DYRK1A – DYRK1A-related intellectual disability syndrome

Heterozygous pathogenic variants in DYRK1A cause DYRK1A-related intellectual disability syndrome, a dominantly inherited neurodevelopmental disorder. Core clinical features include intellectual disability, microcephaly, speech impairment, feeding difficulties and characteristic facial dysmorphism. Ocular anomalies such as myopia and strabismus have also been reported, with the first description of albinism-like ocular findings in a 21-month-old female patient ([PMID:32838606]).

The disorder follows an autosomal dominant pattern with almost all cases arising from de novo DYRK1A variants. Across a cohort of 50 unrelated individuals, de novo truncating and missense mutations in DYRK1A were identified, establishing the mutation spectrum ([PMID:34345024]). In a large ocular phenotype survey of 145 molecularly confirmed patients, 62.1% displayed ocular manifestations ranging from optic nerve hypoplasia to refractive errors and strabismus, supporting the pleiotropic expressivity of the syndrome ([PMID:33562844]). Representative variants include c.95G>A (p.Gly32Glu) in a patient presenting with gut and spleen anomalies ([PMID:36741085]).

Segregation analysis is limited by the de novo occurrence of DYRK1A variants, with no reported multi-generational transmission. Family studies consistently demonstrate simplex cases, underscoring the dominant and highly penetrant nature of these mutations.

Functional studies corroborate haploinsufficiency as the mechanism of pathogenicity. Dyrk1a(+/−) mice exhibit growth delay, microcephaly and neurobehavioral deficits aligning with human phenotypes ([PMID:12192061]). A dyrk1aa knockout zebrafish model recapitulates social interaction impairments reminiscent of autism spectrum behaviors ([PMID:29021890]). In vitro assays of patient-derived missense variants show loss of kinase autophosphorylation and reduced catalytic activity for multiple substitutions (e.g., p.Leu286Phe), confirming deleterious effects on protein function ([PMID:29700199]).

No conflicting evidence has been reported disputing the link between DYRK1A haploinsufficiency and this syndromic intellectual disability. Variant interpretation tools and methylation signatures further refine pathogenicity assessments, enhancing diagnostic confidence.

Key Take-home: DYRK1A haploinsufficiency is a definitive cause of a syndromic neurodevelopmental disorder; genetic testing enables early diagnosis and tailored multidisciplinary management including neurodevelopmental, feeding, and ophthalmologic evaluations.

References

• Ophthalmic genetics • 2020 • Ocular findings of albinism in DYRK1A-related intellectual disability syndrome. PMID:32838606
• Molecular genetics & genomic medicine • 2020 • DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature. PMID:33159716
• Genetics in medicine : official journal of the American College of Medical Genetics • 2021 • Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder. PMID:34345024
• Genes • 2021 • Ocular Phenotype Associated with DYRK1A Variants. PMID:33562844
• Molecular and cellular biology • 2002 • Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. PMID:12192061
• Molecular autism • 2017 • Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism. PMID:29021890
• Biology open • 2018 • Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism. PMID:29700199

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