X-linked Intellectual Disability via the IL1RAPL1 Gene

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 ID cases in males.

Mental Retardation X-linked 21, MRX21 (also known as MRX34) is a form of ID, which can be both nonsyndromic and syndromic (Nawara et al. 2008. PubMed ID: 19012350; des Portes et al. 1998. PubMed ID: 9611075). The affected individuals present with variable features that may include (but may not be limited to) delayed psychomotor development, intellectual disability, hypotonia, seizures, strabismus, pectus excavatum, skin pigmentation abnormalities, hyperextensible joints, behavioral abnormalities including hyperactivity, impulsivity, oppositional disorder, depression, autism and mild facial dysmorphism such as elongated face, prominent jaw, synophrys, high nasal bridge, anteverted nostrils, high arched palate, and short philtrum (Kozák et al. 1993. PubMed ID: 8230164; Bhat et al. 2008. PubMed ID: 18005360; Franek et al. 2011. PubMed ID: 21484992). At least one affected female has been reported with autism and Asperger syndrome without any language delay (Kozák et al. 1993. PubMed ID: 8230164; Piton et al. 2008. PubMed ID: 18801879). Of note, carrier females can remain asymptomatic or develop mild intellectual disability and/or behavioral problems, suggesting incomplete penetrance in females (Kozák et al. 1993. PubMed ID: 8230164; Leprêtre et al. 2003. PubMed ID: 14610352, Tabolacci et al. 2006. PubMed ID: 16470793).

Pathogenic variants (familial and de novo) in human ‘Interleukin-1 Receptor Accessory Protein-like 1’ (IL1RAPL1) have been reported in several cases with MRX21, a form of X-linked intellectual disability. IL1RAPL1 maps to chromosome Xp21.3-p21.2 and consists of 10 coding exons that translate into a 696 amino acid polypeptide of the transmembrane protein IL1RAPL1. IL1RAPL1 consists of three extracellular immunoglobulin-like domains, an intracellular Toll/IL1R-related (TIR) domain and a C-terminal domain that interacts with neuronal calcium sensor-1 (NCS-1) protein (Tabolacci et al. 2006. PubMed ID: 16470793). IL1RAPL1 plays a role in the down-regulation of voltage-dependent calcium channels (VGCC), calcium-dependent exocytosis and NGF-induced neurite outgrowth in PC-12 cells (Piton et al. 2008. PubMed ID: 18801879). Although small deletions, missense and nonsense variants have been reported in human IL1RAPL1 gene, the majority of the pathogenic variants are gross deletions/duplications and complex rearrangements involving IL1RAPL1 (Human Gene Mutation Database; Carrié et al. 1999. PubMed ID: 10471494). 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 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 single nucleotide variants reported within this gene to date are detectable by sequencing.

To date, 29 gross deletions/duplications and complex rearrangements involving IL1RAPL1 have been reported (Human Gene Mutation Database). We expect the clinical sensitivity of this test to be <0.1% of ID cases.

This test provides full coverage of all coding exons of the IL1RAPL1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).