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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>VLDLR Cerebellar Hypoplasia - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="VLDLR Cerebellar Hypoplasia">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2020/02/27">
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<meta name="citation_author" content="Kym M Boycott">
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<meta name="citation_author" content="Stella K MacDonald">
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<meta name="citation_author" content="Jillian S Parboosingh">
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<meta name="citation_keywords" content="Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 1 (CAMRQ1)">
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<meta name="citation_keywords" content="Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 1 (CAMRQ1)">
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<meta name="citation_keywords" content="Very low-density lipoprotein receptor">
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<meta name="citation_keywords" content="VLDLR">
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<meta name="citation_keywords" content="VLDLR Cerebellar Hypoplasia">
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<meta name="DC.Title" content="VLDLR Cerebellar Hypoplasia">
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<meta name="DC.Contributor" content="Kym M Boycott">
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<meta name="DC.Contributor" content="Stella K MacDonald">
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<meta name="DC.Contributor" content="Jillian S Parboosingh">
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<meta name="description" content="VLDLR cerebellar hypoplasia (VLDLR-CH) is characterized by non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation, moderate-to-profound intellectual disability, dysarthria, strabismus, and seizures. Children either learn to walk very late (often after age 6 years) or never achieve independent ambulation. Brain MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified gyration of the cerebral hemispheres, and small brain stem – particularly the pons.">
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<meta name="og:description" content="VLDLR cerebellar hypoplasia (VLDLR-CH) is characterized by non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation, moderate-to-profound intellectual disability, dysarthria, strabismus, and seizures. Children either learn to walk very late (often after age 6 years) or never achieve independent ambulation. Brain MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified gyration of the cerebral hemispheres, and small brain stem – particularly the pons.">
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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="_NBK1874_"><span class="title" itemprop="name"><i>VLDLR</i> Cerebellar Hypoplasia</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 1 (CAMRQ1)</div><p class="contribs">Boycott KM, MacDonald SK, Parboosingh JS.</p><p class="fm-aai"><a href="#_NBK1874_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 18 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="vldlr-ch.Summary" itemprop="description"><h2 id="_vldlr-ch_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH) is characterized by non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation, moderate-to-profound intellectual disability, dysarthria, strabismus, and seizures. Children either learn to walk very late (often after age 6 years) or never achieve independent ambulation. Brain MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified gyration of the cerebral hemispheres, and small brain stem – particularly the pons.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>VLDLR</i> cerebellar hypoplasia is established in a proband with suggestive clinical and brain MRI findings by identification of biallelic pathogenic variants in <i>VLDLR</i> on molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Seizures and strabismus are treated in the standard manner. Referral to an early intervention program is recommended for access to occupational, physical, and speech therapy, as well as infant mental health services and special educators.</p><p><i>Surveillance:</i> Annual neurologic and rehabilitation evaluations.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>VLDLR</i>-CH is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible when the pathogenic variants in a family are known.</p></div></div><div id="vldlr-ch.Diagnosis"><h2 id="_vldlr-ch_Diagnosis_">Diagnosis</h2><p><i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH) is a subgroup of dysequilibrium syndrome (DES), a spectrum of genetically heterogeneous conditions that combines non-progressive cerebellar ataxia with intellectual disability inherited in an autosomal recessive manner.</p><div id="vldlr-ch.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>VLDLR</i> cerebellar hypoplasia <b>should be suspected</b> in individuals with the following major diagnostic features:</p><ul><li class="half_rhythm"><div>Non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation</div></li><li class="half_rhythm"><div>Moderate-to-profound intellectual disability</div></li><li class="half_rhythm"><div>Dysarthria</div></li><li class="half_rhythm"><div>MRI findings (see <a class="figpopup" href="/books/NBK1874/figure/vldlr-ch.F1/?report=objectonly" target="object" rid-figpopup="figvldlrchF1" rid-ob="figobvldlrchF1">Figure 1</a>) that include the following:</div><ul><li class="half_rhythm"><div>Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres</div></li><li class="half_rhythm"><div>Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient</div></li><li class="half_rhythm"><div>Small brain stem, particularly the pons</div></li></ul></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figvldlrchF1" co-legend-rid="figlgndvldlrchF1"><a href="/books/NBK1874/figure/vldlr-ch.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figvldlrchF1" rid-ob="figobvldlrchF1"><img class="small-thumb" src="/books/NBK1874/bin/vldlr-ch-Image001.gif" src-large="/books/NBK1874/bin/vldlr-ch-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndvldlrchF1"><h4 id="vldlr-ch.F1"><a href="/books/NBK1874/figure/vldlr-ch.F1/?report=objectonly" target="object" rid-ob="figobvldlrchF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">MRI of the brain demonstrating typical neuroimaging findings of VLDLR-CH A. Sagittal T<sub>1</sub>-weighted</p></div></div></div><div id="vldlr-ch.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>VLDLR</i> cerebellar hypoplasia <b>is established</b> in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in <i>VLDLR</i> on molecular genetic testing (see <a href="/books/NBK1874/table/vldlr-ch.T.molecular_genetic_testing_use/?report=objectonly" target="object" rid-ob="figobvldlrchTmoleculargenetictestinguse">Table 1</a>).</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="#vldlr-ch.REF.richards.2015.405" rid="vldlr-ch.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 biallelic <i>VLDLR</i> variants of uncertain significance (or of one known <i>VLDLR</i> pathogenic variant and one <i>VLDLR</i> variant of uncertain significance) does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of VLDLR cerebellar hypoplasia is often recognizable, individuals with the distinctive MRI findings described in <a href="#vldlr-ch.Suggestive_Findings">Suggestive Findings</a> can often be diagnosed using gene-targeted testing (see <a href="#vldlr-ch.Option_1">Option 1</a>), whereas those in whom the diagnosis of VLDLR cerebellar hypoplasia has not been considered are more likely to be diagnosed using genomic testing (see <a href="#vldlr-ch.Option_2">Option 2</a>).</p><div id="vldlr-ch.Option_1"><h4>Option 1</h4><p>When the phenotypic and radiographic findings suggest the diagnosis of <i>VLDLR</i> cerebellar hypoplasia, molecular genetic testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel</b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>VLDLR</i> is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.</div><div class="half_rhythm">Note: Targeted analysis for pathogenic variants can be performed first in individuals of Hutterite ancestry. See <a href="/books/NBK1874/table/vldlr-ch.T.notable_vldlr_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobvldlrchTnotablevldlrpathogenicvari">Table 6</a>.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes <i>VLDLR</i> and other genes of interest (see <a href="#vldlr-ch.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. For this disorder a multigene panel that also includes deletion/duplication analysis can be considered if only one or no pathogenic variant is found on sequencing.</div><div class="half_rhythm">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>.</div></li></ul></div><div id="vldlr-ch.Option_2"><h4>Option 2</h4><p>When the diagnosis of <i>VLDLR</i> cerebellar hypoplasia is not considered because of its rarity and/or because an individual has atypical phenotypic features, <b>comprehensive</b>
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<b>genomic testing</b> (which does not require the clinician to determine which gene[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.</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="figvldlrchTmoleculargenetictestinguse"><a href="/books/NBK1874/table/vldlr-ch.T.molecular_genetic_testing_use/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobvldlrchTmoleculargenetictestinguse"><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="vldlr-ch.T.molecular_genetic_testing_use"><a href="/books/NBK1874/table/vldlr-ch.T.molecular_genetic_testing_use/?report=objectonly" target="object" rid-ob="figobvldlrchTmoleculargenetictestinguse">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>VLDLR</i> Cerebellar Hypoplasia </p></div></div></div></div></div><div id="vldlr-ch.Clinical_Characteristics"><h2 id="_vldlr-ch_Clinical_Characteristics_">Clinical Characteristics</h2><div id="vldlr-ch.Clinical_Description"><h3>Clinical Description</h3><p><i>VLDLR</i> cerebellar hypoplasia is a congenital non-progressive disorder characterized by cerebellar ataxia and intellectual disability.</p><p>To date, more than 50 individuals have been identified with a pathogenic variant in <i>VLDLR</i> [<a class="bibr" href="#vldlr-ch.REF.boycott.2005.477" rid="vldlr-ch.REF.boycott.2005.477">Boycott et al 2005</a>, <a class="bibr" href="#vldlr-ch.REF.glass.2005.691" rid="vldlr-ch.REF.glass.2005.691">Glass et al 2005</a>, <a class="bibr" href="#vldlr-ch.REF.moheb.2008.270" rid="vldlr-ch.REF.moheb.2008.270">Moheb et al 2008</a>, <a class="bibr" href="#vldlr-ch.REF.ozcelik.2008.4232" rid="vldlr-ch.REF.ozcelik.2008.4232">Ozcelik et al 2008</a>, <a class="bibr" href="#vldlr-ch.REF.t_rkmen.2008.1070" rid="vldlr-ch.REF.t_rkmen.2008.1070">Türkmen et al 2008</a>, <a class="bibr" href="#vldlr-ch.REF.boycott.2009.1310" rid="vldlr-ch.REF.boycott.2009.1310">Boycott et al 2009</a>, <a class="bibr" href="#vldlr-ch.REF.kolb.2010.319" rid="vldlr-ch.REF.kolb.2010.319">Kolb et al 2010</a>, <a class="bibr" href="#vldlr-ch.REF.ali.2012.80" rid="vldlr-ch.REF.ali.2012.80">Ali et al 2012</a>, <a class="bibr" href="#vldlr-ch.REF.azmanov.2013.71" rid="vldlr-ch.REF.azmanov.2013.71">Azmanov et al 2013</a>, <a class="bibr" href="#vldlr-ch.REF.kruer.2013.1904" rid="vldlr-ch.REF.kruer.2013.1904">Kruer et al 2013</a>, <a class="bibr" href="#vldlr-ch.REF.schlotawa.2013.1678" rid="vldlr-ch.REF.schlotawa.2013.1678">Schlotawa et al 2013</a>, <a class="bibr" href="#vldlr-ch.REF.sonmez.2013.379" rid="vldlr-ch.REF.sonmez.2013.379">Sonmez et al 2013</a>, <a class="bibr" href="#vldlr-ch.REF.giorgio.2016.1772" rid="vldlr-ch.REF.giorgio.2016.1772">Giorgio et al 2016</a>, <a class="bibr" href="#vldlr-ch.REF.micalizzi.2016.191" rid="vldlr-ch.REF.micalizzi.2016.191">Micalizzi et al 2016</a>, <a class="bibr" href="#vldlr-ch.REF.valence.2016.545" rid="vldlr-ch.REF.valence.2016.545">Valence et al 2016</a>, <a class="bibr" href="#vldlr-ch.REF.wilker.2019.404" rid="vldlr-ch.REF.wilker.2019.404">Wilker et al 2019</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figvldlrchTfeaturesofvldlrcerebellar"><a href="/books/NBK1874/table/vldlr-ch.T.features_of_vldlr_cerebellar/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobvldlrchTfeaturesofvldlrcerebellar"><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="vldlr-ch.T.features_of_vldlr_cerebellar"><a href="/books/NBK1874/table/vldlr-ch.T.features_of_vldlr_cerebellar/?report=objectonly" target="object" rid-ob="figobvldlrchTfeaturesofvldlrcerebellar">Table 2. </a></h4><p class="float-caption no_bottom_margin">Features of <i>VLDLR</i> Cerebellar Hypoplasia </p></div></div><p><b>Brain MRI.</b> All affected individuals demonstrate hypoplasia of the inferior portion of the cerebellar vermis and hemispheres. In addition, the majority of affected individuals show a simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex, lack of clear anteroposterior gradient, and small brain stem (particularly the pons). Some individuals are described as demonstrating neuroimaging features of pontocerebellar hypoplasia.</p><p><b>Cerebellar ataxia.</b> All affected individuals demonstrate significant truncal ataxia. Children either learn to walk very late (often after age 6 years) or never achieve independent ambulation. For those able to ambulate independently, gait is wide based; affected individuals are not able to perform a tandem gait. Affected individuals from Turkey demonstrate quadrupedal locomotion in which the palms of the hands touch the ground and the elbows, back, and knees are straight [<a class="bibr" href="#vldlr-ch.REF.ozcelik.2008.4232" rid="vldlr-ch.REF.ozcelik.2008.4232">Ozcelik et al 2008</a>, <a class="bibr" href="#vldlr-ch.REF.t_rkmen.2009.e1000487" rid="vldlr-ch.REF.t_rkmen.2009.e1000487">Türkmen et al 2009</a>], an interesting behavioral adaptation which likely depends on the presence of special environmental influences during child development [<a class="bibr" href="#vldlr-ch.REF.herz.2008.e25" rid="vldlr-ch.REF.herz.2008.e25">Herz et al 2008</a>, <a class="bibr" href="#vldlr-ch.REF.t_rkmen.2009.e1000487" rid="vldlr-ch.REF.t_rkmen.2009.e1000487">Türkmen et al 2009</a>]. Limb ataxia is present in most individuals but is not severe.</p><p><b>Intellectual disability.</b> All reported affected individuals have intellectual disability, ranging from moderate to profound. Most individuals can follow simple commands. Some can communicate verbally using short phrases or sentences. Adults are unable to live independently.</p><p><b>Dysarthria.</b> Those who are able to communicate verbally demonstrate dysarthria.</p><p><b>Strabismus.</b> The majority of individuals have strabismus.</p><p>
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<b>Other</b>
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</p><ul><li class="half_rhythm"><div>Nystagmus is reported in some individuals and is described as gaze evoked.</div></li><li class="half_rhythm"><div>Epileptic seizures were reported in 40% of the affected individuals from the Hutterite population [<a class="bibr" href="#vldlr-ch.REF.glass.2005.691" rid="vldlr-ch.REF.glass.2005.691">Glass et al 2005</a>], and appear to be less frequent in non-Hutterite individuals. The seizures tend to be generalized.</div></li><li class="half_rhythm"><div>Deep tendon reflexes in the lower extremities tend to be brisk.</div></li><li class="half_rhythm"><div>Microcephaly (2-4 SD below the mean) has been reported in a few affected individuals.</div></li><li class="half_rhythm"><div>Short stature (height just below the 2nd centile) is a feature in a few affected individuals.</div></li></ul><p><b>Life span.</b> There has been no formal study of life span in this disorder, but experience from the Hutterite population suggests that life span is not significantly reduced.</p></div><div id="vldlr-ch.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No genotype-phenotype correlations have been identified.</p></div><div id="vldlr-ch.Nomenclature"><h3>Nomenclature</h3><p><i>VLDLR</i>-CH is a clinically and molecularly well-defined subgroup of dysequilibrium syndrome (DES).</p></div><div id="vldlr-ch.Prevalence"><h3>Prevalence</h3><p>The actual frequency of <i>VLDLR</i>-CH is unknown.</p><p>More than 25 individuals with <i>VLDLR</i>-CH from the Hutterite population in Canada and the US have been followed for many years. This condition is present in all three Hutterite <i>leuts</i> (branches) (i.e., <i>Schmiedeleut</i>, <i>Lehrerleut</i>, and <i>Dariusleut</i>).</p><p>The estimated carrier frequency in the Hutterite population is one in 15 [<a class="bibr" href="#vldlr-ch.REF.glass.2005.691" rid="vldlr-ch.REF.glass.2005.691">Glass et al 2005</a>].</p></div></div><div id="vldlr-ch.Genetically_Related_Allelic_Dis"><h2 id="_vldlr-ch_Genetically_Related_Allelic_Dis_">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>VLDLR</i>.</p></div><div id="vldlr-ch.Differential_Diagnosis"><h2 id="_vldlr-ch_Differential_Diagnosis_">Differential Diagnosis</h2><p>The differential diagnosis of <i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH) includes autosomal recessive conditions characterized by congenital or very early-onset cerebellar ataxia associated with cerebellar hypoplasia. Because cerebellar hypoplasia can be difficult to distinguish from cerebellar atrophy on early imaging, conditions characterized by the latter should also be considered (see <a href="/books/NBK1874/table/vldlr-ch.T.genes_and_disorders_of_intere/?report=objectonly" target="object" rid-ob="figobvldlrchTgenesanddisordersofintere">Table 3</a>).</p><p>Note: Diverse phenotypes associated with childhood- and adult-onset ataxia are to be excluded (see <a href="/books/n/gene/ataxias/?report=reader#ataxias.T.autosomal_recessive_cerebellar">Hereditary Ataxia Overview, Table 3. Autosomal Recessive Cerebellar Ataxias: Single-Gene Disorders</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figvldlrchTgenesanddisordersofintere"><a href="/books/NBK1874/table/vldlr-ch.T.genes_and_disorders_of_intere/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobvldlrchTgenesanddisordersofintere"><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="vldlr-ch.T.genes_and_disorders_of_intere"><a href="/books/NBK1874/table/vldlr-ch.T.genes_and_disorders_of_intere/?report=objectonly" target="object" rid-ob="figobvldlrchTgenesanddisordersofintere">Table 3. </a></h4><p class="float-caption no_bottom_margin">Genes and Disorders of Interest in the Differential Diagnosis of <i>VLDLR</i> Cerebellar Hypoplasia </p></div></div></div><div id="vldlr-ch.Management"><h2 id="_vldlr-ch_Management_">Management</h2><div id="vldlr-ch.Evaluations_Following_Initial_D"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with <i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH), the evaluations summarized in <a href="/books/NBK1874/table/vldlr-ch.T.recommended_evaluations_follo/?report=objectonly" target="object" rid-ob="figobvldlrchTrecommendedevaluationsfollo">Table 4</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="figvldlrchTrecommendedevaluationsfollo"><a href="/books/NBK1874/table/vldlr-ch.T.recommended_evaluations_follo/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobvldlrchTrecommendedevaluationsfollo"><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="vldlr-ch.T.recommended_evaluations_follo"><a href="/books/NBK1874/table/vldlr-ch.T.recommended_evaluations_follo/?report=objectonly" target="object" rid-ob="figobvldlrchTrecommendedevaluationsfollo">Table 4. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with <i>VLDLR</i> Cerebellar Hypoplasia </p></div></div></div><div id="vldlr-ch.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Treatment of seizures and strabismus is done in the standard manner.</p><div id="vldlr-ch.Developmental_Delay__Intellectu"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.</p><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:</p><ul><li class="half_rhythm"><div>IEP services:</div><ul><li class="half_rhythm"><div>An IEP provides specially designed instruction and related services to children who qualify.</div></li><li class="half_rhythm"><div>IEP services will be reviewed annually to determine whether any changes are needed.</div></li><li class="half_rhythm"><div>As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.</div></li><li class="half_rhythm"><div>Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.</div></li><li class="half_rhythm"><div>PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</div></li><li class="half_rhythm"><div>As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.</div></li></ul></li><li class="half_rhythm"><div>A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.</div></li><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="vldlr-ch.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
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<b>Gross motor dysfunction</b>
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</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to promote ambulation.</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="http://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Augmentative and Alternative Communication</a> [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, and in many cases can improve it.</p></div></div><div id="vldlr-ch.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figvldlrchTrecommendedsurveillancefor"><a href="/books/NBK1874/table/vldlr-ch.T.recommended_surveillance_for/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobvldlrchTrecommendedsurveillancefor"><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="vldlr-ch.T.recommended_surveillance_for"><a href="/books/NBK1874/table/vldlr-ch.T.recommended_surveillance_for/?report=objectonly" target="object" rid-ob="figobvldlrchTrecommendedsurveillancefor">Table 5. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with <i>VLDLR</i> Cerebellar Hypoplasia </p></div></div></div><div id="vldlr-ch.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#vldlr-ch.Related_Genetic_Counseling_Issu">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="vldlr-ch.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><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. Note: There may not be clinical trials for this disorder.</p></div></div><div id="vldlr-ch.Genetic_Counseling"><h2 id="_vldlr-ch_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="vldlr-ch.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>VLDLR</i> cerebellar hypoplasia (<i>VLDLR</i>-CH) is inherited in an autosomal recessive manner.</p></div><div id="vldlr-ch.Risk_to_Family_Members"><h3>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 an affected child are obligate heterozygotes (i.e., carriers of one <i>VLDLR</i> pathogenic variant).</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</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>At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.</div></li><li class="half_rhythm"><div>Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.</div></li></ul><p><b>Offspring of a proband.</b> To date, individuals with <i>VLDLR</i>-CH are not known to reproduce.</p><p><b>Other family members.</b> Each sib of the proband's parents is at a 50% risk of being a carrier of a <i>VLDLR</i> pathogenic variant.</p></div><div id="vldlr-ch.Carrier_Detection"><h3>Carrier Detection</h3><p>Carrier testing for at-risk relatives requires prior identification of the <i>VLDLR</i> pathogenic variants in the family.</p></div><div id="vldlr-ch.Related_Genetic_Counseling_Issu"><h3>Related Genetic Counseling Issues</h3><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, clarification of carrier status, 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 carriers or are at risk of being carriers.</div></li></ul><p><b>Population screening.</b> In the Hutterite population, the high carrier frequency (~1:15) could warrant population screening for reproductive purposes [<a class="bibr" href="#vldlr-ch.REF.glass.2005.691" rid="vldlr-ch.REF.glass.2005.691">Glass et al 2005</a>]. Carrier testing for the Hutterite population involves targeted analysis for the founder deletion [<a class="bibr" href="#vldlr-ch.REF.boycott.2005.477" rid="vldlr-ch.REF.boycott.2005.477">Boycott et al 2005</a>].</p><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bibr" href="#vldlr-ch.REF.huang.2022.389" rid="vldlr-ch.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="vldlr-ch.Prenatal_Testing_and_Preimplant"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>VLDLR</i> pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for <i>VLDLR</i>-CH are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="vldlr-ch.Resources"><h2 id="_vldlr-ch_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>National Institute of Neurological Disorders and Stroke (NINDS)</b>
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</div><div>PO Box 5801</div><div>Bethesda MD 20824</div><div><b>Phone:</b> 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)</div><div>
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<a href="https://www.ninds.nih.gov/Disorders/All-Disorders/Cerebellar-Hypoplasia-Information-Page" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cerebellar Hypoplasia Information Page</a>
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</div></li><li class="half_rhythm"><div>
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<b>American Association on Intellectual and Developmental Disabilities (AAIDD)</b>
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</div><div><b>Phone:</b> 202-387-1968</div><div>
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<a href="https://www.aaidd.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">aaidd.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>CDC - Child Development</b>
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</div><div><b>Phone:</b> 800-232-4636</div><div>
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<a href="https://www.cdc.gov/child-development/about/developmental-disability-basics.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Developmental Disability Basics</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Ataxia Foundation</b>
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</div><div><b>Phone:</b> 763-553-0020</div><div><b>Email:</b> naf@ataxia.org</div><div>
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<a href="https://www.ataxia.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ataxia.org</a>
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</div></li></ul>
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</div><div id="vldlr-ch.Molecular_Genetics"><h2 id="_vldlr-ch_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="figvldlrchmolgenTA"><a href="/books/NBK1874/table/vldlr-ch.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobvldlrchmolgenTA"><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="vldlr-ch.molgen.TA"><a href="/books/NBK1874/table/vldlr-ch.molgen.TA/?report=objectonly" target="object" rid-ob="figobvldlrchmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">VLDLR Cerebellar Hypoplasia: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figvldlrchmolgenTB"><a href="/books/NBK1874/table/vldlr-ch.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobvldlrchmolgenTB"><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="vldlr-ch.molgen.TB"><a href="/books/NBK1874/table/vldlr-ch.molgen.TB/?report=objectonly" target="object" rid-ob="figobvldlrchmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for VLDLR Cerebellar Hypoplasia (View All in OMIM) </p></div></div><div id="vldlr-ch.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>VLDLR</i> encodes a protein of 873 amino acids and is expressed abundantly in the heart, skeletal muscle, kidney, and brain. VLDLR protein is part of the reelin signaling pathway, which guides neuroblast migration in the developing cerebral cortex and cerebellum [<a class="bibr" href="#vldlr-ch.REF.tissir.2003.496" rid="vldlr-ch.REF.tissir.2003.496">Tissir & Goffinet 2003</a>]. In an evolutionarily conserved pathway, reelin engages two lipoprotein receptors, VLDLR and apolipoprotein E receptor-2 (Apoer2), resulting in phosphorylation of disabled-1 (Dab1) and activation of an intracellular signaling cascade that allows neuroblasts to complete migration.</p><p>VLDLR belongs to a subset of cell surface receptors called the LDL receptor protein family. Family members share a number of domains arranged in a similar pattern: ligand-binding repeat domain, EGF repeat, YWTD domain, O-linked sugar domain, transmembrane domain, and a cytoplasmic domain containing a NPXY motif. VLDLR was initially identified to function in the receptor-mediated endocytosis of apoE-containing lipoproteins.</p><p><b>Mechanism of disease causation.</b> All of the reported pathogenic variants to date are predicted to result in loss of function of the VLDLR protein. In the absence of this receptor, neuroblasts are unable to complete migration and adopt their ultimate position in the developing central nervous system.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figvldlrchTnotablevldlrpathogenicvari"><a href="/books/NBK1874/table/vldlr-ch.T.notable_vldlr_pathogenic_vari/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobvldlrchTnotablevldlrpathogenicvari"><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="vldlr-ch.T.notable_vldlr_pathogenic_vari"><a href="/books/NBK1874/table/vldlr-ch.T.notable_vldlr_pathogenic_vari/?report=objectonly" target="object" rid-ob="figobvldlrchTnotablevldlrpathogenicvari">Table 6. </a></h4><p class="float-caption no_bottom_margin">Notable <i>VLDLR</i> Pathogenic Variants </p></div></div></div></div><div id="vldlr-ch.Chapter_Notes"><h2 id="_vldlr-ch_Chapter_Notes_">Chapter Notes</h2><div id="vldlr-ch.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>27 February 2020 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>8 August 2013 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>26 August 2008 (cg) Review posted live</div></li><li class="half_rhythm"><div>7 July 2008 (kmb) Original submission</div></li></ul></div></div><div id="vldlr-ch.References"><h2 id="_vldlr-ch_References_">References</h2><div id="vldlr-ch.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="vldlr-ch.REF.ali.2012.80">Ali
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BR, Silhavy
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JL, Gleeson
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MJ, Gleeson
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JG, Al-Gazali
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L. A missense founder mutation in VLDLR is associated with dysequilibrium syndrome without quadrupedal locomotion.
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BMC Med Genet.
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2012;13:80.
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[<a href="/pmc/articles/PMC3495048/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3495048</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22973972" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22973972</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="vldlr-ch.REF.azmanov.2013.71">Azmanov
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DN, Chamova
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T, Tankard
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R, Gelev
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V, Bynevelt
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M, Florez
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L, Tzoneva
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D, Zlatareva
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D, Guergueltcheva
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V, Bahlo
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M, Tournev
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I, Kalaydjieva
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L. Challenges of diagnostic exome sequencing in an inbred founder population.
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Mol Genet Genomic Med.
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2013;1:71-6.
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[<a href="/pmc/articles/PMC3865571/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3865571</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24498604" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24498604</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="vldlr-ch.REF.boycott.2009.1310">Boycott
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KM, Bonnemann
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C, Herz
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J, Neuert
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S, Beaulieu
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C, Scott
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JN, Venkatasubramanian
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A, Parboosingh
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JS. Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with mental retardation (dysequilibrium syndrome).
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J Child Neurol.
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2009;24:1310-5.
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|
[<a href="/pmc/articles/PMC2849979/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2849979</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19332571" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19332571</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="vldlr-ch.REF.boycott.2005.477">Boycott
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KM, Flavelle
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S, Bureau
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A, Glass
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HC, Fujiwara
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TM, Wirrell
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E, Davey
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K, Chudley
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AE, Scott
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JN, McLeod
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DR, Parboosingh
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JS. Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification.
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Am J Hum Genet.
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2005;77:477-83.
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[<a href="/pmc/articles/PMC1226212/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1226212</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16080122" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16080122</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="vldlr-ch.REF.giorgio.2016.1772">Giorgio
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E, Ciolfi
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A, Biamino
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E, Caputo
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V, Di Gregorio
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E, Belligni
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EF, Calcia
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A, Gaidolfi
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E, Bruselles
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A, Mancini
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C, Cavalieri
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S, Molinatto
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C, Cirillo Silengo
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M, Ferrero
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GB, Tartaglia
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M, Brusco
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A. Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: Two proof-of-concept examples.
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Am J Med Genet A.
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2016;170:1772-9.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/27108886" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27108886</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="vldlr-ch.REF.glass.2005.691">Glass
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HC, Boycott
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K, Adams
|
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C, Barlow
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K, Scott
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JN, Chudley
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AE, Fujiwara
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T, Morgan
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K, Wirrell
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E, McLeod
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D. Autosomal recessive cerebellar hypoplasia in the Hutterite population: a syndrome of nonprogressive cerebellar ataxia with mental retardation.
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Dev Med Child Neurol.
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2005;47:691-5.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/16174313" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16174313</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="vldlr-ch.REF.herz.2008.e25">Herz
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J, Boycott
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KM, Parboosingh
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JS. "Devolution" of bipedality.
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Proc Natl Acad Sci U S A.
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2008;105:E25.
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[<a href="/pmc/articles/PMC2396673/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2396673</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18487453" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18487453</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="vldlr-ch.REF.huang.2022.389">Huang
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SJ, Amendola
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LM, Sternen
|
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DL. Variation among DNA banking consent forms: points for clinicians to bank on.
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J Community Genet.
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2022;13:389-97.
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[<a href="/pmc/articles/PMC9314484/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9314484</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35834113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35834113</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="vldlr-ch.REF.kolb.2010.319">Kolb
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LE, Arlier
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Z, Yalcinkaya
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C, Ozturk
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AK, Moliterno
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JA, Erturk
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O, Bayrakli
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F, Korkmaz
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B, DiLuna
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ML, Yasuno
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[<a href="https://pubmed.ncbi.nlm.nih.gov/31261436" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31261436</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK1874_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Kym M Boycott</span>, PhD, MD<div class="affiliation small">Department of Genetics<br />Children's Hospital of Eastern Ontario<br />Professor of Pediatrics<br />University of Ottawa<br />Ottawa, Ontario, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.no.oehc@ttocyobk" class="oemail">ac.no.oehc@ttocyobk</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Stella K MacDonald</span>, BSc<div class="affiliation small">Clinical Research Associate, Department of Genetics<br />Children's Hospital of Eastern Ontario<br />Ottawa, Ontario, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.no.oehc@dlanodcams" class="oemail">ac.no.oehc@dlanodcams</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Jillian S Parboosingh</span>, PhD<div class="affiliation small">Molecular Diagnostic Laboratory<br />Alberta Children's Hospital<br />Associate Professor of Medical Genetics<br />University of Calgary<br />Calgary, Alberta, Canada<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ac.sbalnoisicerpatrebla@hgnisoobrap.naillij" class="oemail">ac.sbalnoisicerpatrebla@hgnisoobrap.naillij</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">August 26, 2008</span>; Last Update: <span itemprop="dateModified">February 27, 2020</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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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>Boycott KM, MacDonald SK, Parboosingh JS. VLDLR Cerebellar Hypoplasia. 2008 Aug 26 [Updated 2020 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/wagner/?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/chac/?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="figobvldlrchTmoleculargenetictestinguse"><div id="vldlr-ch.T.molecular_genetic_testing_use" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.molecular_genetic_testing_use/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.molecular_genetic_testing_use_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vldlr-ch.T.molecular_genetic_testing_use_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_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>VLDLR</i>
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</td><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">85% <sup>4</sup></td></tr><tr><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_vldlr-ch.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15% <sup>4</sup></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="vldlr-ch.TF.1.1"><p class="no_margin">See <a href="/books/NBK1874/?report=reader#vldlr-ch.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="vldlr-ch.TF.1.2"><p class="no_margin">See <a href="#vldlr-ch.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="vldlr-ch.TF.1.3"><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>4. </dt><dd><div id="vldlr-ch.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#vldlr-ch.REF.stenson.2020.1197" rid="vldlr-ch.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="vldlr-ch.TF.1.5"><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.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobvldlrchTfeaturesofvldlrcerebellar"><div id="vldlr-ch.T.features_of_vldlr_cerebellar" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Features of <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.features_of_vldlr_cerebellar/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.features_of_vldlr_cerebellar_lrgtbl__"><table><thead><tr><th id="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Number (%) of Persons w/Feature</th><th id="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_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_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar hypoplasia</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">44/44 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pontine hypoplasia</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">36/44 (81.8%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Simplified cortical gyration</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">43/44 (97.7%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar ataxia</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">53/53 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predominantly truncal; peripheral ataxia reported in some</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hypotonia</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">28/37 (75.7%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysarthria</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">34/42 (81.0%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nystagmus</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11/47 (23.4%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strabismus</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">40/51 (78.4%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cognitive impairment</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">53/53 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Moderate to profound</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental delay</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">53/53 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Delayed ambulation</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">53/53 (100%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Independent ambulation (if achieved) often in mid-childhood.</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Epilepsy</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7/53 (13.2%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brisk reflexes</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">31/40 (77.5%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Microcephaly</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">8/38 (21.1%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Head circumference -2SD to -4SD</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dysmorphism</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1/53 (1.89%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May not be related to <i>VLDLR</i>-CH</td></tr><tr><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Short stature</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19/42 (45.2%)</td><td headers="hd_h_vldlr-ch.T.features_of_vldlr_cerebellar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobvldlrchTgenesanddisordersofintere"><div id="vldlr-ch.T.genes_and_disorders_of_intere" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Genes and Disorders of Interest in the Differential Diagnosis of <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.genes_and_disorders_of_intere/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.genes_and_disorders_of_intere_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Brain Imaging</th><th id="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic Findings</th></tr></thead><tbody><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>AHI1</i><br /><i>CPLANE1</i><br /><i>CC2D2A</i><br /><i>CEP290</i><br />(~34 genes) <sup>1</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/joubert/?report=reader">Joubert syndrome & related disorders</a> <sup>2</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">"Molar tooth sign" (hypoplasia of cerebellar vermis & assoc brain stem abnormalities resembling a tooth)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>DD & severe cognitive impairment (in some individuals)</div></li><li class="half_rhythm"><div>Episodic hyperpnea or apnea &/or atypical eye movements</div></li><li class="half_rhythm"><div>Truncal ataxia</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>ALG1</i><br /><i>ALG6</i><br /><i>PMM2</i><br />(~42 genes) <sup>3</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/cdg/?report=reader">Congenital disorders of glycosylation</a>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar atrophy</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>DD/ID</div></li><li class="half_rhythm"><div>Hypotonia & ataxia</div></li><li class="half_rhythm"><div>Strabismus</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ATCAY</i>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cayman-type cerebellar ataxia (OMIM <a href="http://omim.org/entry/601238" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">601238</a>) <sup>4</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CH</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cerebellar ataxia w/wide-based gait</div></li><li class="half_rhythm"><div>Dysarthria</div></li><li class="half_rhythm"><div>Intention tremor</div></li><li class="half_rhythm"><div>DD/ID</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ATM</i>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/ataxia-telangiectas/?report=reader">Ataxia-telangiectasia</a> <sup>5</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar atrophy (may not be obvious in very young individuals)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Choreoathetosis</div></li><li class="half_rhythm"><div>Oculomotor apraxia</div></li><li class="half_rhythm"><div>Progressive cerebellar ataxia beginning at ages 1-4 yrs</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ATP8A2</i>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CAMRQ4 (OMIM <a href="https://omim.org/entry/615268" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615268</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar atrophy</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital cerebellar ataxia</div></li><li class="half_rhythm"><div>ID</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CA8</i>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CAMRQ3 (OMIM <a href="https://omim.org/entry/613227" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">613227</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital cerebellar ataxia</div></li><li class="half_rhythm"><div>ID</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>EXOSC3</i><br /><i>RARS2</i><br /><i>SEPSECS</i><br /><i>TSEN2</i><br /><i>TSEN34</i><br /><i>TSEN54</i><br /><i>VRK1</i> <sup>6</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PCH types 1 & 2 (see <a href="/books/n/gene/exosc3-pc-hypo-p/?report=reader"><i>EXOSC3</i>-PCH</a> & <a href="/books/n/gene/pc-hypo-p/?report=reader"><i>TSEN54</i>-PCH</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar vermis hypoplasia & hypoplasia of the pons (more severe than small pons seen in <i>VLDLR</i>-CH)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Progressive motor degeneration (similar to <a href="/books/n/gene/sma/?report=reader">spinal muscular atrophy</a>) in PCH1</div></li><li class="half_rhythm"><div>Dyskinesia in PCH2</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>RELN</i>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>RELN</i> lissencephaly w/CH <sup>7</sup> (OMIM <a href="https://omim.org/entry/257320" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">257320</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar signs of <i>RELN</i>-LCH that differ from <i>VLDLR</i>-CH:<br />More significant lissencephaly w/anterior>posterior gradient<br />A malformed hippocampus<br />Profound CH w/complete absence of detectable folia</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital cerebellar ataxia</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>ID</div></li><li class="half_rhythm"><div>Epilepsy</div></li><li class="half_rhythm"><div>Strabismus</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SACS</i>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/arsacs/?report=reader">ARSACS</a> (<i>a</i>utosomal <i>r</i>ecessive <i>s</i>pastic <i>a</i>taxia of <i>C</i>harlevoix-<i>S</i>aguenay)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Atrophy of superior vermis</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Distal muscle wasting</div></li><li class="half_rhythm"><div>Distal sensorimotor neuropathy (predominant in legs)</div></li><li class="half_rhythm"><div>Dysarthria</div></li><li class="half_rhythm"><div>Early-onset ataxia</div></li><li class="half_rhythm"><div>Extensor plantar reflexes</div></li><li class="half_rhythm"><div>Horizontal gaze-evoked nystagmus</div></li><li class="half_rhythm"><div>Spasticity</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SIL1</i>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/mss/?report=reader">Marinesco-Sjögren syndrome</a> <sup>8</sup></td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cerebellar atrophy</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cerebellar ataxia</div></li><li class="half_rhythm"><div>Mild-to-severe cognitive impairment</div></li><li class="half_rhythm"><div>Hypotonia & muscle weakness</div></li></ul>
|
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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|
<i>TWNK</i>
|
|
</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Infantile-onset spinocerebellar ataxia <sup>9</sup> (OMIM <a href="https://omim.org/entry/271245" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">271245</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Atrophy of cerebellum, brain stem, & spinal cord</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Normal development until age 1 yr, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, athetosis, ophthalmoplegia, & sensorineural deafness in childhood <sup>10</sup></div></li><li class="half_rhythm"><div>Epilepsy can → serious & often fatal encephalopathy.</div></li></ul>
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|
</td></tr><tr><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>WDR81</i>
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</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CAMRQ2 (OMIM <a href="https://omim.org/entry/610185" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">610185</a>)</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CH</td><td headers="hd_h_vldlr-ch.T.genes_and_disorders_of_intere_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Congenital cerebellar ataxia</div></li><li class="half_rhythm"><div>ID</div></li></ul>
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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><p class="no_margin">CAMRQ = cerebellar ataxia, mental retardation, and dysequilibrium syndrome; CDG = congenital disorder of glycosylation; CH = cerebellar hypoplasia; DD = developmental delay; ID = intellectual disability; LCH = lissencephaly with cerebellar hypoplasia; PCH = pontocerebellar hypoplasia</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="vldlr-ch.TF.3.1"><p class="no_margin">To date, pathogenic variants in 34 genes are known to cause Joubert syndrome. <i>AHI1</i>, <i>CPLANE1</i>, <i>CC2D2A</i>, and <i>CEP290</i> are some of the most commonly involved genes.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="vldlr-ch.TF.3.2"><p class="no_margin">Variable features include: retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="vldlr-ch.TF.3.3"><p class="no_margin"><i>PMM2-</i>CDG (CDG-Ia), <i>ALG6-</i>CDG (CDG-Ic), and <i>ALG1</i>-CDG (CDG-Ik) represent some of the more frequently identified CDG types. Forty-two different enzymes in the N-linked oligosaccharide synthetic pathway or interactive pathways are currently recognized to be deficient in each of the types of CDG-N-linked or among the multiple-pathway disorders (see <a href="/books/n/gene/cdg/?report=reader">Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview</a>).</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="vldlr-ch.TF.3.4"><p class="no_margin">Affected individuals are from a Grand Cayman Island isolate.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="vldlr-ch.TF.3.5"><p class="no_margin">Also characterized by immunodeficiency, frequent infections, telangiectasias of the conjunctivae, and increased risk for malignancy (particularly leukemia and lymphoma)</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="vldlr-ch.TF.3.6"><p class="no_margin">About 50% of individuals with pontocerebellar hypoplasia type 1 (PCH1) have pathogenic variants in <i>EXOSC3</i>. See <a href="http://omim.org/phenotypicSeries/PS607596" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Pontocerebellar hypoplasia: OMIM Phenotypic Series</a> for other genes associated with PCH in OMIM.</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="vldlr-ch.TF.3.7"><p class="no_margin">The presentation of lissencephalies with cerebellar hypoplasia (LCH) ranges from the classic pattern of pachygyria/agyria to less severe phenotypes. The cerebellar manifestations range from relatively preserved hemispheres to marked hypoplasia with foliation defects. The malformations seen in VLDLR-CH fall within the LCH spectrum. Forms of LCH other than <i>RELN</i>-LCH are easily distinguished from VLDLR-CH based on the severity of the cortical phenotype or additional features.</p></div></dd></dl><dl class="bkr_refwrap"><dt>8. </dt><dd><div id="vldlr-ch.TF.3.8"><p class="no_margin">Also characterized by early-onset cataracts</p></div></dd></dl><dl class="bkr_refwrap"><dt>9. </dt><dd><div id="vldlr-ch.TF.3.9"><p class="no_margin">Infantile-onset spinocerebellar ataxia is well recognized in Finland.</p></div></dd></dl><dl class="bkr_refwrap"><dt>10. </dt><dd><div id="vldlr-ch.TF.3.10"><p class="no_margin">By adolescence affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobvldlrchTrecommendedevaluationsfollo"><div id="vldlr-ch.T.recommended_evaluations_follo" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.recommended_evaluations_follo/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.recommended_evaluations_follo_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vldlr-ch.T.recommended_evaluations_follo_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_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Brain MRI</div></li><li class="half_rhythm"><div>Consider EEG if seizures are a concern.</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Developmental</b>
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</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adaptive, cognitive, & speech-language eval</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Musculoskeletal</b>
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</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedics / physical medicine & rehab / PT & OT eval</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl assessment of:
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<ul><li class="half_rhythm"><div>Mobility, activities of daily living, & need for adaptive devices;</div></li><li class="half_rhythm"><div>Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);</div></li></ul>
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</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Eyes</b>
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</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for strabismus</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Miscellaneous/</b>
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<br />
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<b>Other</b>
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</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl genetic counseling & reproductive options</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Family support/resources</td><td headers="hd_h_vldlr-ch.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>School support</div></li><li class="half_rhythm"><div>Community support</div></li></ul>
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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><p class="no_margin">OT = occupational therapy; PT = physical therapy</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobvldlrchTrecommendedsurveillancefor"><div id="vldlr-ch.T.recommended_surveillance_for" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with <i>VLDLR</i> Cerebellar Hypoplasia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.recommended_surveillance_for/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.recommended_surveillance_for_lrgtbl__"><table><thead><tr><th id="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_vldlr-ch.T.recommended_surveillance_for_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_vldlr-ch.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Seizures</b>
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</td><td headers="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic evaluation</td><td headers="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cerebellar ataxia</b>
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</td><td headers="hd_h_vldlr-ch.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rehabilitation evaluation</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobvldlrchmolgenTA"><div id="vldlr-ch.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>VLDLR Cerebellar Hypoplasia: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_vldlr-ch.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_vldlr-ch.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/7436" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>VLDLR</i>
|
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</a>
|
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</td><td headers="hd_b_vldlr-ch.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=7436" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">9p24<wbr style="display:inline-block"></wbr>​.2</a>
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</td><td headers="hd_b_vldlr-ch.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/P98155" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Very low-density lipoprotein receptor</a>
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</td><td headers="hd_b_vldlr-ch.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://databases.lovd.nl/shared/genes/VLDLR" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VLDLR database</a>
|
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</td><td headers="hd_b_vldlr-ch.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=VLDLR" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VLDLR</a>
|
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</td><td headers="hd_b_vldlr-ch.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=VLDLR[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">VLDLR</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="vldlr-ch.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="figobvldlrchmolgenTB"><div id="vldlr-ch.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for VLDLR Cerebellar Hypoplasia (<a href="/omim/192977,224050" 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/NBK1874/table/vldlr-ch.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.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/192977" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">192977</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VERY LOW DENSITY LIPOPROTEIN RECEPTOR; VLDLR</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/224050" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">224050</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CEREBELLAR ATAXIA, IMPAIRED INTELLECTUAL DEVELOPMENT, AND DYSEQUILIBRIUM SYNDROME 1; CAMRQ1</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobvldlrchTnotablevldlrpathogenicvari"><div id="vldlr-ch.T.notable_vldlr_pathogenic_vari" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Notable <i>VLDLR</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1874/table/vldlr-ch.T.notable_vldlr_pathogenic_vari/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__vldlr-ch.T.notable_vldlr_pathogenic_vari_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NC_000009" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NC<wbr style="display:inline-block"></wbr>​_000009</a>
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</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">g.2479657_2678818del</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Entire gene deletion</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hutterite founder variant [<a class="bibr" href="#vldlr-ch.REF.boycott.2005.477" rid="vldlr-ch.REF.boycott.2005.477">Boycott et al 2005</a>]</td></tr><tr><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_1" scope="row" 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_003383" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM<wbr style="display:inline-block"></wbr>​_003383</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_003374.3" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_003374<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1256G>A</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Cys419Tyr</td><td headers="hd_h_vldlr-ch.T.notable_vldlr_pathogenic_vari_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Person reported w/less severe phenotype, predicted due to pathogenic variant in a less essential domain (EGF-B) [<a class="bibr" href="#vldlr-ch.REF.micalizzi.2016.191" rid="vldlr-ch.REF.micalizzi.2016.191">Micalizzi et al 2016</a>]</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></div></div></div></article><article data-type="fig" id="figobvldlrchF1"><div id="vldlr-ch.F1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK1874/bin/vldlr-ch-Image001.jpg" alt="Figure 1. " /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>MRI of the brain demonstrating typical neuroimaging findings of VLDLR-CH</p><p>A. Sagittal T<sub>1</sub>-weighted</p><p>B. Coronal T<sub>2</sub>-weighted images demonstrating hypoplasia of the inferior vermis and cerebellar hemispheres</p><p>C. Axial T<sub>1</sub>-weighted image demonstrating simplification of cortical gyri, a mildly thickened cerebral cortex and lack of clear anteroposterior gradient</p></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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