Syndromic Intellectual Disability/Autism Spectrum Disorder via the DYRK1A Gene

Autism Spectrum Disorders (ASD) encompass several neurodevelopmental disorders characterized by varying degrees of social impairment, communication ability, and propensity for restricted interests and repetitive behavior(s) which usually present by age 3. Diagnosis is based on the degree and severity of symptoms and behaviors (Diagnostic and Statistical Manual of Mental Disorders (DSM-5); Levy et al., 2009. PubMed ID: 19819542; McPartland et al., 2016.). Comorbidities occur in more than 70% of cases and include intellectual disability (ID), epilepsy, language deficits, and gastrointestinal problems (Sztainberg & Zoghbi 2016. PubMed ID: 27786181). ID specifically 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 (Kaufman et al., 2010. PubMed ID: 21124998; Vissers et al., 2016. PubMed ID: 26503795).

Variants impacting the DYRK1A gene have been implicated in a syndromic form of ID and ASD characterized by moderate to severe ID (100%), absent or delayed speech (100%), primary or acquired microcephaly (100%), feeding difficulties (~93%), and seizures (87.5%). Additional clinical features such as a thin upper lip (~87%), deep-set eyes with full/hooded upper lids (86%), stereotypies (80%), hyperopia/myopia (~78%), micrognathia (~71%), and uncoordinated movement (75%) allow for distinction from other disorders that share the same cardinal features (Bronicki et al., 2015. PubMed ID: 25920557). Short stature, skeletal issues, gait abnormalities, constipation, gastroesophageal reflux, pyloric stenosis, tapered fingers, and brain abnormalities including hypoplastic pituitary stalk and corpus callosum, white matter hypomyelination, frontal lobe and cortical atrophy, gliosis, and thin optic chiasm have also been reported (Ji et al., 2015. PubMed ID: 25944381).

DYRK1A (dual-specificity tyrosine-phosphorylation-regulated kinase, DYRK) is a DYRK kinase protein that is 763 amino acids in length. All DYRK kinase proteins contain a catalytic kinase domain (residues 159-479 in DYRK1A) and a DYRK homology box. DYRK1A specifically includes two nuclear localization signals, a PEST domain, a speckle-targeting signal, and histidine, serine/threonine repeat domains. DYRK1A is located on chromosome 21 within the Down’s syndrome critical region (DSCR) that, when triplicated, results in Down’s syndrome features (Evers et al., 2017. PubMed ID: 28053047). It is widely expressed in the developing nervous system, and dosage is strictly regulated as both overexpression and haploinsufficiency adversely impact neurite length and axonal outgrowth (Dang et al., 2017. PubMed ID: 28167836).

DYRK1A pathogenic variants are almost exclusively de novo and result in syndromic ID and ASD phenotypes in an autosomal dominant manner. Comparisons of variants identified in affected individuals with apparently benign DYRK1A variants identified in population databases have revealed that pathogenic variants tend to occur before the C-terminal end of the kinase domain (residue 479), whereas variants identified in population databases occur before the first N-terminal nuclear localization signal or after the kinase domain. Genotype-phenotype correlations have been suggested as more severe phenotypes are associated with variants in close proximity to the catalytic loop or substrate binding site of the kinase domain (Evers et al., 2017. PubMed ID: 28053047).

Currently, the contribution of de novo and inherited factors to Autism Spectrum Disorders (ASD) risk is estimated to be approximately 50-60% (Krumm et al., 2015. PubMed ID: 25961944) and 25-50% for intellectual disability (ID), with the percentage increasing proportionately with phenotypic severity (McLaren & Bryson 1987. PubMed ID: 3322329). DYRK1A is classified in the Simons Foundation Autism Research Initiative (SFARI) Database as a ‘high confidence, syndromic’ gene candidate regarding ASD risk (https://gene.sfari.org/database/human-gene/DYRK1A). However, more than 700 genes total have been associated with ASD features (Bourgeron 2016. PubMed ID: 27289453). A recent report has suggested that de novo loss of function variants within DYRK1A account for 0.5% of syndromic intellectual disability cases (Evers et al., 2017. PubMed ID: 28053047) with well over 100 de novo heterozygous nonsense, frameshift, splice-altering, and chromosomal rearrangements being described in the literature (Dang et al., 2017. PubMed ID: 28167836).

Overall, de novo copy number variants (CNVs) are estimated to account for approximately 6% of ASD risk (Lim et al., 2013. PubMed ID: 23352160). The contribution of DYRK1A CNVs specifically is unclear; however, DYRK1A resides in the Down syndrome critical region (DSCR) in which numerous deletions and duplications have been reported. Most microdeletions in this region encompass multiple genes, but all include the entire DYRK1A gene. Chromosomal translocations and deletions encompassing only the 5’UTR region of DYRK1A have also been reported in affected individuals (Ji et al., 2015. PubMed ID: 25944381).

This test provides full coverage of all coding exons of the DYRK1A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.