Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature

Abstract

Background: Chromosomal deletions encompassing DYRK1A have been associated with intellectual disability for several years. More recently, point mutations in DYRK1A have been shown to be responsible for a recognizable syndrome characterized by microcephaly, developmental delay and intellectual disability (ID) as well as characteristic facial features. Here we present 2 individuals with novel mutations in DYRK1A, and a review of the cases reported to date.

Case presentation: Both individuals presented with the well-known characteristic features, as well as rarer anomalies seen in a minority of patients. Patient 1 presented shortly after birth with an enlarged cisterna magna, distal contractures, and distinctive facies that included bitemporal narrowing and deep set eyes. A de novo splice site mutation in DYRK1A [c.951 + 4_951 + 7delAGTA; p.Val222Aspfs*22] was identified by next generation sequencing. Patient 2 presented at 7 months of age with microcephaly and dysmorphic features. She went several years without a diagnosis until a de novo DYRK1A nonsense mutation [c.787C>T; p.(Arg263*)] was identified at age 12. These individuals, and the 52 cases reviewed from the literature, show the characteristic features of the DYRK1A-related syndrome including global developmental delay, ID, microcephaly, feeding difficulties, and the facial gestalt. Other common findings include seizures, vision defects, brain abnormalities and skeletal abnormalities of the hands and feet. Less common features include optic nerve defects, contractures, ataxia, and cardiac anomalies.

Conclusion: DYRK1A testing should be considered in individuals with the facial features, intellectual disability and post-natal microcephaly. Once diagnosed with DYRK1A-related intellectual disability, a cardiac and ophthalmologic assessment would be recommended as would routine surveillance by a pediatrician for psychomotor development, growth, and feeding.

Fig. 1

The characteristic facies of 2 individuals with DYRK1A mutation. a-b Patient 1 with bitemporal narrowing, down-slanted palpebral fissures, deep-set eyes and dysplastic ears. c MR Images in Patient 1 showing thin corpus callosum, enlarged cisterna magna and 4th ventricle. d distal contractures seen in Patient 1. e-g Patient 2 with with bitemporal narrowing, deep-set eyes and dysplastic ears

Fig. 2

a Schematic representation of the coding sequence of DYRK1A (NM_001396.3) showing the localization of the two de novo mutations identified in this study. b Agarose gel electrophoresis of the RT-PCR products from patient 1 (Pat 1) and a control individual (CTR). A fragment covering exons 5–8 was amplified by RT-PCR (yellow in a). The expected 528 bp PCR product was observed from both patient 1 and the control individual, whereas a smaller PCR product (~240 bp) was only detected in patient 1. A 100 bp ladder was used for reference. c Sequencing of both the wild type (WT) and mutant fragments from patient 1 showing the WT DYRK1A transcript sequence covering exons 6 and 7, and mutant DYRK1A transcript lacking exon 6, resulting in a frameshift and a premature stop codon 22 codons downstream

Fig. 3

a The DYRK1A coding sequence with the 5 reported splice site mutations. b The DYRK1A protein with the missense and nonsense mutations shown above, and the frameshift variants indicated below. The nuclear localization signal shown in red, the DYRK homology (DH) box shown in purple, the kinase domain shown in blue, and the speckle-targeting signal shown in green. Two mutations were identified in multiple individuals: p.Arg205* in 4 individuals and p.Glu208Asnfs*3 in 2 individuals