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

Abstract

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have 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 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 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 with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was 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.

Figure 1

a) Characteristic facial features can be noted in SSC12099, Troina1818, UMCN1, GF2852, UMCN2, and Leuven 306636. During infancy and childhood, the face is characterized by deep-set eyes, mild upslanting palpebral fissures, a short nose with a broad tip, and a retrognathic but prominent chin. In adulthood, the nasal bridge becomes high and the alae nasi short, giving the nose a more prominent appearance. If the facial gestalt is not clearly visible in childhood, it may still develop in adulthood (Supplementary Figure 1B). b) RefSeq DYRK1A splice isoforms examined in this study. Resequencing covered all coding exons (3 to 13). An asterisk indicates alternatively spliced exon variants. c) Diagram of the largest protein isoform (RefSeq: NM_101396.3, UniProt: Q13627). Truncating variants are listed in purple. Splice variants are on the bottom, referenced by their cDNA effect for in frame exon loss (blue, or black if not likely pathogenic) or likely protein effect. Previously published variants from Redin et al. and Courcet et al. are indicated in italics.^,