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
Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
Medical Genetics Division, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Medical Genetic Division, Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia.
Genet Med. 2023 Feb;25(2):100323. doi: 10.1016/j.gim.2022.10.006. Epub 2022 Nov 19.
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.
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.
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.
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.
已知编码泛素E3连接酶的基因中的致病变异会导致神经发育综合征。与其他编码E3连接酶的基因相关的其他神经发育障碍尚待确定。
采用染色体分析和外显子组测序来确定来自7个不相关家庭的10例患有综合征性神经发育、癫痫、运动障碍和神经行为表型的患者的遗传病因。
总共发现4例患者有3种不同的纯合功能丧失（LoF）变异，3例患者在候选E3连接酶基因HECTD4中有4种复合杂合错义变异，这些变异罕见，在对照组中不存在纯合形式，并且在计算机模拟中预测为有害。在2个患有天使综合征样综合征家庭的3例患者中，旁系同源物定向候选基因方法在另一个候选E3连接酶基因UBE3C中检测到2种LoF变异，UBE3C是天使综合征E3连接酶基因UBE3A的旁系同源物。对4例在HECTD4和UBE3C中有LoF变异的患者进行的RNA研究为LoF效应提供了证据。
HECTD4和UBE3C是新的双等位基因罕见病基因，扩展了其他HECT E3连接酶组与神经发育综合征的关联，并可以解释一些临床诊断提示为天使综合征患者中缺失的遗传度。
