Sequence variants in HECTD1 result in a variable neurodevelopmental disorder
Zerafati-Jahromi, G. (Washington University in St. Louis)
Oxman, E. (Children's National Hospital)
Hoang, H.D. (Washington University in St. Louis)
Charng, W.L. (Washington University in St. Louis)
Kotla, T. (Washington University in St. Louis)
Yuan, Wenping (Washington University in St. Louis)
Ishibashi, K. (Children's National Hospital)
Sebaoui, S. (Children's National Hospital)
Luedtke, K. (Children's National Hospital)
Winrow, B. (Children's National Hospital)
Ganetzky, R.D. (Children's Hospital of Philadelphia (Pennsilvània))
Ruiz, Anna (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Manso-Bazús, Carmen (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Spataro, Nino (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Kannu, P. (Alberta Health Services)
Athey, T. (Alberta Health Services)
Peroutka, C. (University of Virginia)
Barnes, C. (University of Virginia)
Sidlow, R. (Valley Children's Hospital)
Anadiotis, G. (Randall Children's Hospital at Legacy Emanuel)
Magnussen, K. (Randall Children's Hospital at Legacy Emanuel)
Valenzuela, Irene (Hospital Universitari Vall d'Hebron)
Moles-Fernández, Alejandro (Hospital Universitari Vall d'Hebron)
Berger, S. (Children's National Hospital)
Grant, C.L. (Children's National Hospital)
Vilain, E. (University of California. Irvine)
Arnadottir, G.A. (deCODE Genetics/Amgen Inc.)
Sulem, P. (deCODE Genetics/Amgen Inc.)
Sulem, T.S. (deCODE Genetics/Amgen Inc.)
Stefansson, K. (deCODE Genetics/Amgen Inc.)
Massey, S. (Children's Hospital of Philadelphia (Pennsilvània))
Ginn, N. (Children's Hospital of Philadelphia (Pennsilvània))
Poduri, A. (Boston Children's Hospital (Boston, Estats Units d'Amèrica))
D'Gama, A.M. (Harvard Medical School)
Valentine, R. (Boston Children's Hospital (Boston, Estats Units d'Amèrica))
Trowbridge, S.K. (Harvard Medical School)
Murali, C.N. (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Franciskovich, R. (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Tran, Y. (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Webb, B.D. (University of Wisconsin School of Medicine and Public Health)
Keppler-Noreuil, K.M. (University of Wisconsin School of Medicine and Public Health)
Hall, A.L. (University of Wisconsin School of Medicine and Public Health)
McGivern, B. (GeneDx)
Monaghan, K.G. (GeneDx)
Guillen Sacoto, M.J. (GeneDx)
Baldridge, D. (Washington University in St. Louis)
Silverman, G.A. (Washington University in St. Louis)
Dahiya, S. (Washington University in St. Louis)
Turner, T.N. (Washington University in St. Louis)
Schedl, T. (Washington University in St. Louis)
Corbin, J.G. (Children's National Hospital)
Pak, S.C. (Washington University in St. Louis)
Zohn, I.E. (Children's National Hospital)
Gurnett, C.A. (Washington University in St. Louis)
Universitat Autònoma de Barcelona

Date:	2025
Abstract:	Dysregulation of genes encoding the homologous to E6AP C-terminus (HECT) E3 ubiquitin ligases has been linked to cancer and structural birth defects. One member of this family, the HECT-domain-containing protein 1 (HECTD1), mediates developmental pathways, including cell signaling, gene expression, and embryogenesis. Through GeneMatcher, we identified 14 unrelated individuals with 15 different variants in HECTD1 (10 missense, 3 frameshift, 1 nonsense, and 1 splicing variant) with neurodevelopmental disorders (NDDs), including autism, attention-deficit/hyperactivity disorder, and epilepsy. Of these 15 HECTD1 variants, 10 occurred de novo, 3 had unknown inheritance, and 2 were compound heterozygous. While all individuals in this cohort displayed NDDs, no genotype-phenotype correlation was apparent. Conditional knockout of Hectd1 in the neural lineage in mice resulted in microcephaly, severe hippocampal malformations, and complete agenesis of the corpus callosum, supporting a role for Hectd1 in embryonic brain development. Functional studies of select variants in C. elegans revealed dominant effects, including either change-of-function or loss-of-function/haploinsufficient mechanisms, which may explain phenotypic heterogeneity. Significant enrichment of de novo variants in HECTD1 was also shown in an independent cohort of 53,305 published trios with NDDs or congenital heart disease. Thus, our clinical and functional data support a critical requirement of HECTD1 for human brain development.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	HECTD1 ; Autism ; Epilepsy ; Neurodevelopmental disorders ; Ubiquitin-proteasome system
Published in:	American Journal of Human Genetics, Vol. 112 Núm. 3 (june 2025) , p. 537-553, ISSN 1537-6605

DOI: 10.1016/j.ajhg.2025.01.001
PMID: 39879987

18 p, 5.8 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Parc Taulí Research and Innovation Institute (I3PT
Articles > Research articles
Articles > Published articles