Ocular Phenotype Associated with DYRK1A Variants

Abstract

Dual-specificity tyrosine phosphorylation-regulated kinase 1A or DYRK1A, contributes to central nervous system development in a dose-sensitive manner. Triallelic DYRK1A is implicated in the neuropathology of Down syndrome, whereas haploinsufficiency causes the rare DYRK1A-related intellectual disability syndrome (also known as mental retardation 7). It is characterised by intellectual disability, autism spectrum disorder and microcephaly with a typical facial gestalt. Preclinical studies elucidate a role for DYRK1A in eye development and case studies have reported associated ocular pathology. In this study families of the DYRK1A Syndrome International Association were asked to self-report any co-existing ocular abnormalities. Twenty-six patients responded but only 14 had molecular confirmation of a DYRK1A pathogenic variant. A further nineteen patients from the UK Genomics England 100,000 Genomes Project were identified and combined with 112 patients reported in the literature for further analysis. Ninety out of 145 patients (62.1%) with heterozygous DYRK1A variants revealed ocular features, these ranged from optic nerve hypoplasia (13%, 12/90), refractive error (35.6%, 32/90) and strabismus (21.1%, 19/90). Patients with DYRK1A variants should be referred to ophthalmology as part of their management care pathway to prevent amblyopia in children and reduce visual comorbidity, which may further impact on learning, behaviour, and quality of life.

High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways

“…Both mutants show decreased daytime activity, while only scn1lab mutants exhibit night-time hyperactivity ( Figures 2D and 2E ). These behaviors likely reflect conserved roles of these genes, given the association of human mutations in DYRK1A with visual deficits 35 and SCN1A with increased sensitivity to visual stimuli 36 ; both genes have been associated with sleep disturbance in humans. 37 , 38 chd8 mutants display a highly specific phenotype of decreased daytime sleep length ( Figure 2F ), consistent with a conserved role of this gene in regulating sleep architecture in Drosophila and humans, 39 while tbr1 mutants exhibit daytime hyperactivity ( Figure 2G ).…”

Evaluation of Genetic Testing in a Cohort of Diverse Pediatric Patients in the United States with Congenital Cataracts

“…Only 2 of the 18 patients (11%) had a positive genetic diagnostic yield from microarray testing. Patient #3 had a deletion in chromosome 21, including the RUNX1 , DYRK1A , and KCNJ6 genes, classified as likely pathogenic as variants in DYRK1A have been associated with bilateral congenital cataracts [ 25 ]. Patient #1 had a deletion on chromosome 11, including PAX6 , which is a gene well-known to be associated with cataracts and other types of anterior segment dysgenesis.…”

<i>DYRK1A</i>-related intellectual disability syndrome: a cohort of Portuguese patients

“…About 500 families are part of the DYRK1A Syndrome International Association (DSIA). According to our acknowledge, there are around 112 patients reported in the literature 1,3,7,[12][13][14][15][16][17][18][19][20][21][22][23][24][25] of whom with chromosomal abnormalities, including large deletions, translocations, inversions, inversion/deletions, and other complex rearrangements, and 87 patients harboring a SNV. Most reported SNVs were frameshift variants, followed by nonsense, missense, and splice site variants 16 .…”

“…Core symptoms of DYRK1A-related ID syndrome (OMIM#614104) (also known as DYRK1A-haploinsufficiency syndrome or autosomal dominant mental retardation 7, MRD7) are ID with impaired speech development of variable degree, features of ASD with anxious and/or stereotypic behavior problems, microcephaly, and a recognizable facial gestalt that evolves with age 3,15 . Patients can also present with gait disturbance or hypertonia, epilepsy, brain-MRI anomalies, feeding issues, eye problems, and foot anomalies [15][16][17] Loss-of-function DYRK1A pathogenic variants include disruptive balanced rearrangements, copy number variants, and single nucleotide variants (SNVs) 16 . About 500 families are part of the DYRK1A Syndrome International Association (DSIA).…”