X-Linked Intellectual Disability via the CLCN4 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9921 CLCN4 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9921CLCN481479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

18 days on average

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD). X-linked Intellectual Disability (XLID) contributes almost 10-15% of intellectual disability (ID) cases in males. Mental Retardation, X-linked 49, MRX49 (also known as MRX15) leads to borderline to profound intellectual disability, which can be both non-syndromic and syndromic. In syndromic forms, the affected individuals may present with additional features like poor or absent speech, congenital and progressive hypotonia, delayed psychomotor development, and slender build (Raynaud et al., 1996. PubMed ID: 8826458; Claes et al., 1997. PubMed ID: 9415477; Veeramah et al., 2013. PubMed ID: 23647072). Sometimes patients also suffer from eye and skeletal abnormalities, epileptic encephalopathy, seizures, cortical atrophy, behavioral problems, autism, mood disorders, obsessive-compulsive behaviors, hetero and auto aggression, dystonia, facial dysmorphism and microcephaly (Veeramah et al., 2013. PubMed ID: 23647072; Hu et al., 2016. PubMed ID: 25644381; Palmer et al., 2016. PubMed ID: 27550844). Heretozygous females can be asymptomatic or can develop mild intellectual disability and/or behavioral problems. Severely affected females have also been reported (Claes et al., 1997. PubMed ID: 9415477; Palmer et al., 2016. PubMed ID: 27550844).

Genetics

Pathogenic variants (familial and de novo) in human ‘Chloride Channel 4’ (CLCN4) have been reported in several cases with MRX49, a form of X-linked intellectual disability. CLCN4 maps to chromosome Xp22.3 and consists of 11 coding exons that encode a 760 amino acid polypeptide of electrogenic chloride/proton exchanger ClC-4 (CLCN4). This gene is a member of the CLCN family of voltage-dependent chloride channel genes that have significant sequence homology (Fisher et al., 1995. PubMed ID: 8575751). To date, a small frameshift deletion and missense variants have been reported, but there are no reports of any gross deletions/duplications that include CLCN4. Using in vivo mouse models, Hu et al. has shown that pathogenic variants in CLCN4 impair normal protein function (Hu et al., 2016. PubMed ID: 25644381). The disease transmission pattern is X-linked recessive as well as X-linked dominant (Palmer et al., 2016. PubMed ID: 27550844).

Clinical Sensitivity - Sequencing with CNV PG-Select

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al., 2016. PubMed ID: 26503795). Analytical sensitivity should be high because all pathogenic variants reported within this gene to date are detectable by sequencing.

Testing Strategy

This test provides full coverage of all coding exons of the CLCN4 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

This test is primarily implicated for patients with intellectual disabilities who are negative for any kind of cytogenetic abnormalities, copy number variations, Fragile-X syndrome and also for the family members of the patients who have known CLCN4 pathogenic variants. Prenatal diagnosis is possible, if the genetic diagnosis has been firmly established in an affected family member.

Gene

Official Gene Symbol OMIM ID
CLCN4 302910
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mental Retardation, X-linked 49 XL 300114

Citations

  • Claes et al., 1997. PubMed ID: 9415477
  • Fisher et al., 1995. PubMed ID: 8575751
  • Hu et al., 2016. PubMed ID: 25644381
  • Palmer et al., 2016. PubMed ID: 27550844
  • Raynaud et al., 1996. PubMed ID: 8826458
  • Veeramah et al., 2013. PubMed ID: 23647072
  • Vissers et al., 2016. PubMed ID: 26503795

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

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