Variants in WASHC3, a Component of the WASH Complex, Cause Short Stature, Variable Neurodevelopmental Abnormalities, and Distinctive Facial Dysmorphism

Authors

Youn Hee Jee
Julian C Lui
Dana Marafi
Zhi-Jie Xia
Ruchika Bhatia
Elaine Zhou
Isabella Herman
Adrian Temnycky
Philip Whalen
Gene Elliot
Ellen W Leschek
Robin Wijngaard
Ronald van Beek
Annemarie de Vreugd
Maaike C de Vries
Clara D M van Karnebeek
Machteld M Oud
Thomas C Markello
Kevin M Barnes
Hadil Alrohaif
Hudson H Freeze
William A Gahl
May Christine V Malicdan
Jennifer E Posey
James R Lupski
Jeffrey Baron

Publication Date

1-1-2025

Journal

Genetics in Medicine Open

DOI

10.1016/j.gimo.2024.101915

PMID

40129681

PMCID

PMC11932664

PubMedCentral® Posted Date

12-16-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Purpose: Genetic defects that impair growth plate chondrogenesis cause a phenotype that varies from skeletal dysplasia to mild short stature with or without other syndromic features. In many individuals with impaired skeletal growth, the genetic causes remain unknown.

Method: Exome sequence was performed in 3 unrelated families with short stature, distinctive facies, and neurodevelopmental abnormalities. The impact of identified variants was studied in vitro.

Results: Exome sequencing identified variants in WASHC3, a component of the WASH complex. In the first family, a de-novo-dominant missense variant (p.L69F) impaired WASHC3 participation in the WASH complex, altered PTH1R endosomal trafficking, diminished PTH1R signaling, and affected growth plate chondrocyte hypertrophic differentiation, providing a likely explanation for the short stature. Knockdown of other WASH complex components also diminished PTH1R signaling. In the second and third families, a homozygous variant in the start codon (p.M1?) markedly reduced WASHC3 protein expression.

Conclusion: In combination with prior studies of WASH complex proteins, our findings provide evidence that the WASH complex is required for normal skeletal growth and that, consequently, genetic abnormalities impairing the function of the WASH complex (WASHopathy) cause short stature, as well as distinctive facies and variable neurodevelopmental abnormalities.

Keywords

Growth, Neurodevelopmental abnormalities, Receptor trafficking, WASH complex, WASHC3

Published Open-Access

yes

Recommended Citation

Jee, Youn Hee; Lui, Julian C; Marafi, Dana; et al., "Variants in WASHC3, a Component of the WASH Complex, Cause Short Stature, Variable Neurodevelopmental Abnormalities, and Distinctive Facial Dysmorphism" (2025). Faculty and Staff Publications. 5066.
https://digitalcommons.library.tmc.edu/baylor_docs/5066