Purpose: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics. Methods: We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature. Results: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice. Conclusion: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene. Graphic abstract: [Figure not available: see fulltext.]
Bibliografisk noteFunding Information:
The authors thank the families for their participation and support. The authors also thank the Agence de Biomédecine, Fondation APLM, Fondation Maladies Rares and Fondation Jérome Lejeune for financial support. We also thank the Centre National de Génotypage, the diagnostic laboratories of Hôpitaux Universitaire de Strasbourg (HUS), clinical genetics residents, the GenomEast sequencing and the molecular biology platforms of IGBMC.
© 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.