Sequence variants in<i> HECTD1</i> result in a variable neurodevelopmental disorder

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,...

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Detalles Bibliográficos
Autores: Zerafati-Jahromi, G, Oxman, E, Hoang, HD, Charng, WL, Kotla, T, Yuan, WM, Ishibashi, K, Sebaoui, S, Luedtke, K, Winrow, B, Ganetzky, RD, Ruiz, A, Manso-Basúz, C, Spataro, N, Kannu, P, Athey, T, Peroutka, C, Barnes, C, Sidlow, R, Anadiotis, G, Magnussen, K, Valenzuela, I, Moles-Fernandez, A, Berger, S, Grant, CL, Vilain, E, Arnadottir, GA, Sulem, P, Sulem, TS, Stefansson, K, Massey, S, Ginn, N, Poduri, A, D'Gama, AM, Valentine, R, Trowbridge, SK, Murali, CN, Franciskovich, R, Tran, Y, Webb, BD, Keppler-Noreuil, KM, Hall, AL, Mcgivern, B, Monaghan, KG, Sacoto, MJG, Baldridge, D, Silverman, GA, Dahiya, S, Turner, TN, Schedl, T, Corbin, JG, Pak, SC, Zohn, IE, Gurnett, CA
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Institut d'Investigació i Innovació Parc Taulí (I3PT)
Repositorio:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
OAI Identifier:oai:i3pt.fundanetsuite.com:p6283
Acceso en línea:https://i3pt.portalinvestigacion.com/publicaciones/6283
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85218079257&doi=10.1016%2Fj.ajhg.2025.01.001&partnerID=40&md5=aeeecbc4929d7db3cff2c9aba6a19f75
Access Level:acceso abierto
Palabra clave:HECTD1, autism, epilepsy, neurodevelopmental disorders, ubiquitin-proteasome system
Descripción
Sumario: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.

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