YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse
Abstract
Purpose: Miller-Dieker syndrome is caused by a multiple-gene deletion, including PAFAH1B1 and YWHAE. While deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder.
Methods: Cases with YWHAE variants were collected through international data-sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae.
Results: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 SNVs, 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (CNVs) from literature review. While, until now, only one intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures and brain malformations including corpus callosum hypoplasia, delayed myelination, ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects including thin cerebral cortex, corpus callosum dysgenesis, hydrocephalus paralleling those seen in humans.
Conclusion: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.
Origin : Publication funded by an institution