35 Individuals With <scp>HUWE1</scp> ‐Related Neurodevelopmental Disorder and Suggested Clinical Evaluations
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).
Authors
- Clara Hildebrandt (ORCID: https://orcid.org/0000-0002-6254-5925)
- Kristin Barañano (ORCID: https://orcid.org/0000-0002-4157-2019)
- Tiffany Busa (ORCID: https://orcid.org/0000-0003-4454-1979)
- Brock Grill (ORCID: https://orcid.org/0000-0002-0379-3267)
- Klaus Dieterich (ORCID: https://orcid.org/0000-0002-4362-4062)
- Rachel Logan (ORCID: https://orcid.org/0000-0002-2771-9969)
- Danielle Luz
- Mindy Li (ORCID: https://orcid.org/0000-0002-5957-7918)
- Kelly Schoch
- Samantha A. Schrier Vergano (ORCID: https://orcid.org/0000-0001-9194-0644)
- Rachel Rabin (ORCID: https://orcid.org/0000-0003-4906-7428)
- Milena Mariani (ORCID: https://orcid.org/0000-0002-7446-7418)
- Newell Belnap (ORCID: https://orcid.org/0009-0003-8868-5891)
- Manuela Morleo (ORCID: https://orcid.org/0000-0002-7553-3245)
- Charles Coutton
- Charlotte Tardy
- John Pappas
- Rebecca Spillmann
- Lindsay Bhandari
- Deziree L. Coleman
- Vincenzo Nigro
- Svetlana Gorokhova
- Jennifer Sullivan
- Kelsey Hogan
- Angelo Selicorni
- Vandana Shashi
Institutions
- University of North Carolina at Chapel Hill (US)
- Translational Genomics Research Institute (US)
- Rush University Medical Center (US)
- Johns Hopkins University (US)
- Inserm (FR)
- Duke University (US)
- University of Campania "Luigi Vanvitelli" (IT)
- University of Washington (US)
- Aix-Marseille Université (FR)
- Johns Hopkins Medicine (US)
- Centre Hospitalier Universitaire de Grenoble (FR)
- Assistance Publique Hôpitaux de Marseille (FR)
- Norcliffe Foundation (US)
- Children's Hospital of The King's Daughters (US)
- Children's Healthcare of Atlanta (US)
- Ospedale Sant'Anna (IT)
- Grenoble Institute of Neurosciences (FR)
- Telethon Institute Of Genetics And Medicine (IT)
- Hôpital de la Timone (FR)
- New York University (US)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- American Journal of Medical Genetics Part A
- Published
- 2026-04-13
- DOI
- https://doi.org/10.1002/ajmg.a.70127
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- Common Fund