Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

Abstract

Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene are thought to play a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7,162 ASD/DD patients (2,446 previously reported) and 2,169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8,696 controls identified a significant enrichment of DYRK1A truncating mutations (p = 0.00851) and an excess of de novo mutations (p = 2.53×10−10) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n = 5) and recontacted (n = 3) cases to previous case reports, including larger CNV and translocation events (n = 7), identifies a syndromal disorder among the 15 patients. It is characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia, and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.

De novo genic mutations among a Chinese autism spectrum disorder cohort

“…In addition, the ADNP proband also has attention problems, and the DYRK1A proband reported febrile seizures in infancy, hypertonia, neonatal feeding problems and sleep disturbances. All of these phenotypes have been described before in association with DN mutation of these genes2627.…”

De Novo Genic Mutations Among a Chinese Autism Spectrum Disorder Cohort

“…proband reported febrile seizures in infancy, hypertonia, neonatal feeding problems and sleep disturbances. All of these phenotypes have been described before in association with DN mutation of these genes 26,27 . Several other novel comorbidities associated with CHD8, ADNP, POGZ, ARHGAP32, GRIN2B, ASH1L, NCKAP1, CHD2 and DSCAM are also recorded (Table 3).…”

The adaptor protein DCAF7 mediates the interaction of the adenovirus E1A oncoprotein with the protein kinases DYRK1A and HIPK2

“…Altered expression levels of DYRK1A, either due to heterozygous loss-of-function mutations or the presence of a third allele in Down syndrome, result in severe neurological alterations and impaired brain development in humans and mice56. DYRK1A belongs to a conserved family of protein kinases, which is comprised of 5 mammalian members that are further subdivided into either class 1 (including DYRK1A and DYRK1B) or class 2 DYRKs (DYRK2-4)4.…”