Submission Details

The relationship between DYRK1A and complex neurodevelopmental disorder (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of 10/05/2019. Variants in DYRK1A were first reported in humans with this disease as early as 2011 (van Bon et al., PMID: 21294719). Numerous unique variants in DYRK1A (e.g. nonsense, frameshift, splice site and missense) have been reported in humans, and most variants occur de novo. The mechanism for disease is haploinsufficiency. Loss of DYRK1A results in a recognizable phenotype, including microcephaly and restricted growth, intellectual disability, delayed or absent speech, autism spectrum disorder or autistic behavior, gait disturbance, seizures, and dysmorphic facial features. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 12 POINTS. Variants in this gene have been reported in at least 13 probands in 10 publications (21294719, 23099646, 23160955, 25167861, 25156961, 25641759, 25920557, 25944381, 26922654, 25707398). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. Experimental evidence: 4.5 POINTS. This gene-disease association is supported by expression studies, animal models, and functional studies in non-patient cells. In summary, DYRK1A is definitely associated with autosomal dominant complex neurodevelopmental disorder.