Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.

TitleBiallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.
Publication TypeJournal Article
Year of Publication2023
AuthorsFaqeih, EA, Alghamdi, MAli, Almahroos, MA, Alharby, E, Almuntashri, M, Alshangiti, AM, Clément, P, Calame, DG, Qebibo, L, Burglen, L, Doco-Fenzy, M, Mastrangelo, M, Torella, A, Manti, F, Nigro, V, Alban, Z, Alharbi, GSaleh, Hashmi, JAmjad, Alraddadi, R, Alamri, R, Mitani, T, Magalie, B, Coban-Akdemir, Z, Geckinli, BBilge, Pehlivan, D, Romito, A, Karageorgou, V, Martini, J, Colin, E, Bonneau, D, Bertoli-Avella, A, Lupski, JR, Pastore, A, Peake, RWA, Dallol, A, Alfadhel, M, Almontashiri, NAM
JournalGenet Med
Date Published2023 Feb
KeywordsAngelman Syndrome, Humans, Neurodevelopmental Disorders, Phenotype, Ubiquitin, Ubiquitin-Protein Ligases

PURPOSE: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified.

METHODS: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes.

RESULTS: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect.

CONCLUSION: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.

Alternate JournalGenet Med
PubMed ID36401616
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States

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