Clinical reportDYRK1A mutations in two unrelated patients
Introduction
The Dual-specify tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene is located on chromosome 21q22.2 and the role of its product, the DYRK1A protein, in neuronal progenitor proliferation and neuronal differentiation is a growing field of research. It has been involved in the pathogenesis of Alzheimer's disease [Ryoo et al., 2007], Parkinson's disease [Kim et al., 2006] and Huntington disease [Kang et al., 2005], as well as in the intellectual disability (ID) of patients with Down syndrome [García-Cerro et al., 2014]. The crucial role of DYRK1A in cerebral development has been further highlighted by the report of patients with cognitive impairment since infancy related to deletions or mutations within the gene (MIM #614104).
To date, 11 patients with developmental delay/ID or autism spectrum disorder (ASD) and de novo heterozygous genetic aberrations in DYRK1A have been clinically well described (Table 1). Two of them harbored partial deletions of DYRK1A identified by array-CGH (aCGH) [Courcet et al., 2012, Van Bon et al., 2011], two carried a balanced translocation inducing DYRK1A truncation [Møller et al., 2008] and seven carried frameshift, nonsense or splice site mutations identified by targeted [Courcet et al., 2012] or next generation sequencing (NGS) [Okamoto et al., 2014, O'Roak et al., 2012, Redin et al., 2014]. Six more patients with a “neurological phenotype” were reported but not described [Yang et al., 2014]. We report on two patients with de novo DYRK1A mutations, including the first described patient harboring a missense mutation, to delineate the phenotype of the DYRK1A-associated developmental disorder (Table 2).
Section snippets
Description of patients
Patient #1 was the first child of healthy nonconsanguineous French parents. His mother had a miscarriage. His paternal grandfather has retinitis pigmentosa. He was born after an uneventful pregnancy at 33 weeks by vacuum-assisted delivery after a premature rupture of membranes. Birth weight was 1700 g (−1 SD), birth length 41.8 cm (−1 SD) and occipito-frontal circumference (OFC) 30.5 cm (mean). During the first months of life, he had congenital torticollis, sucking-swallowing difficulties
Methods and results
In Patient #1, a panel of 150 genes involved in epilepsy with or without ID has been sequenced by NGS (Life Tech technology: Ampli-seq® and Ion proton®) and showed the heterozygous nonsense c.613C >T (p.Arg205*) DYRK1A mutation (NM_001396.3). The presence of the mutation was further confirmed by Sanger sequencing but was not found in the patient's parents. This mutation has already been reported [Redin et al., 2014].
In Patient #2, NGS analysis using the TruSight One panel (Illumina) disclosed
Discussion
The involvement of DYRK1A in the ID of patients with Down syndrome brought the attention of many researchers on its role in brain development [Song et al., 1996]. The products of DYRK1A and its orthologs are expressed during different neurodevelopmental phases in invertebrates and vertebrates and appear as key elements in neuronal development [Dierssen and de Lagrán, 2006, Hämmerle et al., 2008]. The phenotype of Dyrk1a-deficient mice includes a decreased neonatal viability, significant body
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