35 Individuals With HUWE1-Related Neurodevelopmental Disorder and Suggested Clinical Evaluations

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1) is a highly conserved ubiquitin ligase located at Xp11.22.
• Genetic variants in HUWE1 are known to cause X-linked intellectual disability (XLID).
• Previous studies have reported on XLID associated with HUWE1, but female cases are less commonly described.

Purpose of the Study:

• To describe 35 additional individuals with HUWE1 variants, expanding the characterization of HUWE1-related neurodevelopmental disorder (HNDD).
• To include and analyze a significant number of female cases, which are underrepresented in previous reports.
• To suggest guidelines for the clinical management of HNDD and identify genetic hotspots.

Main Methods:

• Clinical data collection and analysis from 35 individuals with identified HUWE1 variants.
• Genetic analysis to identify variants in HUWE1, including de novo and inherited cases.
• Comparison of clinical features with previously reported cases to define the spectrum of HNDD.

Main Results:

• Confirmed previously reported features such as developmental delay, autism, hypotonia, short stature, and dysmorphic facial features.
• Identified additional multisystemic findings, including intrauterine growth restriction (IUGR) and neonatal feeding difficulties.
• Found that nearly all female cases had de novo variants, while males had de novo or inherited variants from carrier mothers. Three genetic hotspots in conserved HUWE1 regions were identified.

Conclusions:

• HUWE1 variants contribute to a spectrum of neurodevelopmental disorders with diverse clinical manifestations.
• The study expands the known clinical spectrum of HNDD, particularly in female patients.
• Identification of genetic hotspots and clinical management guidelines aids in diagnosing and managing HNDD.