Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.
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Faqeih Eissa A, Alghamdi Malak Ali, Almahroos Marwa A, Alharby Essa, Almuntashri Makki, Alshangiti Amnah M, Clément Prouteau, Calame Daniel G, Qebibo Leila, Burglen Lydie, Doco-Fenzy Martine, Mastrangelo Mario, Torella Annalaura, Manti Filippo, Nigro Vincenzo, Alban Ziegler, Alharbi Ghadeer Saleh, Hashmi Jamil Amjad, Alraddadi Rawya, Alamri Razan, Mitani Tadahiro, Magalie Barth, Coban-Akdemir Zeynep, Geckinli Bilgen Bilge, Pehlivan Davut, Romito Antonio, Karageorgou Vasiliki, Martini Javier, Colin Estelle, Bonneau Dominique, Bertoli-Avella Aida, Lupski James R, Pastore Annalisa, Peake Roy W A, Dallol Ashraf, Alfadhel Majid, Almontashiri Naif A M
Аннотация
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.