YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Genetics in Medicine Year : 2023

YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse

Binnaz Yalcin

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.
Fichier principal
Vignette du fichier
PIIS1098360023008481.pdf (3.36 Mo) Télécharger le fichier
Origin : Publication funded by an institution

Dates and versions

inserm-04094776 , version 1 (11-05-2023)

Identifiers

Cite

Anne-Sophie Denommé-Pichon, Stephan C Collins, Ange-Line Bruel, Anna Mikhaleva, Christel Wagner, et al.. YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse. Genetics in Medicine, 2023, pp.100835. ⟨10.1016/j.gim.2023.100835⟩. ⟨inserm-04094776⟩
71 View
68 Download

Altmetric

Share

Gmail Facebook X LinkedIn More