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Intellectual Disability (Syndromic and Non-Syndromic) via the IQSEC2 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
9845 IQSEC2 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9845IQSEC281479 81479,81479 $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.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Renee Bend, PhD

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, below 70). ID is diagnosed in ~1–3% of the population before 18 years of age. X-linked Intellectual Disability (XLID) contributes 10-15% of intellectual disability (ID) cases in males.

Mental Retardation, X-linked 1, MRX1 (also known as MRX18 or MRX78) can be clinically similar to the Rett-like syndrome and presented as both syndromic and non-syndromic forms. The affected males mostly display moderate to severe non-progressive intellectual disabilities that may be associated with psychomotor retardations (speech and movement disabilities), hypotonia, epileptic seizures, autistic traits, psychiatric problems, microcephaly, hypermetropia, and strabismus (Tran Mau-Them et al. 2014). Notably, carrier females in the MRX1 families are phenotypically diverse, mostly ranging from asymptomatic to mildly affected (mild ID, learning difficulties) (Zerem A. et al. 2016).

Genetics

Hemizygous and heterozygous pathogenic variants of ‘IQ motif and Sec7 domain-containing protein 2’ gene (IQSEC2) have been reported in multiple families with MRX1. IQSEC2 is a GDP-GTP exchange factor for the Arf family of GTPases (ArfGEF) and involved in neuronal development in the brain and excitatory synaptic transmission (synaptic plasticity) (Tran Mau-Them et al. 2014; Kalscheuer et al. 2016; Zerem A. et al. 2016). Loss-of-function variants of IQSEC2 significantly impair ARF6 (ADP ribosylation factor 6) activation, thereby probable alteration of the actin cytoskeleton dynamics and MRX1 (Ramakers 2002; Shoubridge et al. 2010).

IQSEC2 maps to chromosome Xp11.22 and consists of 15 exons that encode a 1488 amino acid polypeptide. IQSEC2, highly expressed in brain hippocampus, is clustered at the excitatory synapses (Zerem A. et al. 2016). Nonsense, missense and splice variants as well as small/large deletions/duplications, complex rearrangements have been described in IQSEC2. It has been speculated that IQSEC2 variants display a genotype-phenotype correlation, as protein truncating variants are often associated with severe syndromic IDs (Tran Mau-Them et al. 2014). Several de novo deleterious IQSEC2 variants have been reported in male and female patients with clinical features ranging from seizure disorders (Rett-like syndrome and Lennox-Gastaut syndrome) to severe IDs, associated with epilepsy and microcephaly (Shoubridge et al. 2010). Interestingly, the pedigrees of MRX1 families demonstrate a full penetrance in males, whereas some carrier females display mild ID phenotypes, sometimes associated with additional features (Zerem A. et al. 2016). This can possibly be explained by the fact that IQSEC2 can escape from X-inactivation, leading to the expression of both alleles in the females (Li et al. 2008). The disease transmission pattern is primarily X-linked recessive.

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 100 genes have been identified in individuals with X-linked intellectual disability (XLID), a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016). Analytical sensitivity should be high because the majority of pathogenic variants reported to date are detectable by sequencing.

To date, there are 5 reports of major gross deletions/duplications events that involve IQSEC2 and 2 of these events include additional genes. We expect the clinical sensitivity of this test to be low (i.e. <0.1% of ID cases).

Testing Strategy

This test provides full coverage of all coding exons of the IQSEC2 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 (X-linked) who are negative for any kind of cytogenetic abnormalities, copy number variations, Fragile-X syndrome, and also for family members of the patients who have IQSEC2 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
IQSEC2 300522
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mental Retardation, X-Linked 1/78 XL 309530

Citations

  • Kalscheuer V.M. et al. 2016. Frontiers in Molecular Neuroscience. 8: 85. PubMed ID: 26793055
  • Li N., Carrel L. 2008. Proceedings of the National Academy of Sciences of the United States of America. 105: 17055-60. PubMed ID: 18971342
  • Ramakers G.J. 2002. Trends in Neurosciences. 25: 191-9. PubMed ID: 11998687
  • Shoubridge C. et al. 2010. Nature Genetics. 42: 486-8. PubMed ID: 20473311
  • Tran Mau-Them F. et al. 2014. European Journal of Human Genetics. 22: 289-92. PubMed ID: 23674175
  • Vissers L.E. et al. 2016. Nature Reviews Genetics 17: 9-18. PubMed ID: 26503795
  • Zerem A. et al. 2016. Epilepsia. 57: 1858-1869. PubMed ID: 27665735

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

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

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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