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.
|Titolo:||Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID|
|Data di pubblicazione:||2015|
|Citazione:||Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID / B W M van Bon; B P Coe; R Bernier; C Green; J Gerdts; K Witherspoon; T Kleefstra; M H Willemsen; R Kumar; P Bosco; Fichera M; D Li; D Amaral; F Cristofoli; H Peeters; E Haan; C Romano; H C Mefford; I Scheffer; J Gecz; B B A de Vries and E E Eichler. - (2015).|
|Appare nelle tipologie:||1.1 Articolo in rivista|