DYRK1A-related intellectual disability syndrome is caused by heterozygous loss-of-function mutations.
All affected individuals reported to date have a de novo pathogenic variant.
DYRK1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase family. It is a highly conserved gene located in the Down syndrome critical region on chromosome 21.
Alternative splicing events yield at least four isoforms of DYRK1A. Three utilize a longer version of exon 5 (exon 5a) and one uses a shorter variant (exon 5b). Both the long and short isoforms are expressed in various tissues, including the brain.
DYRK1A encodes for a specific protein, which catalyzes the phosphorylation of serine and threonine residues on exogenous substrates, as well as its own kinase domain.
Haploinsufficiency of the DYRK1A protein product results in DYRK1A-related intellectual disability syndrome.
Diagnostic testing
Diagnostic testing is performed by sequence and CNV analysis of the entire coding region. Diagnostic interpretation of variants in DYRK1A should not rely solely on the impact based on gene annotation but also take into account these isoform differences.