Intellectual Disability (Syndromic and Non-Syndromic) via the IQSEC2 Gene

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).

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.

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).

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.