DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature

Abstract

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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).…”

Whole-Exome Sequencing Identified a Novel DYRK1A Variant in a Patient With Intellectual Developmental Disorder, Autosomal Dominant 7

“…MRD7 has facial features such as prominent ears, deep-set eyes, upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia. Given that the reported prevalence of MRD7 is less than 1/1,000,000 [1,2], which is rare compared to 1:10,000 to 30,000 for CdLS [9], it is not easy for nonexpert clinicians to differentiate these syndromes based on facial dysmorphisms. Therefore, Face2Gene helped us introduce candidate diseases for the patient.…”

“…The overexpression of DYRK1A produces intellectual disabilities in DS. Contrarily, haploinsufficiency of DYRK1A through a heterozygous chromosomal loss or intragenic variants causes MRD7 [ 7 , 8 ], suggesting that DYRK1A influences the cognitive function in a dose-dependent manner [ 2 ]. Herein, we report a case of MRD7 in whom Face2Gene introduced several genetic syndromes, including MRD7, as candidates.…”

“…Intellectual developmental disorder, autosomal dominant 7 (MRD7; OMIM 614104), also known as DYRK1A (haploinsufficiency) syndrome, is a rare autosomal dominant disease with a prevalence of less than 1/1,000,000 [1][2][3]. MRD7 is characterized by microcephaly, intellectual disability, speech delay, feeding difficulties, and distinct facial dysmorphisms, including prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia [1,4,5].…”

Case Report: Gut and spleen anomalies associated with DYRK1A syndrome

“…DYRK1A is a gene located on the critical region of chromosome 21q22 ( 1 ). It codifies for a dual-specificity tyrosine kinase, enrolled in the phosphorylation of serine and threonine residues ( 2 , 3 ) and tyrosine residues in their own loop ( 3 ). This protein is expressed in numerous systems and its role is pivotal, especially for neuronal differentiation, neurogenesis, and neurodegeneration ( 2 ) through MAP kinase activation.…”