Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Eur J Hum Genet. 2018 Dec;26(12):1797-1809. doi: 10.1038/s41431-018-0222-3. Epub 2018 Aug 10.
Whole exome sequencing (WES) is utilized in diagnostic odyssey cases to identify the underlying genetic cause associated with complex phenotypes. Recent publications suggest that WES reveals the genetic cause in ~25% of these cases and is most successful when applied to children with neurological disease. The residual 75% of cases remain genetically elusive until more information becomes available in the literature or functional studies are pursued. WES performed on three families with presumed ciliopathy diagnoses, including orofaciodigital (OFD) syndrome, fetal encephalocele, or Joubert-related disorder, identified compound heterozygous variants in C2CD3. Biallelic variants in C2CD3 have previously been associated with ciliopathies, including OFD syndrome type 14 (OFD14; MIM: 615948). As three of the six identified variants were predicted to affect splicing, exon-skipping analysis using either RNA sequencing or PCR-based methods were completed to determine the pathogenicity of these variants, and showed that each of the splicing variants led to a frameshifted protein product. Using these studies in combination with the 2015 ACMG guidelines, each of the six identified variants were classified as either pathogenic or likely pathogenic, and are therefore likely responsible for our patients' phenotypes. Each of the families had a distinct clinical phenotype and severity of disease, extending from lethal to viable. These findings highlight that there is a broad phenotypic spectrum associated with C2CD3-mediated disease and not all patients present with the typical features of OFD14.
全外显子测序（WES）用于诊断探索病例，以确定与复杂表型相关的潜在遗传原因。最近的出版物表明，WES 揭示了这些病例中约 25%的遗传原因，当应用于患有神经疾病的儿童时最为成功。其余 75%的病例仍然难以确定遗传原因，直到文献中有更多信息或进行功能研究。对三个被认为患有纤毛病的家庭进行 WES 检测，包括口面指（趾）畸形（OFD）综合征、胎儿脑膨出或与 Joubert 相关的疾病，发现 C2CD3 中的复合杂合变异。C2CD3 的双等位基因变异以前与纤毛病有关，包括 OFD 综合征 14 型（OFD14；MIM：615948）。由于鉴定出的六种变异中有三种预测会影响剪接，因此使用 RNA 测序或基于 PCR 的方法完成外显子跳跃分析，以确定这些变异的致病性，并表明每种剪接变异都导致了移码的蛋白质产物。结合 2015 年 ACMG 指南使用这些研究，鉴定出的六种变异中的每一种都被归类为致病性或可能致病性，因此很可能是导致我们患者表型的原因。每个家庭都有不同的临床表型和疾病严重程度，从致死到存活不等。这些发现强调了 C2CD3 介导的疾病存在广泛的表型谱，并非所有患者都具有 OFD14 的典型特征。
