Relevance to Autism

Recurrent mutations in the DYRK1A gene have been identified in multiple individuals with ASD as described below. A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified DYRK1A as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD in van Bon et al., 2016 identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Furthermore, phenotypic comparison of 15 cases with DYRK1A disruptions in this report identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes. Evers et al., 2017 reported additional de novo DYRK1A variants identified in individuals from the Deciphering Developmental Disorders study presenting with intellectual disability and other features (PMID 28053047). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified DYRK1A as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a member of the Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. It is localized in the Down syndrome critical region of chromosome 21, and is considered to be a strong candidate gene for learning defects associated with Down syndrome. Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:614104].

External Links

References

Model Summary

Dyrk1a knockout in zebrafish causes reductioni n size in various brain regions including the telencephalon, cerebellum and optic tectum.

References