Alport Syndrome

Clinical characteristics.

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.

Diagnosis/testing.

The molecular diagnosis of Alport syndrome is established in a proband with suggestive findings and a pathogenic variant(s) in COL4A3, COL4A4, or COL4A5 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.

Management.

Treatment of manifestations: 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 COL4A5 extending into intron 2 of COL4A6, surgical intervention for symptomatic leiomyomas as needed.

Surveillance: 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 COL4A5 truncating pathogenic variant and in persons with ARAS.

Agents/circumstances to avoid: 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.

Evaluation of relatives at risk: 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.

Genetic counseling.

COL4A5-related Alport syndrome is inherited in an X-linked manner (XLAS). COL4A3- and COL4A4-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 COL4A3 and COL4A4 (in cis or in trans) or, more rarely, a pathogenic variant in COL4A5 in addition to a pathogenic variant in COL4A3 or COL4A4.

XLAS: The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has a COL4A5 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 COL4A5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a COL4A5 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.

ARAS: If both parents are known to be heterozygous for a COL4A3 or COL4A4 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.

ADAS: If a parent of the proband is affected and/or is known to have the COL4A3 or COL4A4 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.

Digenic Alport syndrome: The risk to sibs depends on the involved genes, the location of the pathogenic variants (i.e., in cis or in trans) in families segregating pathogenic variants in COL4A3 and COL4A4, and the sex of the proband (in families segregating pathogenic variants in COL4A5 and COL4A3 or COL4A4).

Once the Alport syndrome-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Molecular genetic testing for Alport syndrome should be considered in an individual with persistent glomerular hematuria, plus one or more of the following clinical findings, family history, pathology, or other findings [Kashtan 2021].

Clinical findings

• Sensorineural deafness
• Anterior lenticonus and/or characteristic retinopathy
• Diffuse leiomyomatosis

Family history findings

• Hematuria
• Chronic kidney disease / kidney failure
• Deafness associated with chronic kidney disease

Pathologic findings on kidney biopsy

• Negative or nonspecific routine immunofluorescence
• Type IV collagen abnormal expression
• Thin glomerular basement membranes
• Characteristic glomerular basement membrane thickening, lamellation, and scalloping

Note: Molecular genetic testing for Alport syndrome can also be considered in those with hematuria and either:

• Family history of hematuria, chronic kidney disease, kidney failure, or deafness associated with chronic kidney disease; OR
• Diagnoses of immunoglobulin A nephropathy, membranous nephropathy, and membranoproliferative glomerular glomerulonephritis (C3 nephropathy) have been ruled out.

Establishing the Diagnosis

Molecular Diagnosis

The molecular diagnosis of Alport syndrome is established in a proband with suggestive findings and one of the following identified by molecular genetic testing (see Table 1):

• Biallelic pathogenic (or likely pathogenic) variants involving COL4A3 or COL4A4 (ARAS)
• A hemizygous pathogenic (or likely pathogenic) variant involving COL4A5 in a male proband or a heterozygous pathogenic (or likely pathogenic) variant involving COL4A5 in a female proband (XLAS)
• A heterozygous pathogenic (or likely pathogenic) variant involving COL4A3 or COL4A4 (ADAS)

Note: Digenic inheritance has been described, typically due to pathogenic variants in both COL4A3 and COL4A4 (in cis or in trans) or, more rarely, a pathogenic variant in COL4A5 in addition to a pathogenic variant in COL4A3 or COL4A4.

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 [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview 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 [Savige et al 2022].

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of Alport syndrome, the recommended molecular genetic testing approach is the use of a multigene panel.

A multigene panel that includes COL4A3, COL4A4, COL4A5, and other genes of interest (see Differential Diagnosis) 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 GeneReview. (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.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

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 Table 8).

Option 2

When the diagnosis of Alport syndrome has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Alport Syndrome

Clinical Description

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.

Table 2.

Alport Syndrome: Frequency of Select Features

Phenotype Correlations by Gene

Table 3.

Phenotype Correlations by Gene

Genotype-Phenotype Correlations

Penetrance

The presence of COL4A3 or COL4A4 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 [Gibson et al 2021]. 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 COL4A3 or COL4A4 pathogenic variant is estimated to be significantly lower than 3% [Torra et al 2024].

Nomenclature

Other terms used to refer to individuals with COL4A3-, COL4A4-, or COL4A5-related kidney manifestations include:

• Thin basement membrane nephropathy
• Type IV collagen-associated kidney disease
• Alport spectrum nephropathy

The variation in these terms reflects differences in diagnostic methods and criteria.

There is a strong consensus that the term "benign familial hematuria" should no longer be used to refer to individuals with COL4A3-, COL4A4-, or COL4A5-related hematuria as the risk of ESKD in these individuals is significantly higher than the risk of ESKD in the general population [Torra et al 2024].

Prevalence

The combined phenotype-based prevalence of XLAS and ARAS estimated from historical literature ranges from 1:5,000 to 1:50,000 [Torra et al 2024]. Analysis of population-based genome sequencing data in gnomAD revealed that predicted pathogenic COL4A5 variants occur in at least one in 2,320 individuals, while heterozygous COL4A3 or COL4A4 pathogenic variants are found in one in 106 individuals, with variations across ethnic groups [Gibson et al 2021]. 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 COL4A3 or COL4A4 pathogenic variant are asymptomatic.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Alport syndrome, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Alport Syndrome: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

Clinical practice recommendations for the treatment of individuals with Alport syndrome have been published [Nozu et al 2019, Kashtan & Gross 2021]. Early intervention is aimed at suppressing proteinuria using angiotensin antagonists.

Table 6.

Alport Syndrome: Treatment of Manifestations

Note on selection of kidney donors. The following discussion considers potential donors [Torra et al 2024].

• It is recommended to determine the exact genotype in all potential donors.
• Heterozygous relatives (males or females with pathogenic variants in COL4A3 or COL4A4 or females with a COL4A5 pathogenic variant) should only be considered as a last-resort option for living kidney donation.
• Living kidney donation is not advisable for individuals younger than age 40 years with a heterozygous pathogenic variant in COL4A3, COL4A4, or COL4A5, or at any age if there is clinical or histologic evidence of kidney damage.
• For individuals older than age 40 years with a heterozygous pathogenic variant in COL4A3, COL4A4, or COL4A5 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.
• Individuals with a heterozygous pathogenic variant in COL4A3, COL4A4, or COL4A5 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.

Surveillance

Clinical practice recommendations for health surveillance of individuals with Alport syndrome have been published [Kashtan et al 2013]. These recommendations encourage early detection of microalbuminuria and proteinuria through regular surveillance.

Table 7.

Alport Syndrome: Recommended Surveillance

Agents/Circumstances to Avoid

Dehydration should be avoided.

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.

Exposure to loud noise should be minimized.

Evaluation of Relatives at Risk

For early diagnosis and treatment. Molecular genetic testing is recommended for at-risk family members of an individual known to have a pathogenic variant (or pathogenic variants) in COL4A3, COL4A4, and/or COL4A5 in order to identify as early as possible those who would benefit from surveillance for Alport syndrome-related manifestations and early intervention [Savige et al 2022]. Early treatment of kidney disease delays onset of ESKD [Gross et al 2012]. Evaluations can include:

• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• 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.

For kidney donation. See Treatment of Manifestations, Note on selection of kidney donors.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

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.

Therapies Under Investigation

A list of Alport syndrome clinical trials can be found at Alport Syndrome Foundation: Active Clinical Trials at a Glance.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

COL4A5-related Alport syndrome is inherited in an X-linked manner (XLAS).

COL4A3- and COL4A4-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 COL4A3 or COL4A4 pathogenic variant is generally avoided because individuals who are heterozygous for a pathogenic variant in COL4A3 or COL4A4 are at risk for clinical manifestations such as hematuria or microalbuminuria and, in some individuals, end-stage kidney disease (ESKD).

Digenic Alport syndrome is caused by pathogenic variants in more than one Alport syndrome-related gene: typically pathogenic variants in both COL4A3 and COL4A4 (in cis or in trans) or, more rarely, a pathogenic variant in COL4A5 in addition to a pathogenic variant in COL4A3 or COL4A4 [Savige et al 2022].

See Table 3 for phenotype correlations by gene and mode of inheritance.

XLAS – Risk to Family Members

Parents of a male proband

• The father of a male with XLAS will not have the disorder nor will he be hemizygous for the COL4A5 pathogenic variant; therefore, he does not require further evaluation/testing.
• 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 COL4A5 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has gonadal mosaicism [Okamoto et al 2019].
• 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 de novo COL4A5 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 de novo pathogenic variant.
• 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 surveillance and treatment:
  • Molecular genetic testing for the COL4A5 pathogenic variant identified in the proband. Note: Genetic testing is more sensitive than urinalysis in identifying affected family members [Savige et al 2022] and is necessary to exclude the heterozygous state in an at-risk female who does not have hematuria or hypertension.
  • Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a COL4A5 pathogenic variant.
• 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.

Parents of a female proband

• A female proband may have inherited the COL4A5 pathogenic variant from either her mother or her father or the pathogenic variant may be de novo.
• Evaluation of the parents of a female proband with XLAS proceeds (for both parents) as described for the mother of a male proband.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a COL4A5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males and females who inherit the pathogenic variant will be affected.
  • All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [Yamamura et al 2020].
  • Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [Yamamura et al 2017]. Both genotype and unbalanced X-chromosome inactivation may affect severity in females [Suzuki et al 2024].
• If the proband represents a simplex case and the COL4A5 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 [Beicht et al 2013, Okamoto et al 2019].

Sibs of a female proband. 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 COL4A5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males and females who inherit the pathogenic variant will be affected (see Sibs of a male proband).
• If the father of the proband has a COL4A5 pathogenic variant, he will transmit it to all of his daughters and none of his sons.
• If the proband represents a simplex case and the COL4A5 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 [Beicht et al 2013, Okamoto et al 2019].

Offspring of a proband

• Affected males transmit the COL4A5 pathogenic variant to all of their daughters and none of their sons.
• Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child.

Other family members. 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.

Heterozygote detection. Molecular genetic testing for at-risk females requires prior identification of the COL4A5 pathogenic variant in the family. Genetic testing is more sensitive than urinalysis in identifying affected family members [Savige et al 2022] and is necessary to exclude the heterozygous state in an at-risk female who does not have hematuria or hypertension.

ARAS – Risk to Family Members

Parents of a proband

• The parents of a child with biallelic COL4A3 or COL4A4 pathogenic variants (ARAS) are presumed to be heterozygous for a COL4A3 or COL4A4 pathogenic variant. A heterozygous parent may have clinical manifestations of Alport syndrome (and be diagnosed with autosomal dominant Alport syndrome) or may be asymptomatic.
• 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 COL4A3 or COL4A4 pathogenic variant, allow reliable recurrence risk assessment, and determine their need for kidney surveillance and treatment.
• 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 de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• While risk of kidney manifestations in individuals who are heterozygous for a COL4A3 or COL4A4 pathogenic variant is higher than that of the general population, the absolute risk of ESKD due to heterozygosity for a COL4A3 or COL4A4 pathogenic variant is estimated to be significantly lower than 3% [Torra et al 2024]

Sibs of a proband

• If both parents are known to be heterozygous for a COL4A3 or COL4A4 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.
• Some individuals who are heterozygous for a COL4A3 or COL4A4 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 COL4A3 or COL4A4 pathogenic variant is higher than that of the general population, the absolute risk of ESKD due to heterozygosity for a COL4A3 or COL4A4 pathogenic variant is estimated to be significantly lower than 3% [Torra et al 2024]

Offspring of a proband. The offspring of an individual with ARAS are obligate heterozygotes for a COL4A3 or COL4A4 pathogenic variant and may or may not have clinical manifestations of Alport syndrome.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for a COL4A3 or COL4A4 pathogenic variant.

Heterozygote detection. Heterozygote testing for at-risk relatives requires prior identification of the COL4A3 or COL4A4 pathogenic variants in the family.

ADAS – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with ADAS have the disorder as the result of a COL4A3 or COL4A4 pathogenic variant inherited from a parent.
• Some individuals diagnosed with ADAS have the disorder as the result of a de novo COL4A3 or COL4A4 pathogenic variant. The proportion of individuals with ADAS caused by a de novo pathogenic variant is unknown.
• If the proband appears to be the only affected family member, molecular genetic testing for the COL4A3 or COL4A4 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 surveillance and treatment. 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, de novo occurrence of a COL4A3 or COL4A4 pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant.
• 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:
  • The proband has a de novo pathogenic variant.
  • 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.

Sibs of a proband. The risk to the sibs of a proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the COL4A3 or COL4A4 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 Penetrance).
• 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 [Rahbari et al 2016].
• 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.

Offspring of a proband. Offspring of an individual with ADAS are at a 50% risk of inheriting the ADAS-related pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has a COL4A3 or COL4A4 pathogenic variant, the parent's family members are at risk.

Digenic Inheritance – Risk to Family Members

Parents of a proband

• If a proband has digenic Alport syndrome caused by COL4A3 and COL4A4 pathogenic variants in cis, both pathogenic variants are presumed to have been inherited from one parent who is also affected with digenic Alport syndrome.
• If a proband has digenic Alport syndrome caused by COL4A3 and COL4A4 pathogenic variants in trans or a pathogenic variant in COL4A5 in addition to a pathogenic variant in COL4A3 or COL4A4, both parents may have an Alport syndrome-related pathogenic variant.
• 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 surveillance and treatment.

Sibs of a proband. The risk to sibs depends on the genetic status of the parents:

• If one parent is heterozygous for a COL4A3 pathogenic variant and the other parent is heterozygous for a COL4A4 pathogenic variant, sibs have a:
  • 25% chance of inheriting two pathogenic variants;
  • 50% chance of inheriting one pathogenic variant;
  • 25% chance of inheriting neither of the familial pathogenic variants.
• If one parent is heterozygous for a COL4A3 and a COL4A4 pathogenic variant in cis and the other parent does not have an Alport syndrome-related pathogenic variant, sibs have a:
  • 50% chance of inheriting two pathogenic variants in cis;
  • 50% chance of inheriting neither of the familial pathogenic variants.
• If the mother of the proband has a COL4A5 pathogenic variant and the father of the proband has a COL4A3 or COL4A4 pathogenic variant, sibs have a:
  • 25% chance of inheriting both the maternal COL4A5 pathogenic variant and the paternal COL4A3 or COL4A4 pathogenic variant;
  • 25% chance of inheriting only the maternal COL4A5 pathogenic variant;
  • 25% chance of inheriting only the paternal COL4A3 or COL4A4 pathogenic variant;
  • 25% chance of inheriting neither of the familial pathogenic variants.
• If the father of the proband has a COL4A5 pathogenic variant and the mother of the proband has a COL4A3 or COL4A4 pathogenic variant:
  • Male sibs have a 50% risk of inheriting the COL4A3 or COL4A4 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 COL4A5 pathogenic variant.)
  • All female sibs will inherit the paternal COL4A5 pathogenic variant: 50% of female sibs will inherit both the paternal COL4A5 pathogenic variant and the maternal COL4A3 or COL4A4 pathogenic variant and 50% will inherit only the paternal COL4A5 pathogenic variant.
• Sibs who inherit pathogenic variants in both COL4A3 and COL4A4 (in cis or in trans) or a pathogenic variant in COL4A5 in addition to a pathogenic variant in COL4A3 or COL4A4 will be affected with digenic Alport syndrome (see Table 3 for phenotype correlations by gene and mode of inheritance).
• Sibs who inherit a single Alport syndrome-related pathogenic variant are at risk for ADAS (if they are heterozygous for a COL4A3 or COL4A4 pathogenic variant) or XLAS (if they are a female heterozygous for a COL4A5 pathogenic variant or a male hemizygous for a COL4A5 pathogenic variant).

Offspring of a proband. If the reproductive partner of the proband does not have an Alport syndrome-related pathogenic variant:

• All offspring of a proband with COL4A3 and COL4A4 pathogenic variants in trans will inherit either a COL4A3 pathogenic variant or a COL4A4 pathogenic variant (i.e., all offspring will be heterozygous for a pathogenic variant in COL4A3 or COL4A4) and will be at risk for ADAS.
• Offspring of a proband with COL4A3 and COL4A4 pathogenic variants in cis have a 50% risk of inheriting both pathogenic variants and having digenic Alport syndrome.
• If a female proband has a COL4A5 pathogenic variant and a COL4A3 or COL4A4 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).
• If a male proband has a COL4A5 pathogenic variant and a COL4A3 or COL4A4 pathogenic variant, female offspring have a 50% risk of inheriting both the COL4A5 pathogenic variant and the COL4A3 or COL4A4 pathogenic variant (and having digenic Alport syndrome) and a 50% risk of inheriting only the COL4A5 pathogenic variant (and having XLAS); male offspring have a 50% risk of inheriting a COL4A3 or COL4A4 pathogenic variant (and being at risk for ADAS).

Other family members. 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.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Screening of potential living related kidney donors. See Treatment of Manifestations, Note on selection of kidney donors.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the Alport syndrome-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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.

Molecular Pathogenesis

Basement membranes. 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.

Collagen IV. 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:

• A (Gly)-X-Y collagenous domain of approximately 1,400 residues
• A carboxy-terminal non-collagenous (NC1) domain of approximately 230 residues and 12 conserved cysteine residues, which participate in intrachain and interchain disulfide bonds
• A non-collagenous amino-terminal sequence of 15-20 residues

Approximately 20 interruptions of the collagenous triplet sequence are present in the collagenous domain.

Collagen IV chains form helical heterotrimers through associations between their COO^- NC1 domains. The heterotrimers form networks through intermolecular interaction such as:

• End-to-end linkages between the COO^- NC1 domains of two heterotrimers;
• Covalent interactions between four heterotrimers at their NH^- ends; and
• Lateral associations between heterotrimers via binding of the COO^- domains to sites along the collagenous region of another heterotrimer.

Linkages between collagen IV molecules form a scaffolding for the deposition of other matrix glycoproteins and for cell attachment.

In the normal developing kidney:

• Collagen IV α1 and α2 chains predominate in the primordial glomerular basement membrane of immature glomeruli;
• 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.
• As glomerular maturation progresses, the collagen IV α3, α4, and α5 chains become the predominant collagen IV chains in the glomerular basement membrane.

Mechanism of disease causation. 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.

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.

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 COL1A1/2-Related Osteogenesis Imperfecta 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.

COL4A3- and COL4A4-specific laboratory technical considerations. Variants in COL4A3 and COL4A4 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.

Table 8.

Pathogenic Variants Referenced in This GeneReview by Gene

Author Notes

Prof Kandai Nozu, MD, PhD
Department of Pediatrics, Kobe University Graduate School of Medicine
Email: pj.ca.u-ebok.dem@uzon
Web page: kuid-rm-web.ofc.kobe-u.ac.jp

Author History

Tomoko Horinouchi, MD, PhD (2025-present)
Clifford E Kashtan, MD; University of Minnesota (2001-2025)
Kandai Nozu, MD, PhD (2025-present)
Tomohiko Yamamura, MD, PhD (2025-present)

Revision History

• 27 February 2025 (sw) Comprehensive update posted live
• 21 February 2019 (ha) Comprehensive update posted live
• 25 November 2015 (me) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 15 July 2010 (me) Comprehensive update posted live
• 23 January 2008 (me) Comprehensive update posted live
• 26 September 2005 (me) Comprehensive update posted live
• 28 August 2003 (me) Comprehensive update posted live
• 28 August 2001 (me) Review posted live
• March 2001 (ck) Original submission

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