A De Novo Mutation in DYRK1A Causes Syndromic Intellectual Disability: A Chinese Case Report

Abstract

Autosomal dominant mental retardation-7 (MRD7) is a rare anomaly, characterized by severe intellectual disability, feeding difficulties, behavior abnormalities, and distinctive facial features, including microcephaly, deep-set eyes, large simple ears, and a pointed or bulbous nasal tip. Some studies show that the disorder has a close correlation with variants in DYRK1A. Herein we described a Chinese girl presenting typical clinical features diagnosed at 4 years old. Whole-exome sequencing of the familial genomic DNA identified a novel mutation c.930C > A (p.Tyr310*) in exon 7 of DYRK1A in the proband. The nonsense mutation was predicted to render the truncation of the protein. Our results suggested that the de novo heterozygous mutation in DYRK1A was responsible for the MRD7 in this Chinese family, which both extended the knowledge of mutation spectrum in MRD7 patients and highlighted the clinical application of exome sequencing.

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

“…Few years after, the first frameshift variant was described in a patient with similar features (Courcet et al , 2012). The clinical spectrum associated with DYRK1A pathogenic variants ( MRD7 for Mental Retardation 7 in OMIM ) was further refined with the publication of additional patients, presenting suggestive facial dysmorphism, severe speech impairment and feeding difficulty, while epilepsy and prenatal microcephaly were not always present (Bronicki et al , 2015; Blackburn et al , 2019a; van Bon et al , 2011, 2016; O’Roak et al , 2012; Courcet et al , 2012; Okamoto et al , 2015; Iglesias et al , 2014; Ruaud et al , 2015; Ji et al , 2015; Rump et al , 2016; Luco et al , 2016; Murray et al , 2017; Evers et al , 2017; Lee et al , 2020a; Dang et al , 2018; Qiao et al , 2019; Ernst et al , 2020; Tran et al , 2020; Møller et al , 2008; Fujita et al , 2010; Oegema et al , 2010; Yamamoto et al , 2011; Valetto et al , 2012; Kim et al , 2017; Meissner et al , 2020; Matsumoto et al , 1997). Pathogenic variants were also identified in cohorts of individuals with ASD (O’Roak et al , 2012), but all have ID (Earl et al , 2017).…”

Clinical course of epilepsy and white matter abnormality linked to a novel DYRK1A variant

“…1 ). This variant is novel, but the same amino acid change (c.957C>A, p.Tyr319*) has previously been reported in DYRK1A -related intellectual disability syndrome [ 5 ]. Based on the ACMG/AMP guidelines, this variant was rated as pathogenic [ 6 ].…”

“…The pathogenesis of white matter lesions in patients with pathogenic DYRK1A variants is unknown. The correlation between genotype and white matter abnormality is unknown in this disorder, and case with a different variant causing the same amino acid change did not show white matter abnormality [ 5 ].…”

Ocular Phenotype Associated with DYRK1A Variants

“…Ocular features were reported in 59.8% of cases (67/112), were declared absent in 15.2% (17/112), and not reported in 25% of cases (28/112). As with patients from the UK Genomics England 100,000 Genomes Project, numerous ocular phenotypes were ambiguous [ 19 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 32 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ].…”

“…There were 112 patients reported in the literature with either chromosome 21 heterozygosity, or specific disease-causing variants involving DYRK1A [19,20,[22][23][24][25][26][27][28][29][30]32,[39][40][41][42][43][44][45][46][47][48][49][50]. Chromosomal abnormalities were reported in 25 patients and included large deletions, translocations, inversions, inversion/deletions and complex defects.…”