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

Authors

• Mindy H. Li, Rush University Medical Center
• Deziree L. Coleman, University of Washington School of Medicine
• Kelsey Hogan, Rush University Medical Center
• Danielle Luz, Rush University Medical Center
• Lindsay Bhandari, Johns Hopkins University Medical Center
• Newell Belnap, Translational Genomics Research Institute
• Tiffany Busa, Timone Children's Hospital
• Charles Coutton, University Grenoble Alpes, Inserm, U1209, CHU Grenoble Alpes, Institut for Advanced Biosciences
• Klaus Dieterich, University Grenoble Alpes, Inserm, U1209, CHU Grenoble Alpes, Institut for Advanced Biosciences
• Svetlana Gorokhova, Timone Children's Hospital, Marseille, France
• Clara Hildebrandt, University of North Carolina
• Rachel Logan, Children's Healthcare of Atlanta
• Milena Mariani, ASST Lariana Carolina
• Manuela Morleo, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
• Vincenzo Nigro, Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
• John Pappas, New York University Grossman School of Medicine
• Rachel Rabin, New York University Grossman School of Medicine
• Kelly Schoch, Duke University School of Medicine
• Angelo Selicorni, ASST Lariana Sant'anna Hospital
• Vandana Shashi, Duke University School of Medicine
• Rebecca Spillman, Duke University School of Medicine
• Jennifer Sullivan, Duke University School of Medicine
• Charlotte Tardy, Timone Children's Hospital, Marseille, France
• Samantha A. Schrier Vergano, Macon & Joan Brock Virginia Health Sciences at Old Dominion University
• Brock Grill, University of Washington
• Kristin Baranano, Johns Hopkins University

ORCID

0000-0001-9194-0644 (Vergano)

Document Type

Article

Publication Date

2026

DOI

10.1002/ajmg.a.70127

Publication Title

American Journal of Medical Genetics Part A

Volume

Advance online publication

Pages

9 pp.

Abstract

HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multiple independent studies cause X-linked intellectual disability, including in the patients identified by Juberg, Marsidi, and Brooks. This report describes 35 additional cases of individuals with variants in HUWE1 and suggested guidelines for clinical management. Our study includes several female cases, which have not been widely reported previously. Our findings confirm earlier reported clinical features including developmental delay, autism, hypotonia, short stature, and dysmorphic facial features as well as additional multisystemic findings. Intrauterine growth restriction (IUGR) and feeding difficulties were common in the neonatal period. It is notable that nearly all females had de novo variants, and males had de novo or inherited variants from clinically unaffected carrier mothers. Three genetic hotspots were identified in evolutionarily conserved regions of HUWE1 that have clinical impact. This report provides additional characterization of the spectrum of HUWE1-related neurodevelopmental disorder (HNDD).

Rights

© 2026 The Authors.

This is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Data Availability

Article states: "The data that supports the findings of this study are available in the S1 of this article."

Original Publication Citation

Li, M. H., Coleman, D. L., Hogan, K., Luz, D., Bhandari, L., Belnap, N., Busa, T., Coutton, C., Dieterich, K., Gorokhova, S., Hildebrandt, C., Logan, R., Mariani, M., Morleo, M., Nigro, V., Pappas, J., Rabin, R., Schoch, K., Selicorni, A.,…Baranano, K. (2026). 35 individuals with HUWE1-related neurodevelopmental disorder and suggested clinical evaluations. American Journal of Medical Genetics Part A. Advance online publication. https://doi.org/10.1002/ajmg.a.70127

Repository Citation

Li, M. H., Coleman, D. L., Hogan, K., Luz, D., Bhandari, L., Belnap, N., Busa, T., Coutton, C., Dieterich, K., Gorokhova, S., Hildebrandt, C., Logan, R., Mariani, M., Morleo, M., Nigro, V., Pappas, J., Rabin, R., Schoch, K., Selicorni, A.,…Baranano, K. (2026). 35 individuals with HUWE1-related neurodevelopmental disorder and suggested clinical evaluations. American Journal of Medical Genetics Part A. Advance online publication. https://doi.org/10.1002/ajmg.a.70127