Sequence variants in HECTD1 result in a variable neurodevelopmental disorder.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Zerafati-Jahromi Gazelle, Oxman Elias, Hoang Hieu D, Charng Wu-Lin, Kotla Tanvitha, Yuan Weimin, Ishibashi Keito, Sebaoui Sonia, Luedtke Kathryn, Winrow Bryce, Ganetzky Rebecca D, Ruiz Anna, Manso-Basúz Carmen, Spataro Nino, Kannu Peter, Athey Taryn, Peroutka Christina, Barnes Caitlin, Sidlow Richard, Anadiotis George, Magnussen Kari, Valenzuela Irene, Moles-Fernandez Alejandro, Berger Seth, Grant Christina L, Vilain Eric, Arnadottir Gudny A, Sulem Patrick, Sulem Telma S, Stefansson Kari, Massey Shavonne, Ginn Natalie, Poduri Annapurna, D'Gama Alissa M, Valentine Rozalia, Trowbridge Sara K, Murali Chaya N, Franciskovich Rachel, Tran Yen, Webb Bryn D, Keppler-Noreuil Kim M, Hall April L, McGivern Bobbi, Monaghan Kristin G, Guillen Sacoto Maria J, Baldridge Dustin, Silverman Gary A, Dahiya Sonika, Turner Tychele N, Schedl Tim, Corbin Joshua G, Pak Stephen C, Zohn Irene E, Gurnett Christina A
Аннотация
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.