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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• The YWHAZ gene encodes the 14-3-3ζ adapter protein, implicated in crucial cellular signaling pathways.
• Its specific role in neurodevelopmental disorders like intellectual disability (ID) and global developmental delay (GDD) remains largely uncharacterized.
• No definitive phenotype has been associated with YWHAZ in the Online Mendelian Inheritance in Man (OMIM) database.

Purpose of the Study:

• To investigate the potential role of the YWHAZ gene in the etiology of intellectual disability and global developmental delay.
• To identify genetic variants in YWHAZ associated with ID/GDD within a large family.
• To functionally validate the identified YWHAZ variant using in silico and in vivo models.

Main Methods:

• Whole-exome sequencing was performed on available family members across three generations.
• A novel missense variant (p.Lys49Asn/c.147A>T) in YWHAZ was identified and segregated with the disease phenotype.
• Computational modeling was used to predict the variant's functional impact, and Drosophila models were employed for knockdown and knockin experiments.

Main Results:

• A novel missense mutation, YWHAZ p.Lys49Asn (c.147A>T), was identified in all affected individuals but not in unaffected members of the family.
• Computational analysis indicated that the c.147A>T variation leads to a loss-of-function by increasing binding energy with its ligand.
• Flies with the YWHAZ variant (knockin) exhibited cognitive defects and mushroom body abnormalities; knockdown flies showed cognitive deficits and hyperactivity.

Conclusions:

• The YWHAZ gene, specifically the p.Lys49Asn variant, is implicated as a novel causative gene for intellectual disability and global developmental delay.
• Experimental validation in Drosophila supports the pathogenic role of YWHAZ variants in neurodevelopmental functions.
• This study expands the genetic landscape of intellectual disability and highlights YWHAZ as a potential target for future research.