The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy

Background DYRK1Aplays different functions during development, with an important role in controlling brain growth through neuronal proliferation and neurogenesis. It is expressed in a gene dosagedependent manner since dyrk1a haploinsufficiencyinduces a reduced brain sizein mice, and DYRK1Aoverexpression is the candidate gene for intellectual disability (ID) and microcephalyin Down syndrome. We have identified a 69 kb deletion including the 5′ region of the DYRK1Agene in a patient with growth retardation, primary microcephaly, facial dysmorphism, seizures, ataxic gait, absent speech and ID. Because four patients previously reported with intragenic DYRK1Arearrangements or 21q22 microdeletions including only DYRK1Apresented with overlapping phenotypes, we hypothesised that DYRK1Amutations could be responsible for syndromic ID with severe microcephalyand epilepsy. Methods The DYRK1Agene was studied by direct sequencing and quantitative PCR in a cohort of 105 patients with ID and at least two symptoms from the Angelman syndromespectrum ( microcephaly< −2.5 SD, ataxic gait, seizures and speech delay). Results We identified a de novo frameshift mutation(c.290_291delCT; p.Ser97Cysfs*98) in a patient with growth retardation, primary severe microcephaly, delayed language, ID, and seizures. Conclusion The identification of a truncating mutation in a patient with ID, severe microcephaly, epilepsy, and growth retardation, combined with its dual function in regulating the neural proliferation/neuronal differentiation, adds DYRK1Ato the list of genes responsible for such a phenotype. ID, microcephaly, epilepsy, and language delayare the more specific features associated with DYRK1Aabnormalities. DYRK1Astudies should be discussed in patients presenting such a phenotype.