Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Abstract

ABBSTRACTDYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboring DYRK1A variants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specific DYRK1A clinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurring de novo.