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YWHAZ  encodes an adapter protein 14–3-3ζ, which is involved in many signaling pathways that control cellular proliferation, migration and differentiation. It has not been definitely correlated to any phenotype in OMIM. To investigate the role of  YWHAZ  gene in intellectual disability and global developmental delay, we conducted whole-exon sequencing in all of the available members from a large three-generation family and we discovered that a novel variant of the  YWHAZ  gene was associated with intellectual disability and global developmental delay. This variant is a missense mutation of  YWHAZ , p.Lys49Asn/c.147A &gt; T, which was found in all affected members but not found in other unaffected members. We also conducted computational modeling and knockdown/knockin with  Drosophila  to confirm the role of the  YWHAZ  variant in intellectual disability. Computational modeling showed that the binding energy was increased in the mutated protein combining with the ligand indicating that the c147A &gt; T variation was a loss-of-function variant. Cognitive defects and mushroom body morphological abnormalities were observed in  YWHAZ  c.147A &gt; T knockin flies. The  YWHAZ  knockdown flies also manifested serious cognitive defects with hyperactivity behaviors, which is consistent with the clinical features. Our clinical and experimental results consistently suggested that  YWHAZ  was a novel intellectual disability pathogenic gene.

YWHAZ variation causes intellectual disability and global developmental delay with brain malformation