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.
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.
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.
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.
摘要：
背景：Ellis-vanCreveld综合征（EvC）是一种隐性疾病，其特征是肩膜肢体缩短，后轴多指，指甲牙齿发育不良和先天性心脏缺陷，主要由EVC或EVC2的致病变异引起。Weyers肩面骨发育不良（WAD）是EvC的一种罕见优势条件。本工作旨在提高对EvC和WAD临床表现的最新认识，并拓宽其突变谱。
方法：我们对来自43个无亲缘关系的初步临床诊断为EvC的家族的46名个体和来自WAD家族的3名受影响个体进行了分子研究，并对临床数据进行了回顾性分析。通过细胞测定评估具有不确定意义的所选变体的有害作用。
结果：我们在43个EvC家族中的41个受影响的个体中发现了EVC/EVC2的致病变异。其余两个家庭的患者分别在WDR35中具有纯合剪接变体，在GLI3中具有从头杂合移码变体。这些患者的表型显示与EvC显著重叠。在患有WAD的家族中鉴定了一种新的EVC2C末端截短变体。队列的深层表型概括了文献中的“经典EvC发现”，并强调了以前未描述或很少描述为EvC一部分的发现。
结论：这项研究提出了迄今为止最大的EvC患者队列，有助于更好地理解EvC的全部临床谱。我们还提供有关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。
方法：我们对来自43个无亲缘关系的初步临床诊断为EvC的家族的46名个体和来自WAD家族的3名受影响个体进行了分子研究，并对临床数据进行了回顾性分析。通过细胞测定评估具有不确定意义的所选变体的有害作用。
结果：我们在43个EvC家族中的41个受影响的个体中发现了EVC/EVC2的致病变异。其余两个家庭的患者分别在WDR35中具有纯合剪接变体，在GLI3中具有从头杂合移码变体。这些患者的表型显示与EvC显著重叠。在患有WAD的家族中鉴定了一种新的EVC2C末端截短变体。队列的深层表型概括了文献中的“经典EvC发现”，并强调了以前未描述或很少描述为EvC一部分的发现。
结论：这项研究提出了迄今为止最大的EvC患者队列，有助于更好地理解EvC的全部临床谱。我们还提供有关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。
