Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Journal of Medical Genetics Pub Date : 2024-06-20 DOI:10.1136/jmg-2023-109546
Umut Altunoglu, Adrian Palencia-Campos, Nilay Güneş, Gozde Tutku Turgut, Julian Nevado, Pablo Lapunzina, Maria Valencia, Asier Iturrate, Ghada Otaify, Rasha Elhossini, Adel Ashour, Asmaa K Amin, Rania F Elnahas, Elisa Fernandez-Nuñez, Carmen-Lisset Flores, Pedro Arias, Jair Tenorio, Carlos Israel Chamorro Fernández, Yeliz Güven, Elif Özsu, Beray Selver Eklioğlu, Marisol Ibarra-Ramirez, Birgitte Rode Diness, Birute Burnyte, Houda Ajmi, Zafer Yüksel, Ruken Yıldırım, Edip Ünal, Ebtesam Abdalla, Mona Aglan, Hulya Kayserili, Beyhan Tuysuz, Victor Ruiz-Pérez
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Abstract

Background: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum.

Methods: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays.

Main results: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC.

Conclusions: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

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一大批埃利斯-范克里夫德综合征患者和一个韦氏acrofacial dysostosis家族的变异特征和临床概况。
背景:埃利斯-范克里夫德综合征(Ellis-van Creveld Syndrome,简称 EvC)是一种隐性遗传疾病,主要由 EVC 或 EVC2 的致病变体引起,其特征为尖头畸形肢体短缩、轴后多指畸形、甲牙发育不良和先天性心脏缺陷。韦氏acrofacial dysostosis(WAD)是一种与EVC等位的超罕见显性遗传病。本研究旨在加强目前对 EvC 和 WAD 临床表现的了解,并扩大其突变范围:方法:我们对来自 43 个非亲缘家庭、初步临床诊断为 EvC 的 46 名患者和来自一个 WAD 家庭的 3 名患者进行了分子研究,并对临床数据进行了回顾性分析。通过细胞检测评估了某些意义不明的变异的有害影响:我们在 43 个 EvC 家族中的 41 个家族的患者体内发现了 EVC/EVC2 的致病变异。其余两个家族的患者分别发现了WDR35中的一个同源剪接变异和GLI3中的一个新发杂合框移位变异。这些患者的表型与 EvC 有明显的重叠。在 WAD 家族中发现了一种新型 EVC2 C 端截短变体。对该患者群进行的深度表型分析再现了文献中的 "经典 EvC 发现",并突出了以前未曾描述或很少描述为 EvC 一部分的发现:这项研究展示了迄今为止最大的在世 EvC 患者群,有助于更好地了解 EvC 的全部临床表现。我们还提供了有关EVC/EVC2突变情况的全面信息,并将GLI3添加到与EvC样表型相关的基因列表中。
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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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