PDF(Pubmed)
Abstract：
Ellis-van Creveld (EvC) syndrome, caused by variants in EVC, is a rare genetic skeletal dysplasia. Its clinical phenotype is highly diverse. EvC syndrome is rarely reported in prenatal stages because its presentation overlaps with other diseases.
A Chinese pedigree diagnosed with EvC syndrome was enrolled in this study. Whole-exome sequencing (WES) was applied in the proband to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in family members. Minigene experiments were applied.
WES identified a homozygous variant (NM_153717.3:c.153_174 + 42del) in EVC which was inherited from the heterozygous parents and confirmed by Sanger sequencing. Further experiments demonstrated that this variant disrupts the canonical splicing site and produces a new splicing site at NM_153717.3: c.-164_174del, which ultimately leads to a 337 bp deletion at the 3\' end of exon 1 and loss of the start codon.
This is the first reported case of EvC syndrome based on a splicing variant and detailed delineation of the aberrant splicing effect in the fetus. Our study demonstrates the pathogenesis of this new variant, expands the spectrum of EVC mutations, and demonstrates that WES is a powerful tool in the clinical diagnosis of diseases with genetic heterogeneity.
A Chinese pedigree diagnosed with EvC syndrome was enrolled in this study. Whole-exome sequencing (WES) was applied in the proband to screen potential genetic variant(s), and then Sanger sequencing was used to identify the variant in family members. Minigene experiments were applied.
WES identified a homozygous variant (NM_153717.3:c.153_174 + 42del) in EVC which was inherited from the heterozygous parents and confirmed by Sanger sequencing. Further experiments demonstrated that this variant disrupts the canonical splicing site and produces a new splicing site at NM_153717.3: c.-164_174del, which ultimately leads to a 337 bp deletion at the 3\' end of exon 1 and loss of the start codon.
This is the first reported case of EvC syndrome based on a splicing variant and detailed delineation of the aberrant splicing effect in the fetus. Our study demonstrates the pathogenesis of this new variant, expands the spectrum of EVC mutations, and demonstrates that WES is a powerful tool in the clinical diagnosis of diseases with genetic heterogeneity.
摘要：
背景：Ellis-vanCreveld（EvC）综合征，由EVC中的变体引起，是一种罕见的遗传性骨骼发育不良.其临床表型高度多样化。在产前阶段很少报道EvC综合征，因为它的表现与其他疾病重叠。
方法：本研究纳入一个诊断为EvC综合征的中国家系。在先证中应用全外显子组测序(WES)来筛选潜在的遗传变异,然后使用Sanger测序来鉴定家族成员中的变异体。应用Minigene实验。
结果：WES在EVC中鉴定了纯合变体（NM_153717.3：c.153_174+42del），该变体是从杂合亲本遗传而来的，并通过Sanger测序确认。进一步的实验表明，该变体破坏了经典剪接位点，并在NM_153717.3：c.-164_174del处产生了新的剪接位点，这最终导致在外显子1的3'末端337bp的缺失和起始密码子的丢失。
结论：这是第一例报道的EvC综合征病例，其基于剪接变体和胎儿异常剪接效应的详细描述。我们的研究证明了这种新变种的发病机制，扩大了EVC突变的范围，并证明WES是遗传异质性疾病临床诊断的有力工具。
方法：本研究纳入一个诊断为EvC综合征的中国家系。在先证中应用全外显子组测序(WES)来筛选潜在的遗传变异,然后使用Sanger测序来鉴定家族成员中的变异体。应用Minigene实验。
结果：WES在EVC中鉴定了纯合变体（NM_153717.3：c.153_174+42del），该变体是从杂合亲本遗传而来的，并通过Sanger测序确认。进一步的实验表明，该变体破坏了经典剪接位点，并在NM_153717.3：c.-164_174del处产生了新的剪接位点，这最终导致在外显子1的3'末端337bp的缺失和起始密码子的丢失。
结论：这是第一例报道的EvC综合征病例，其基于剪接变体和胎儿异常剪接效应的详细描述。我们的研究证明了这种新变种的发病机制，扩大了EVC突变的范围，并证明WES是遗传异质性疾病临床诊断的有力工具。
