Autism Spectrum Disorders/Intellectual Disability via the MED13 Gene

Autism spectrum disorder (ASD) and intellectual disability (ID) are heterogeneous groups of neurodevelopmental disorders. ASD is characterized by varying degrees of social impairment, communication ability, propensity for repetitive behavior(s), and restricted interests (Levy et al. 2009. PubMed ID: 19819542); whereas ID refers to significant impairment of cognitive and adaptive development (intelligence quotient, IQ<70) due to abnormalities of brain structure and/or function (American Association of Intellectual and Developmental Disabilities, AAIDD). ID is not a single entity, but rather a general symptom of neurologic dysfunction that is diagnosed before age 18 in ~1%-3% of the population, irrespective of social class and culture (Kaufman et al. 2010. PubMed ID: 21124998; Vissers et al. 2016. PubMed ID: 26503795). In contrast, ASD symptoms usually present by age 3, and diagnosis is based on the degree and severity of symptoms and behaviors (McPartland et al. 2016). ASDs and ID are highly comorbid, suggesting shared etiologies in many forms. For ASD specifically, comorbidities have been observed in more than 70% of cases, and include ID, epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi. 2016. PubMed ID: 27786181). Recent studies using whole exome trio studies have identified novel gene candidates, with familial and de novo variants from several hundred genes now implicated in the development of ASD and ID (Bourgeron. 2016. PubMed ID: 27289453).

Pathogenic variants in MED13 have been implicated in the development of ASD and ID phenotypes. All individuals present with developmental delay, intellectual disability, speech delay or speech anomalies of varying severity. The majority of patients also display gross motor development, and eye or vision anomalies. Dysmorphic features include widely spaced eyes, narrow palpebral fissures, broad/high nasal bridge, full nasal tip, synophrys, flat philtrum, thin upper lip, and wide mouth. Minor features include attention-deficit hyperactivity disorder, a formal diagnosis of ASD (~40%), delayed fine motor development, hypotonia, myoclonic epilepsy, Duane anomaly, strabismus, nystagmus, visual impairment, optic nerve abnormalities, hearing loss, heart defects, and chronic obstipation (Snijders Blok et al. 2018. PubMed ID: 29740699).

Genetic aberrations are reported to be responsible for 50%-90% and 15%-50% of ASD and ID cases, respectively. Inheritance overall is multifactorial (Larsen et al. 2016. PubMed ID: 27790361; Karam et al. 2015. PubMed ID: 25728503). Incidence of ASD is approximately 1 in 68 individuals with a male-to-female ratio of 4:1 (Centers for Disease Control and Prevention. 2014. PubMed ID: 24670961). De novo missense and likely gene disrupting variants are 15% and 75% more frequent in ASD patients than unaffected controls, respectively (Iossifov et al. 2014. PubMed ID: 25363768).

MED13 pathogenic variants result in ASD and ID symptoms in an autosomal dominant manner, as nearly all reported individuals are heterozygous for de novo missense or loss-of-function (nonsense, frameshift) variants. At least one report of an inherited MED13 nonsense variant from an affected parent has been documented in the literature.

The human MED13 gene contains 30 protein-coding exons which encode a 2,174 amino acid protein. The MED13 protein includes an N-terminal domain (residues 11-383) encoding a phosphodegron motif involved in protein degradation as well as a C-terminal domain (residue 1640-2163) with unspecified function. While phenotype-genotype correlations have not been reported, the majority or reported pathogenic variants cluster within the N- and C- terminal domains (Snijders Blok et al. 2018. PubMed ID: 29740699).

MED13 (mediator complex subunit 13) encodes a component of the CDK8 regulatory subunit of the Mediator complex. The Mediator complex is a necessary for the formation of the pre-initiation complex and stable RNA polymerase II-dependent transcriptional activity. MED13 degradation via ubiquitination is believed to be the mechanism by which CDK8-dependent Mediator activity is regulated within the cell (Snijders Blok et al. 2018. PubMed ID: 29740699). Disruption of Mediator and CDK8-regulatory protein subunits have also been implicated in other neurodevelopmental disorder phenotypes (Donnio et al. 2017. PubMed ID: 28369444; Vulto-van Silfhout et al. 2013. PubMed ID: 23395478).

Genetic variants have been found responsible in 25-50% of intellectual disability cases, and this percentage increases proportionally with the severity of the phenotype (McLaren and Bryson. 1987. PubMed ID: 3322329). For autism spectrum disorder (ASD), while heritability estimates have been reported as high as 90% (Bailey et al. 1995. PubMed ID: 7792363; Lichtenstein et al. 2010. PubMed ID: 20686188), only 20% of ASD cases can be explained to date using genetic approaches (Devlin and Scherer. 2012. PubMed ID: 22463983).

While MED13 is categorized as a gene with ‘syndromic, strong evidence’ regarding its association with ASD in the Simons Foundation Autism Research Initiative (SFARI) Database (https://gene.sfari.org/database/human-gene/MED13), no single gene has been reported to account for more than 1% of all ASD cases to date (Hoang et al. 2018. PubMed ID: 28803755). Furthermore, large cohort studies of individuals with neurodevelopmental phenotypes have implicated hundreds of genes (Larsen et al. 2016. PubMed ID: 27790361; Bourgeron. 2016. PubMed ID: 27289453). Therefore, the clinical sensitivity of any single gene test with regard to a neurodevelopmental phenotype is expected to be low (less than or equal to 1%).

This test provides full coverage of all coding exons of the MED13 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).