <i>COL4A5</i>, or at any age if there is clinical or histologic evidence of kidney damage.</div></li><li class="half_rhythm"><div>For individuals older than age 40 years with a heterozygous pathogenic variant in <i>COL4A3</i>, <i>COL4A4</i>, or <i>COL4A5</i> who lack albuminuria or reduced estimated glomerular filtration rate, a kidney biopsy is recommended to identify evidence of subclinical kidney damage (e.g., scarring exceeding what is normal for their age) before considering kidney donation. The decision to proceed with donation should be made only after careful consideration of the risks and benefits for the individual and their family.</div></li><li class="half_rhythm"><div>Individuals with a heterozygous pathogenic variant in <i>COL4A3</i>, <i>COL4A4</i>, or <i>COL4A5</i> who have donated a kidney should undergo lifelong monitoring to enable prompt nephroprotective renin-angiotensin system (RAS) blockade therapy if microalbuminuria or hypertension develops, as is recommended for all living kidney donors.</div></li></ul></div><div id="alport.Surveillance"><h3>Surveillance</h3><p>Clinical practice recommendations for health surveillance of individuals with Alport syndrome have been published [<a class="bibr" href="#alport.REF.kashtan.2013.5" rid="alport.REF.kashtan.2013.5">Kashtan et al 2013</a>]. These recommendations encourage early detection of microalbuminuria and proteinuria through regular surveillance.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportTalportsyndromerecommendedsur"><a href="/books/NBK1207/table/alport.T.alport_syndrome_recommended_sur/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobalportTalportsyndromerecommendedsur"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.T.alport_syndrome_recommended_sur"><a href="/books/NBK1207/table/alport.T.alport_syndrome_recommended_sur/?report=objectonly" target="object" rid-ob="figobalportTalportsyndromerecommendedsur">Table 7. </a></h4><p class="float-caption no_bottom_margin">Alport Syndrome: Recommended Surveillance </p></div></div></div><div id="alport.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Dehydration should be avoided.</p><p>Individuals who suffer recurrent corneal erosions may need to take measures (e.g., wearing goggles when riding a bicycle) to protect their corneas from minor trauma.</p><p>Exposure to loud noise should be minimized.</p></div><div id="alport.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p><b>For early diagnosis and treatment.</b> Molecular genetic testing is recommended for at-risk family members of an individual known to have a pathogenic variant (or pathogenic variants) in <i>COL4A3</i>, <i>COL4A4</i>, and/or <i>COL4A5</i> in order to identify as early as possible those who would benefit from <a href="#alport.Surveillance">surveillance</a> for Alport syndrome-related manifestations and early intervention [<a class="bibr" href="#alport.REF.savige.2022.143" rid="alport.REF.savige.2022.143">Savige et al 2022</a>]. Early <a href="#alport.Treatment_of_Manifestations">treatment</a> of kidney disease delays onset of ESKD [<a class="bibr" href="#alport.REF.gross.2012.494" rid="alport.REF.gross.2012.494">Gross et al 2012</a>]. Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if the pathogenic variant(s) in the family are known;</div></li><li class="half_rhythm"><div>If the pathogenic variant(s) in the family are not known, urinalysis for proteinuria and hematuria and blood pressure measurement should be done. In the absence of microalbuminuria, overt proteinuria, hematuria, or elevated blood pressure, relatives at risk should, at a minimum, have annual urinalysis and blood pressure measurement.</div></li></ul><p><b>For kidney donation.</b> See <a href="#alport.Treatment_of_Manifestations">Treatment of Manifestations</a>, <b>Note on selection of kidney donors</b>.</p><p>See <a href="#alport.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="alport.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Women with Alport syndrome are at risk for pregnancy complications including increased proteinuria, kidney insufficiency, worsened hypertension, and preeclampsia. The risks of these complications are higher in women with preexisting kidney insufficiency, proteinuria, or hypertension. Optimal maternal and fetal outcomes may require the involvement of a nephrologist as well as high-risk obstetrics.</p></div><div id="alport.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>A list of Alport syndrome clinical trials can be found at <a href="https://alportsyndrome.org/for-patients/clinical-trials/current-past-clinical-trials/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Alport Syndrome Foundation: Active Clinical Trials at a Glance</a>.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="alport.Genetic_Counseling"><h2 id="_alport_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="alport.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>COL4A5</i>-related Alport syndrome is inherited in an X-linked manner (XLAS)<i>.</i></p><p><i>COL4A3-</i> and <i>COL4A4-</i>related Alport syndrome are inherited in an autosomal dominant (ADAS) or autosomal recessive (ARAS) manner. Note: Use of the term "ARAS carrier" to refer to individuals with a heterozygous <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant is generally avoided because individuals who are heterozygous for a pathogenic variant in <i>COL4A3</i> or <i>COL4A4</i> are at risk for clinical manifestations such as hematuria or microalbuminuria and, in some individuals, end-stage kidney disease (ESKD).</p><p>Digenic Alport syndrome is caused by pathogenic variants in more than one Alport syndrome-related gene: typically pathogenic variants in both <i>COL4A3</i> and <i>COL4A4</i> (in <i>cis</i> or in <i>trans)</i> or, more rarely, a pathogenic variant in <i>COL4A5</i> in addition to a pathogenic variant in <i>COL4A3</i> or <i>COL4A4</i> [<a class="bibr" href="#alport.REF.savige.2022.143" rid="alport.REF.savige.2022.143">Savige et al 2022</a>].</p><p>See <a href="/books/NBK1207/table/alport.T.phenotype_correlations_by_gene/?report=objectonly" target="object" rid-ob="figobalportTphenotypecorrelationsbygene">Table 3</a> for phenotype correlations by gene and mode of inheritance.</p></div><div id="alport.XLAS__Risk_to_Family_Members"><h3>XLAS – Risk to Family Members</h3><p>
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<b>Parents of a male proband</b>
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</p><ul><li class="half_rhythm"><div>The father of a male with XLAS will not have the disorder nor will he be hemizygous for the <i>COL4A5</i> pathogenic variant; therefore, he does not require further evaluation/testing.</div></li><li class="half_rhythm"><div>In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the <i>COL4A5</i> pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism [<a class="bibr" href="#alport.REF.okamoto.2019.155" rid="alport.REF.okamoto.2019.155">Okamoto et al 2019</a>].</div></li><li class="half_rhythm"><div>If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a <i>de novo</i>
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<i>COL4A5</i> pathogenic variant (in which case the mother is not a heterozygote), or the mother may have somatic/gonadal mosaicism. Approximately 10%-15% of male probands have XLAS as the result of a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>The following evaluations are recommended for the mother of a male known to have XLAS in order to confirm her genetic status, allow reliable recurrence risk assessment, and assess her need for kidney <a href="#alport.Surveillance">surveillance</a> and <a href="#alport.Treatment_of_Manifestations">treatment</a>:</div><ul><li class="half_rhythm"><div>Molecular genetic testing for the <i>COL4A5</i> pathogenic variant identified in the proband. Note: Genetic testing is more sensitive than urinalysis in identifying affected family members [<a class="bibr" href="#alport.REF.savige.2022.143" rid="alport.REF.savige.2022.143">Savige et al 2022</a>] and is necessary to exclude the heterozygous state in an at-risk female who does not have hematuria or hypertension.</div></li><li class="half_rhythm"><div>Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a <i>COL4A5</i> pathogenic variant.</div></li></ul></li><li class="half_rhythm"><div>If the mother of an affected male is not found to have proteinuria or hypertension and if molecular genetic testing is not possible, she should have, at a minimum, annual urinalysis and measurement of blood pressure.</div></li></ul><p>
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<b>Parents of a female proband</b>
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</p><ul><li class="half_rhythm"><div>A female proband may have inherited the <i>COL4A5</i> pathogenic variant from either her mother or her father or the pathogenic variant may be <i>de novo.</i></div></li><li class="half_rhythm"><div>Evaluation of the parents of a female proband with XLAS proceeds (for both parents) as described for the mother of a male proband.</div></li></ul><p><b>Sibs of a male proband.</b> The risk to sibs depends on the genetic status of the mother:</p><ul><li class="half_rhythm"><div>If the mother of the proband has a <i>COL4A5</i> pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males and females who inherit the pathogenic variant will be affected.</div><ul><li class="half_rhythm"><div>All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [<a class="bibr" href="#alport.REF.yamamura.2020.1605" rid="alport.REF.yamamura.2020.1605">Yamamura et al 2020</a>].</div></li><li class="half_rhythm"><div>Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [<a class="bibr" href="#alport.REF.yamamura.2017.850" rid="alport.REF.yamamura.2017.850">Yamamura et al 2017</a>]. Both genotype and unbalanced X-chromosome inactivation may affect severity in females [<a class="bibr" href="#alport.REF.suzuki.2024" rid="alport.REF.suzuki.2024">Suzuki et al 2024</a>].</div></li></ul></li><li class="half_rhythm"><div>If the proband represents a simplex case and the <i>COL4A5</i> pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal gonadal mosaicism [<a class="bibr" href="#alport.REF.beicht.2013.474" rid="alport.REF.beicht.2013.474">Beicht et al 2013</a>, <a class="bibr" href="#alport.REF.okamoto.2019.155" rid="alport.REF.okamoto.2019.155">Okamoto et al 2019</a>].</div></li></ul><p><b>Sibs of a female proband.</b> The risk to the sibs of a female proband depends on the genetic status of the parents:</p><ul><li class="half_rhythm"><div>If the mother of the proband has a <i>COL4A5</i> pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males and females who inherit the pathogenic variant will be affected (see <b>Sibs of a male proband</b>).</div></li><li class="half_rhythm"><div>If the father of the proband has a <i>COL4A5</i> pathogenic variant, he will transmit it to all of his daughters and none of his sons.</div></li><li class="half_rhythm"><div>If the proband represents a simplex case and the <i>COL4A5</i> pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [<a class="bibr" href="#alport.REF.beicht.2013.474" rid="alport.REF.beicht.2013.474">Beicht et al 2013</a>, <a class="bibr" href="#alport.REF.okamoto.2019.155" rid="alport.REF.okamoto.2019.155">Okamoto et al 2019</a>].</div></li></ul><p>
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<b>Offspring of a proband</b>
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</p><ul><li class="half_rhythm"><div>Affected males transmit the <i>COL4A5</i> pathogenic variant to all of their daughters and none of their sons.</div></li><li class="half_rhythm"><div>Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child.</div></li></ul><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.</p><p><b>Heterozygote detection.</b> Molecular genetic testing for at-risk females requires prior identification of the <i>COL4A5</i> pathogenic variant in the family. Genetic testing is more sensitive than urinalysis in identifying affected family members [<a class="bibr" href="#alport.REF.savige.2022.143" rid="alport.REF.savige.2022.143">Savige et al 2022</a>] and is necessary to exclude the heterozygous state in an at-risk female who does not have hematuria or hypertension.</p></div><div id="alport.ARAS__Risk_to_Family_Members"><h3>ARAS – Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>The parents of a child with biallelic <i>COL4A3</i> or <i>COL4A4</i> pathogenic variants (ARAS) are presumed to be heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant. A heterozygous parent may have clinical manifestations of Alport syndrome (and be diagnosed with autosomal dominant Alport syndrome) or may be asymptomatic.</div></li><li class="half_rhythm"><div>Molecular genetic testing for the pathogenic variants identified in the proband is recommended for the parents of a proband to confirm that both parents are heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant, allow reliable recurrence risk assessment, and determine their need for kidney <a href="#alport.Surveillance">surveillance</a> and <a href="#alport.Treatment_of_Manifestations">treatment</a>.</div></li><li class="half_rhythm"><div>If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a <i>de novo</i> event in the proband or as a postzygotic <i>de novo</i> event in a mosaic parent [<a class="bibr" href="#alport.REF.j_nsson.2017.519" rid="alport.REF.j_nsson.2017.519">Jónsson et al 2017</a>]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:</div><ul><li class="half_rhythm"><div>A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;</div></li><li class="half_rhythm"><div>Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.</div></li></ul></li><li class="half_rhythm"><div>While risk of kidney manifestations in individuals who are heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant is higher than that of the general population, the absolute risk of ESKD due to heterozygosity for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant is estimated to be significantly lower than 3% [<a class="bibr" href="#alport.REF.torra.2024" rid="alport.REF.torra.2024">Torra et al 2024</a>]</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>If both parents are known to be heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and having ARAS, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.</div></li><li class="half_rhythm"><div>Some individuals who are heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant may be asymptomatic, and some may develop ESKD. The severity of clinical manifestations can vary greatly even within the same family. While the risk of kidney manifestations in sibs who are heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant is higher than that of the general population, the absolute risk of ESKD due to heterozygosity for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant is estimated to be significantly lower than 3% [<a class="bibr" href="#alport.REF.torra.2024" rid="alport.REF.torra.2024">Torra et al 2024</a>]</div></li></ul><p><b>Offspring of a proband.</b> The offspring of an individual with ARAS are obligate heterozygotes for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant and may or may not have clinical manifestations of Alport syndrome.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant.</p><p><b>Heterozygote detection.</b> Heterozygote testing for at-risk relatives requires prior identification of the <i>COL4A3</i> or <i>COL4A4</i> pathogenic variants in the family.</p></div><div id="alport.ADAS__Risk_to_Family_Members"><h3>ADAS – Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with ADAS have the disorder as the result of a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant inherited from a parent.</div></li><li class="half_rhythm"><div>Some individuals diagnosed with ADAS have the disorder as the result of a <i>de novo COL4A3</i> or <i>COL4A4</i> pathogenic variant. The proportion of individuals with ADAS caused by a <i>de novo</i> pathogenic variant is unknown.</div></li><li class="half_rhythm"><div>If the proband appears to be the only affected family member, molecular genetic testing for the <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for kidney <a href="#alport.Surveillance">surveillance</a> and <a href="#alport.Treatment_of_Manifestations">treatment</a>. If a molecular diagnosis has not been established in the proband, urinalysis is recommended for the evaluation of the parents of a proband. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, <i>de novo</i> occurrence of a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant.</div></li><li class="half_rhythm"><div>If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The proband has a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.</div></li></ul></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of a proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the proband is affected and/or is known to have the <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. The severity of clinical manifestations may vary greatly among heterozygous family members; some heterozygotes may be asymptomatic and some may develop ESKD (see <a href="#alport.Penetrance">Penetrance</a>).</div></li><li class="half_rhythm"><div>If the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [<a class="bibr" href="#alport.REF.rahbari.2016.126" rid="alport.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents are clinically asymptomatic (e.g., urinalysis is normal in both parents) but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Offspring of an individual with ADAS are at a 50% risk of inheriting the ADAS-related pathogenic variant.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent is affected or has a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant, the parent's family members are at risk.</p></div><div id="alport.Digenic_Inheritance__Risk_to_Fami"><h3>Digenic Inheritance – Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>If a proband has digenic Alport syndrome caused by <i>COL4A3</i> and <i>COL4A4</i> pathogenic variants in <i>cis</i>, both pathogenic variants are presumed to have been inherited from one parent who is also affected with digenic Alport syndrome.</div></li><li class="half_rhythm"><div>If a proband has digenic Alport syndrome caused by <i>COL4A3</i> and <i>COL4A4</i> pathogenic variants in <i>trans</i> or a pathogenic variant in <i>COL4A5</i> in addition to a pathogenic variant in <i>COL4A3</i> or <i>COL4A4</i>, both parents may have an Alport syndrome-related pathogenic variant.</div></li><li class="half_rhythm"><div>Molecular genetic testing for the pathogenic variants identified in the proband is recommended for both parents of the proband to confirm their genetic status, allow reliable recurrence risk assessment, and determine their need for kidney <a href="#alport.Surveillance">surveillance</a> and <a href="#alport.Treatment_of_Manifestations">treatment</a>.</div></li></ul><p><b>Sibs of a proband.</b> The risk to sibs depends on the genetic status of the parents:</p><ul><li class="half_rhythm"><div>If one parent is heterozygous for a <i>COL4A3</i> pathogenic variant and the other parent is heterozygous for a <i>COL4A4</i> pathogenic variant, sibs have a:</div><ul><li class="half_rhythm"><div>25% chance of inheriting two pathogenic variants;</div></li><li class="half_rhythm"><div>50% chance of inheriting one pathogenic variant;</div></li><li class="half_rhythm"><div>25% chance of inheriting neither of the familial pathogenic variants.</div></li></ul></li><li class="half_rhythm"><div>If one parent is heterozygous for a <i>COL4A3</i> and a <i>COL4A4</i> pathogenic variant in <i>cis</i> and the other parent does not have an Alport syndrome-related pathogenic variant, sibs have a:</div><ul><li class="half_rhythm"><div>50% chance of inheriting two pathogenic variants in <i>cis</i>;</div></li><li class="half_rhythm"><div>50% chance of inheriting neither of the familial pathogenic variants.</div></li></ul></li><li class="half_rhythm"><div>If the mother of the proband has a <i>COL4A5</i> pathogenic variant and the father of the proband has a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant, sibs have a:</div><ul><li class="half_rhythm"><div>25% chance of inheriting both the maternal <i>COL4A5</i> pathogenic variant and the paternal <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant;</div></li><li class="half_rhythm"><div>25% chance of inheriting only the maternal <i>COL4A5</i> pathogenic variant;</div></li><li class="half_rhythm"><div>25% chance of inheriting only the paternal <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant;</div></li><li class="half_rhythm"><div>25% chance of inheriting neither of the familial pathogenic variants.</div></li></ul></li><li class="half_rhythm"><div>If the father of the proband has a <i>COL4A5</i> pathogenic variant and the mother of the proband has a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant:</div><ul><li class="half_rhythm"><div>Male sibs have a 50% risk of inheriting the <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant from their mother and a 50% likelihood of inheriting neither of the familial pathogenic variants. (Male sibs are not at risk of inheriting the paternal <i>COL4A5</i> pathogenic variant.)</div></li><li class="half_rhythm"><div>All female sibs will inherit the paternal <i>COL4A5</i> pathogenic variant: 50% of female sibs will inherit both the paternal <i>COL4A5</i> pathogenic variant and the maternal <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant and 50% will inherit only the paternal <i>COL4A5</i> pathogenic variant.</div></li></ul></li><li class="half_rhythm"><div>Sibs who inherit pathogenic variants in both <i>COL4A3</i> and <i>COL4A4</i> (in <i>cis</i> or in <i>trans</i>) or a pathogenic variant in <i>COL4A5</i> in addition to a pathogenic variant in <i>COL4A3</i> or <i>COL4A4</i> will be affected with digenic Alport syndrome (see <a href="/books/NBK1207/table/alport.T.phenotype_correlations_by_gene/?report=objectonly" target="object" rid-ob="figobalportTphenotypecorrelationsbygene">Table 3</a> for phenotype correlations by gene and mode of inheritance).</div></li><li class="half_rhythm"><div>Sibs who inherit a single Alport syndrome-related pathogenic variant are at risk for ADAS (if they are heterozygous for a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant) or XLAS (if they are a female heterozygous for a <i>COL4A5</i> pathogenic variant or a male hemizygous for a <i>COL4A5</i> pathogenic variant).</div></li></ul><p><b>Offspring of a proband.</b> If the reproductive partner of the proband does not have an Alport syndrome-related pathogenic variant:</p><ul><li class="half_rhythm"><div>All offspring of a proband with <i>COL4A3</i> and <i>COL4A4</i> pathogenic variants in <i>trans</i> will inherit either a <i>COL4A3</i> pathogenic variant or a <i>COL4A4</i> pathogenic variant (i.e., all offspring will be heterozygous for a pathogenic variant in <i>COL4A3</i> or <i>COL4A4</i>) and will be at risk for ADAS.</div></li><li class="half_rhythm"><div>Offspring of a proband with <i>COL4A3</i> and <i>COL4A4</i> pathogenic variants in <i>cis</i> have a 50% risk of inheriting both pathogenic variants and having digenic Alport syndrome.</div></li><li class="half_rhythm"><div>If a female proband has a <i>COL4A5</i> pathogenic variant and a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant, offspring have a 25% risk of inheriting two pathogenic variants (and having digenic Alport syndrome) and a 50% risk of inheriting one pathogenic variant (and being at risk for ADAS).</div></li><li class="half_rhythm"><div>If a male proband has a <i>COL4A5</i> pathogenic variant and a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant, female offspring have a 50% risk of inheriting both the <i>COL4A5</i> pathogenic variant and the <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant (and having digenic Alport syndrome) and a 50% risk of inheriting only the <i>COL4A5</i> pathogenic variant (and having XLAS); male offspring have a 50% risk of inheriting a <i>COL4A3</i> or <i>COL4A4</i> pathogenic variant (and being at risk for ADAS).</div></li></ul><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has an Alport syndrome-related pathogenic variant (or pathogenic variants), the parent's family members are at risk.</p></div><div id="alport.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#alport.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p><b>Screening of potential living related kidney donors.</b> See <a href="#alport.Treatment_of_Manifestations">Treatment of Manifestations</a>, <b>Note on selection of kidney donors</b>.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul></div><div id="alport.Prenatal_Testing_and_Preimplantat"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the Alport syndrome-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and in families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="alport.Resources"><h2 id="_alport_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>Alport Syndrome Foundation</b>
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</div><div><b>Phone:</b> 480-800-3510</div><div><b>Email:</b> info@alportsyndrome.org</div><div>
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<a href="https://alportsyndrome.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">alportsyndrome.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="https://medlineplus.gov/genetics/condition/alport-syndrome/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Alport syndrome</a>
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</div></li><li class="half_rhythm"><div>
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<b>NCBI Genes and Disease</b>
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</div><div>
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<a href="/books/NBK22265/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Alport syndrome</a>
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</div></li><li class="half_rhythm"><div>
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<b>Kidney Foundation of Canada</b>
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</div><div>Canada</div><div><b>Phone:</b> 514-369-4806</div><div><b>Email:</b> info@kidney.ca</div><div>
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<a href="https://kidney.ca/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">kidney.ca</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Association of the Deaf</b>
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</div><div><b>Phone:</b> 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)</div><div><b>Fax:</b> 301-587-1791</div><div><b>Email:</b> nad.info@nad.org</div><div>
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<a href="https://www.nad.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">nad.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Kidney Foundation</b>
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</div><div><b>Phone:</b> 855-NKF-CARES; 855-653-2273</div><div><b>Email:</b> nkfcares@kidney.org</div><div>
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<a href="http://www.kidney.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">kidney.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>Alport Syndrome Treatments and Outcomes Registry (ASTOR)</b>
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</div><div>University of Minnesota, Department of Pediatrics</div><div><b>Email:</b> alport@umn.edu</div><div>
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<a href="https://astor.umn.edu/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">astor.umn.edu</a>
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</div></li></ul>
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</div><div id="alport.Molecular_Genetics"><h2 id="_alport_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportmolgenTA"><a href="/books/NBK1207/table/alport.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobalportmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.molgen.TA"><a href="/books/NBK1207/table/alport.molgen.TA/?report=objectonly" target="object" rid-ob="figobalportmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Alport Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportmolgenTB"><a href="/books/NBK1207/table/alport.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobalportmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.molgen.TB"><a href="/books/NBK1207/table/alport.molgen.TB/?report=objectonly" target="object" rid-ob="figobalportmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Alport Syndrome (View All in OMIM) </p></div></div><div id="alport.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><b>Basement membranes.</b> Basement membranes, the sheet-like structures that support epithelial and endothelial cells, are composed of several major and minor glycoproteins. Collagen IV is present ubiquitously in basement membranes, where it is the major collagenous component. Collagen IV molecules secreted by endothelial and epithelial cells self-associate into polygonal networks, which interact with laminin networks as well as with nidogens, proteoglycans, and other glycoproteins to form basement membranes.</p><p><b>Collagen IV.</b> Collagen IV alpha (α) chains share basic structural features and show extensive sequence homology. The major structural features of collagen IV α chains are the following:</p><ul><li class="half_rhythm"><div>A (Gly)-X-Y collagenous domain of approximately 1,400 residues</div></li><li class="half_rhythm"><div>A carboxy-terminal non-collagenous (NC1) domain of approximately 230 residues and 12 conserved cysteine residues, which participate in intrachain and interchain disulfide bonds</div></li><li class="half_rhythm"><div>A non-collagenous amino-terminal sequence of 15-20 residues</div></li></ul><p>Approximately 20 interruptions of the collagenous triplet sequence are present in the collagenous domain.</p><p>Collagen IV chains form helical heterotrimers through associations between their COO<sup>-</sup> NC1 domains. The heterotrimers form networks through intermolecular interaction such as:</p><ul><li class="half_rhythm"><div>End-to-end linkages between the COO<sup>-</sup> NC1 domains of two heterotrimers;</div></li><li class="half_rhythm"><div>Covalent interactions between four heterotrimers at their NH<sup>-</sup> ends; and</div></li><li class="half_rhythm"><div>Lateral associations between heterotrimers via binding of the COO<sup>-</sup> domains to sites along the collagenous region of another heterotrimer.</div></li></ul><p>Linkages between collagen IV molecules form a scaffolding for the deposition of other matrix glycoproteins and for cell attachment.</p><p>In the normal developing kidney:</p><ul><li class="half_rhythm"><div>Collagen IV α1 and α2 chains predominate in the primordial glomerular basement membrane of immature glomeruli;</div></li><li class="half_rhythm"><div>The formation of capillary loops within the maturing glomeruli is associated with the appearance of collagen IV α3, α4, and α5 chains in the glomerular basement membrane.</div></li><li class="half_rhythm"><div>As glomerular maturation progresses, the collagen IV α3, α4, and α5 chains become the predominant collagen IV chains in the glomerular basement membrane.</div></li></ul><p><b>Mechanism of disease causation.</b> Absence or underexpression of the collagen IV α3, α4, α5, and possibly α6 chains in the basement membrane such that the networks that they form are absent – or, if present, are defective – cause the clinical features of Alport syndrome.</p><p>A pathogenic variant affecting one of the chains involved in the collagen IV α3/α4/α5 network can prevent basement membrane expression not only of that chain but of the other two chains as well. Similarly, a pathogenic variant involving the collagen IV α5 chain can interfere with basement membrane expression of the collagen IV α6 chain.</p><p>Most missense collagen IV variants occur in glycine-encoding codons. The presence of a bulkier amino acid in a glycine position presumably creates a kink or an unfolding in the triple helix, as is observed in the collagen I α1 chain (see <a href="/books/n/gene/oi/?report=reader"><i>COL1A1/2</i>-Related Osteogenesis Imperfecta</a> and other genetic disorders of collagen). Abnormally folded collagen triple helices exhibit increased susceptibility to proteolytic degradation. The position of the substituted glycine, or the substituting amino acid itself, may influence protein folding and ultimately the severity of the clinical phenotype.</p><p><b><i>COL4A3-</i> and <i>COL4A4</i>-specific laboratory technical considerations.</b> Variants in <i>COL4A3</i> and <i>COL4A4</i> can be associated with either autosomal recessive or autosomal dominant disease. There is no specific association between the type of variant (e.g., missense, nonsense, splice site) and inheritance pattern.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figalportTpathogenicvariantsreferenced"><a href="/books/NBK1207/table/alport.T.pathogenic_variants_referenced/?report=objectonly" target="object" title="Table 8. " class="img_link icnblk_img" rid-ob="figobalportTpathogenicvariantsreferenced"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="alport.T.pathogenic_variants_referenced"><a href="/books/NBK1207/table/alport.T.pathogenic_variants_referenced/?report=objectonly" target="object" rid-ob="figobalportTpathogenicvariantsreferenced">Table 8. </a></h4><p class="float-caption no_bottom_margin">Pathogenic Variants Referenced in This <i>GeneReview</i> by Gene </p></div></div></div></div><div id="alport.Chapter_Notes"><h2 id="_alport_Chapter_Notes_">Chapter Notes</h2><div id="alport.Author_Notes"><h3>Author Notes</h3><p>Prof Kandai Nozu, MD, PhD<br />Department of Pediatrics, Kobe University Graduate School of Medicine<br />Email: <a href="mailto:dev@null" data-email="pj.ca.u-ebok.dem@uzon" class="oemail">pj.ca.u-ebok.dem@uzon</a><br />Web page: <a href="https://kuid-rm-web.ofc.kobe-u.ac.jp/search/detail.html?systemId=cfe7f9e40ab7db60520e17560c007669&lang=en" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">kuid-rm-web.ofc.kobe-u.ac.jp</a></p></div><div id="alport.Author_History"><h3>Author History</h3><p>Tomoko Horinouchi, MD, PhD (2025-present)<br />Clifford E Kashtan, MD; University of Minnesota (2001-2025)<br />Kandai Nozu, MD, PhD (2025-present)<br />Tomohiko Yamamura, MD, PhD (2025-present)</p></div><div id="alport.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>27 February 2025 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 February 2019 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>25 November 2015 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 February 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>15 July 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>23 January 2008 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>26 September 2005 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 August 2003 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 August 2001 (me) Review posted live</div></li><li class="half_rhythm"><div>March 2001 (ck) Original submission</div></li></ul></div></div><div id="alport.References"><h2 id="_alport_References_">References</h2><div id="alport.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="alport.REF.antignac.1996.172">Antignac
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Y, Ishiko
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S, Nakanishi
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K, Shima
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Y, Nagase
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H, Takeda
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H, Rossanti
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R, Ye
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MJ, Nozu
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Y, Ishimori
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S, Ninchoji
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T, Kaito
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H, Morisada
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N, Iijima
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K, Nozu
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K. Genotype-phenotype correlations influence the response to angiotensin-targeting drugs in Japanese patients with male X-linked Alport syndrome.
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Kidney Int.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/32712167" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32712167</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alport.REF.yamamura.2017.850">Yamamura
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T, Nozu
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K, Fu
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XJ, Nozu
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Y, Ye
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MJ, Shono
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A, Yamanouchi
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S, Minamikawa
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S, Morisada
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N, Nakanishi
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K, Shima
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Y, Yoshikawa
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N, Ninchoji
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T, Morioka
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I, Kaito
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H, Iijima
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K. Natural history and genotype-phenotype correlation in female X-Linked Alport syndrome.
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2017;2:850-5.
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[<a href="/pmc/articles/PMC5733817/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5733817</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29270492" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29270492</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alport.REF.yamamura.2019.e883">Yamamura
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T, Nozu
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K, Minamikawa
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S, Horinouchi
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T, Sakakibara
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N, Nagano
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C, Aoto
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Y, Ishiko
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S, Nakanishi
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K, Shima
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Y, Nagase
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H, Rossanti
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R, Ye
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MJ, Nozu
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Y, Ishimori
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S, Morisada
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N, Kaito
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H, Iijima
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K. Comparison between conventional and comprehensive sequencing approaches for genetic diagnosis of Alport syndrome.
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Mol Genet Genomic Med.
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2019;7:e883.
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[<a href="/pmc/articles/PMC6732293/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6732293</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31364286" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31364286</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alport.REF.zhang.2018.229">Zhang
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X, Zhang
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Y, Zhang
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Y, Gu
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H, Chen
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Z, Ren
|
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L, Lu
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X, Chen
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L, Wang
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F, Liu
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Y, Ding
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J.
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X-linked Alport syndrome: pathogenic variant features and further auditory genotype-phenotype correlations in males.
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Orphanet J Rare Dis.
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2018;13:229.
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[<a href="/pmc/articles/PMC6303895/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6303895</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30577881" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30577881</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alport.REF.zhang.2021.2719">Zhang
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Y, Böckhaus
|
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J, Wang
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F, Wang
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S, Rubel
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D, Gross
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O, Ding
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J. Genotype-phenotype correlations and nephroprotective effects of RAAS inhibition in patients with autosomal recessive Alport syndrome.
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Pediatr Nephrol.
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2021;36:2719-30.
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[<a href="/pmc/articles/PMC8370956/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8370956</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33772369" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33772369</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alport.REF.zhou.1993.1167">Zhou
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J, Mochizuki
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T, Smeets
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H, Antignac
|
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C, Laurila
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P, de Paepe
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A, Tryggvason
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K, Reeders
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ST. Deletion of the paired alpha 5(IV) and alpha 6(IV) collagen genes in inherited smooth muscle tumors.
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Science.
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1993;261:1167–9.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/8356449" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8356449</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="alport.REF.zlotogora.2018.867">Zlotogora
|
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J, Patrinos
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GP, Meiner
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V. Ashkenazi Jewish genomic variants: integrating data from the Israeli National Genetic Database and gnomAD.
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Genet Med.
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2018;20:867-71.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/29144512" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29144512</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1207_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Kandai Nozu</span>, MD, PhD<div class="affiliation small">Kobe University<br />Kobe, Japan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.liamg@uzoniadnak" class="oemail">moc.liamg@uzoniadnak</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Tomohiko Yamamura</span>, MD, PhD<div class="affiliation small">Kobe University<br />Kobe, Japan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="pj.ca.u-ebok.dem@okihomot" class="oemail">pj.ca.u-ebok.dem@okihomot</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Tomoko Horinouchi</span>, MD, PhD<div class="affiliation small">Kobe University<br />Kobe, Japan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="pj.ca.u-ebok.dem@irohot" class="oemail">pj.ca.u-ebok.dem@irohot</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">August 28, 2001</span>; Last Update: <span itemprop="dateModified">February 27, 2025</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Nozu K, Yamamura T, Horinouchi T. Alport Syndrome. 2001 Aug 28 [Updated 2025 Feb 27]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/a-thal/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/alstrom/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobalportTmoleculargenetictestingused"><div id="alport.T.molecular_genetic_testing_used" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Alport Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.T.molecular_genetic_testing_used/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.T.molecular_genetic_testing_used_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup></th><th id="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_2" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of AS<br />Attributed to Pathogenic Variants in Gene <sup>3</sup></th><th id="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>4</sup> Identified by Method</th></tr><tr><th headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_2" id="hd_h_alport.T.molecular_genetic_testing_used_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Total</th><th headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_2" id="hd_h_alport.T.molecular_genetic_testing_used_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Per MOI</th><th headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_3" id="hd_h_alport.T.molecular_genetic_testing_used_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>5, 6</sup></th><th headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_3" id="hd_h_alport.T.molecular_genetic_testing_used_1_1_2_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>6, 7</sup></th></tr></thead><tbody><tr><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL4A3</i>
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</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_2 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%-15%</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_2 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR: ~45%<br />AD: ~55%</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_3 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~98%</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_3 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~2%</td></tr><tr><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL4A4</i>
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</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_2 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5%-8%</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_2 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR: ~45%<br />AD: 55%</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_3 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~98%</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_3 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~2%</td></tr><tr><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL4A5</i>
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</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_2 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">80%-85%</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_2 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL: 100%</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_3 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">85%-90%</td><td headers="hd_h_alport.T.molecular_genetic_testing_used_1_1_1_3 hd_h_alport.T.molecular_genetic_testing_used_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10%-15%</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AS = Alport syndrome; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alport.TF.1.1"><p class="no_margin">Genes are listed in alphabetic order.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="alport.TF.1.2"><p class="no_margin">See <a href="/books/NBK1207/?report=reader#alport.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="alport.TF.1.3"><p class="no_margin"><a class="bibr" href="#alport.REF.fallerini.2014.252" rid="alport.REF.fallerini.2014.252">Fallerini et al [2014]</a>, <a class="bibr" href="#alport.REF.morini_re.2014.2740" rid="alport.REF.morini_re.2014.2740">Morinière et al [2014]</a>, <a class="bibr" href="#alport.REF.bullich.2018.363" rid="alport.REF.bullich.2018.363">Bullich et al [2018]</a>, <a class="bibr" href="#alport.REF.yamamura.2019.e883" rid="alport.REF.yamamura.2019.e883">Yamamura et al [2019]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="alport.TF.1.4"><p class="no_margin">See <a href="#alport.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="alport.TF.1.5"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="alport.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="alport.TF.1.7"><p class="no_margin"><a class="bibr" href="#alport.REF.yamamura.2019.e883" rid="alport.REF.yamamura.2019.e883">Yamamura et al [2019]</a> and data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#alport.REF.stenson.2020.1197" rid="alport.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalportTalportsyndromefrequencyofse"><div id="alport.T.alport_syndrome_frequency_of_se" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Alport Syndrome: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.T.alport_syndrome_frequency_of_se/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.T.alport_syndrome_frequency_of_se_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_1" rowspan="3" scope="rowgroup" colspan="1" headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2" colspan="4" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">% of Persons w/Feature</th></tr><tr><th headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2" id="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">XLAS</th><th headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_2" id="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_2" rowspan="2" scope="col" colspan="1" style="text-align:left;vertical-align:middle;">ARAS</th><th headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_3" id="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_3" rowspan="2" scope="col" colspan="1" style="text-align:left;vertical-align:middle;">ADAS</th></tr><tr><th headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1" id="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Males</th><th headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1" id="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Females</th></tr></thead><tbody><tr><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hematuria</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>90%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>50% <sup>1</sup></td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Proteinuria</b>
|
|
</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>ESKD <sup>2</sup></b>
|
|
</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~80%<br />(by age 40 yrs)</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~20%<br />(by age 60 yrs)</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~80%<br />(by age 30 yrs)</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>SNHL</b>
|
|
</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~50%-60% <sup>3</sup></td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~50%-60% <sup>4</sup></td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Anterior lenticonus <sup>5</sup></b>
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|
</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">50%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><5%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">75%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Central or perimacular fleck retinopathy <sup>5</sup></b>
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|
</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_1 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_3_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">20%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">75%</td><td headers="hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_1_2 hd_h_alport.T.alport_syndrome_frequency_of_se_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ADAS = autosomal dominant Alport syndrome: ARAS = autosomal recessive Alport syndrome; ESKD = end-stage kidney disease; ND = no data; SNHL = sensorineural hearing loss; XLAS = X-linked Alport syndrome</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alport.TF.2.1"><p class="no_margin">In those with autosomal dominant <i>COL4A3-</i> or <i>COL4A4-</i>related Alport syndrome</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="alport.TF.2.2"><p class="no_margin"><a class="bibr" href="#alport.REF.oka.2014.1535" rid="alport.REF.oka.2014.1535">Oka et al [2014]</a>, <a class="bibr" href="#alport.REF.kamiyoshi.2016.1441" rid="alport.REF.kamiyoshi.2016.1441">Kamiyoshi et al [2016]</a>, <a class="bibr" href="#alport.REF.yamamura.2017.850" rid="alport.REF.yamamura.2017.850">Yamamura et al [2017]</a>, <a class="bibr" href="#alport.REF.yamamura.2020.1605" rid="alport.REF.yamamura.2020.1605">Yamamura et al [2020]</a>, <a class="bibr" href="#alport.REF.torra.2024" rid="alport.REF.torra.2024">Torra et al [2024]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="alport.TF.2.3"><p class="no_margin">
|
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<a class="bibr" href="#alport.REF.zhang.2018.229" rid="alport.REF.zhang.2018.229">Zhang et al [2018]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="alport.TF.2.4"><p class="no_margin">
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<a class="bibr" href="#alport.REF.zhang.2021.2719" rid="alport.REF.zhang.2021.2719">Zhang et al [2021]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="alport.TF.2.5"><p class="no_margin">
|
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<a class="bibr" href="#alport.REF.savige.2015.703" rid="alport.REF.savige.2015.703">Savige et al [2015]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalportTphenotypecorrelationsbygene"><div id="alport.T.phenotype_correlations_by_gene" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Phenotype Correlations by Gene</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.T.phenotype_correlations_by_gene/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.T.phenotype_correlations_by_gene_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Kidney Disease</th><th id="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">SNHL</th><th id="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ocular</th></tr></thead><tbody><tr><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>COL4A5</i>
|
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</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe in males, milder in females</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressive in males</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common in males (e.g., lenticonus)</td></tr><tr><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>COL4A3</i>
|
|
<br />
|
|
<i>COL4A4</i>
|
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</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe, early ESKD</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Similar to males w/XLAS</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Similar to males w/XLAS</td></tr><tr><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable, late ESKD</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare, later in life</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare</td></tr><tr><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>COL4A3</i>
|
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<br />
|
|
<i>COL4A4</i>
|
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<br />
|
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<i>COL4A5</i>
|
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</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Digenic inheritance</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intermediate severity</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable</td><td headers="hd_h_alport.T.phenotype_correlations_by_gene_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Variable</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; ESKD = end-stage kidney disease; SNHL = sensorineural hearing loss; XL = X-linked</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalportTgeneticdisordersofinteresti"><div id="alport.T.genetic_disorders_of_interest_i" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Genetic Disorders of Interest in the Differential Diagnosis of Alport Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.T.genetic_disorders_of_interest_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.T.genetic_disorders_of_interest_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Features of Disorder</th></tr><tr><th headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4" id="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/Alport syndrome</th><th headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4" id="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from Alport syndrome</th></tr></thead><tbody><tr><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>C3</i>
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<br />
|
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<i>CD46</i>
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<br />
|
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<i>CFB</i>
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<br />
|
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<i>CFH</i>
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<br />
|
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<i>CFHR1</i>
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<br />
|
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<i>CFHR5</i>
|
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<br />
|
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<i>CFI</i>
|
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<a href="/books/n/gene/mpgn/?report=reader">C3 glomerulopathy</a>
|
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rarely inherited in a simple mendelian fashion <sup>1</sup></td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hematuria</div></li><li class="half_rhythm"><div>Proteinuria</div></li></ul>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypocomplementemia</td></tr><tr><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>EYA1</i>
|
|
<br />
|
|
<i>SIX1</i>
|
|
<br />
|
|
<i>SIX5</i>
|
|
</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Branchiootorenal (BOR) syndrome (See <a href="/books/n/gene/bor/?report=reader">Branchiootorenal Spectrum Disorder</a>.)</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Hearing loss</div></li><li class="half_rhythm"><div>Kidney failure</div></li><li class="half_rhythm"><div>FSGS</div></li><li class="half_rhythm"><div>Cataracts</div></li></ul>
|
|
</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>External ear anomalies such as eustachian fistulas & accessory ear</div></li><li class="half_rhythm"><div>Branchial fistulae</div></li></ul>
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</td></tr><tr><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>LAMA5</i>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">FSGS (OMIM <a href="https://omim.org/entry/620049" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">620049</a>)</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD <sup>2</sup></td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Lamellated GBM FSGS</div></li><li class="half_rhythm"><div>Kidney failure</div></li></ul>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Pulmonary defects</div></li><li class="half_rhythm"><div>Skin abnormalities</div></li><li class="half_rhythm"><div>Neurodevelopmental delay</div></li></ul>
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</td></tr><tr><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>LAMB2</i>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pierson syndrome / FSGS w/o ocular abnormalities (OMIM <a href="https://omim.org/entry/614199" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614199</a>, <a href="https://omim.org/entry/609049" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">609049</a>)</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Lamellated GBM FSGS</div></li><li class="half_rhythm"><div>Kidney failure</div></li><li class="half_rhythm"><div>Ocular changes</div></li></ul>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital nephrotic syndrome</div></li><li class="half_rhythm"><div>Neurodevelopmental delay</div></li><li class="half_rhythm"><div>Microcoria (Pierson syndrome)</div></li></ul>
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</td></tr><tr><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
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<i>LMX1B</i>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_2" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/nail-ps/?report=reader">Nail-patella syndrome</a>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_3" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_1" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Lamellated GBM FSGS</div></li><li class="half_rhythm"><div>Kidney failure</div></li></ul>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_2" rowspan="1" colspan="1" style="background-color:rgb(255,255,255);text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Nail dysplasia</div></li><li class="half_rhythm"><div>Patellar hypoplasia</div></li></ul>
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</td></tr><tr><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MYH9</i>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/myh9/?report=reader"><i>MYH9</i>-related disease</a> <sup>3</sup></td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Combined nephritis & hearing loss</div></li><li class="half_rhythm"><div>Some persons exhibit ultrastructural changes of glomerular capillary wall reminiscent of those seen in persons w/Alport syndrome.</div></li></ul>
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</td><td headers="hd_h_alport.T.genetic_disorders_of_interest_i_1_1_1_4 hd_h_alport.T.genetic_disorders_of_interest_i_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Macrothrombocytopenia</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; AR = autosomal recessive; GBM = glomerular basement membrane; FSGS = focal segmental glomerular sclerosis; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alport.TF.4.1"><p class="no_margin">C3 glomerulopathy (C3G) is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. In most persons with C3G, inheritance is complex and incompletely understood.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="alport.TF.4.2"><p class="no_margin"><a class="bibr" href="#alport.REF.kaimori.2022.e158378" rid="alport.REF.kaimori.2022.e158378">Kaimori et al [2022]</a>; K Nozu, unpublished data</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="alport.TF.4.3"><p class="no_margin">In the past, the phenotypes included in <i>MYH9</i>-related disease were known as Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, Sebastian syndrome (Sebastian platelet syndrome), and autosomal dominant deafness 17 (DFNA17).</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalportTalportsyndromerecommendedeva"><div id="alport.T.alport_syndrome_recommended_eva" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Alport Syndrome: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.T.alport_syndrome_recommended_eva/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.T.alport_syndrome_recommended_eva_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/<br />Concern</th><th id="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Renal</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Measurement of urine albumin-to-protein excretion</td><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Microalbuminuria (urine albumin-to-creatinine ratio >30 mg/g) or overt proteinuria (urine protein-to-creatinine ratio >0.2 mg/mg or, in a child, 24-hr urine protein >4 mg/m<sup>2</sup>/hr) is an important indicator of kidney disease progression in persons w/Alport syndrome.</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiogram</td><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">High-frequency sensorineural deafness typically becomes detectable by audiogram in late childhood.</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Vision</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval</td><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluate for maculopathy, anterior lenticonus, & retinopathy, which are typically asymptomatic.</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic counseling</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>1</sup></td><td headers="hd_h_alport.T.alport_syndrome_recommended_eva_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of Alport syndrome to facilitate medical & personal decision making.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alport.TF.5.1"><p class="no_margin">Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalportTalportsyndrometreatmentofma"><div id="alport.T.alport_syndrome_treatment_of_ma" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Alport Syndrome: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.T.alport_syndrome_treatment_of_ma/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.T.alport_syndrome_treatment_of_ma_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_1" rowspan="3" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Kidney disease</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Early treatment delays onset of ESKD. <sup>1</sup><br />Indication for treatment:
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<ul><li class="half_rhythm"><div>XLAS (males): at diagnosis, if age >12-24 mos</div></li><li class="half_rhythm"><div>XLAS (females): presence of microalbuminuria</div></li><li class="half_rhythm"><div>ARAS: at diagnosis, if age >12-24 mos</div></li><li class="half_rhythm"><div>ADAS: presence of microalbuminuria</div></li></ul>
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</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Standard mgmt for hypertension</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Kidney transplantation for ESKD</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Special considerations apply to selection of potential living related kidney donors for individuals w/AS (see <b>Note on selection of kidney donors</b>).</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing deficit</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hearing aids as needed</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Vision issues</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cataract removal</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Diffuse leiomyomatosis</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Symptomatic leiomyomas may require surgical intervention.</td><td headers="hd_h_alport.T.alport_syndrome_treatment_of_ma_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Occurs in those w/deletions of <i>COL4A5</i> extending into intron 2 of <i>COL4A6</i></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ADAS = autosomal dominant Alport syndrome; ARAS = autosomal recessive Alport syndrome; AS = Alport syndrome; ESKD = end-stage kidney disease; XLAS = X-linked Alport syndrome</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alport.TF.6.1"><p class="no_margin">
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<a class="bibr" href="#alport.REF.gross.2012.494" rid="alport.REF.gross.2012.494">Gross et al [2012]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalportTalportsyndromerecommendedsur"><div id="alport.T.alport_syndrome_recommended_sur" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Alport Syndrome: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.T.alport_syndrome_recommended_sur/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.T.alport_syndrome_recommended_sur_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/<br />Concern</th><th id="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Renal</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment by nephrologist to incl urinalysis, kidney function assessment, & blood pressure determination <sup>1</sup></td><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Annually if urine microalbumin-to-creatinine ratio <30 mg/g or urine protein-to-creatinine ratio <0.2 mg/mg</div></li><li class="half_rhythm"><div>Every 6 mos if urine microalbumin-to-creatinine ratio >30 mg/g or urine protein-to-creatinine ratio >0.2 mg/mg</div></li></ul>
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</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Monitor for development of anti-glomerular basement membrane antibody-mediated glomerulonephritis.</td><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">In at-risk transplant recipients <sup>2</sup> monthly for 1st 12 mos post transplant</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hearing</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 1-2 yrs starting at age 6-7 yrs</td></tr><tr><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Vision</b>
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</td><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval to assess for maculopathy, anterior lenticonus, corneal erosions, & cataracts</td><td headers="hd_h_alport.T.alport_syndrome_recommended_sur_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 1-2 yrs starting in adolescence in males w/truncating pathogenic variant in <i>COL4A5</i> & in persons w/ARAS.</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alport.TF.7.1"><p class="no_margin">Although most females with XLAS exhibit only asymptomatic microhematuria, there can be a significant risk for progression to ESKD [<a class="bibr" href="#alport.REF.jais.2003.2603" rid="alport.REF.jais.2003.2603">Jais et al 2003</a>]. For this reason, all women with a diagnosis of Alport syndrome need to be monitored regularly for the development of proteinuria and hypertension.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="alport.TF.7.2"><p class="no_margin">Males with XLAS and a truncating pathogenic variant in <i>COL4A5</i> and individuals with ARAS</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalportmolgenTA"><div id="alport.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Alport Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_alport.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_alport.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_alport.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_alport.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_alport.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_alport.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_alport.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/1285" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>COL4A3</i>
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</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=1285" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">2q36<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/Q01955" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Collagen alpha-3(IV) chain</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://databases.lovd.nl/shared/genes/COL4A3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL4A3 gene homepage - Collagen, type IV, alpha 3</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=COL4A3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL4A3</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=COL4A3[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL4A3</a>
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</td></tr><tr><td headers="hd_b_alport.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/1286" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>COL4A4</i>
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</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=1286" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">2q36<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/P53420" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Collagen alpha-4(IV) chain</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://databases.lovd.nl/shared/genes/COL4A4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL4A4 homepage - Collagen, type IV, alpha 4</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=COL4A4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL4A4</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=COL4A4[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL4A4</a>
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</td></tr><tr><td headers="hd_b_alport.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/1287" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>COL4A5</i>
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</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=1287" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Xq22<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/P29400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Collagen alpha-5(IV) chain</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://databases.lovd.nl/shared/genes/COL4A5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL4A5 homepage - Collagen, type IV, alpha 5</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=COL4A5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL4A5</a>
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</td><td headers="hd_b_alport.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=COL4A5[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">COL4A5</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="alport.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobalportmolgenTB"><div id="alport.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Alport Syndrome (<a href="/omim/104200,120070,120131,203780,301050,303630,620536" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/104200" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">104200</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ALPORT SYNDROME 3A, AUTOSOMAL DOMINANT; ATS3A</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/120070" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">120070</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COLLAGEN, TYPE IV, ALPHA-3; COL4A3</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/120131" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">120131</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COLLAGEN, TYPE IV, ALPHA-4; COL4A4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/203780" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">203780</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ALPORT SYNDROME 2, AUTOSOMAL RECESSIVE; ATS2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/301050" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">301050</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ALPORT SYNDROME 1, X-LINKED; ATS1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/303630" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">303630</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COLLAGEN, TYPE IV, ALPHA-5; COL4A5</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/620536" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">620536</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ALPORT SYNDROME 3B, AUTOSOMAL RECESSIVE; ATS3B</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobalportTpathogenicvariantsreferenced"><div id="alport.T.pathogenic_variants_referenced" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Pathogenic Variants Referenced in This <i>GeneReview</i> by Gene</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1207/table/alport.T.pathogenic_variants_referenced/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alport.T.pathogenic_variants_referenced_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>COL4A3</i>
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</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000091.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000091<wbr style="display:inline-block"></wbr>​.5</a>
|
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<br />
|
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000082.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000082<wbr style="display:inline-block"></wbr>​.2</a>
|
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</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.40_63del24</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu14_Leu21del</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Founder variant in persons of Ashkenazi Jewish ancestry [<a class="bibr" href="#alport.REF.shi.2017.599" rid="alport.REF.shi.2017.599">Shi et al 2017</a>, <a class="bibr" href="#alport.REF.zlotogora.2018.867" rid="alport.REF.zlotogora.2018.867">Zlotogora et al 2018</a>]</td></tr><tr><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_1" rowspan="3" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>COL4A5</i>
|
|
</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_2" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000495.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_000495<wbr style="display:inline-block"></wbr>​.3</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000486.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_000486<wbr style="display:inline-block"></wbr>​.1</a>
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</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.4692G>A</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys1564Ser</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_5" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Common variant in US</td></tr><tr><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.4946T>G</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Leu1649Arg</td></tr><tr><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_3" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.5030G>A</td><td headers="hd_h_alport.T.pathogenic_variants_referenced_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg1677Gln</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="alport.TF.8.1"><p class="no_margin">Genes from <a href="/books/NBK1207/table/alport.T.molecular_genetic_testing_used/?report=objectonly" target="object" rid-ob="figobalportTmoleculargenetictestingused">Table 1</a> are in alphabetic order.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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