Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Sheba Road 2, 5262100, Tel Hashomer, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Dig Dis Sci. 2018 May;63(5):1192-1199. doi: 10.1007/s10620-018-4983-x. Epub 2018 Feb 26.
Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease.
To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis.
Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function.
We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface.
THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.
基因组学的进步促进了具有独特胃肠表型的患者中单基因疾病的发现。综合征性腹泻，也称为毛肝肠（tricho-hepato-enteric，THE）综合征，是由 SKIV2L 或 TTC37 基因突变引起的。这种疾病的主要特征是难治性腹泻、毛发异常、面部畸形、免疫缺陷和肝病。
报告一例 THE 综合征患者，并介绍有助于诊断的基因分析。
对一名 4 个月大的女性患者进行全外显子组测序（whole-exome sequencing，WES），该患者有先天性腹泻和严重生长发育不良的病史，但无毛发异常或畸形。由于父母是一级表亲，分析集中在常染色体隐性遗传模式上。使用 Sanger 测序验证可疑变异。对突变蛋白结构进行建模，以评估突变对蛋白功能的影响。
我们在 SKIV2L 基因中发现了一个常染色体隐性 C.1891G>A 错义突变（NM_006929），该突变以前仅在复合杂合状态下被描述为导致 THE 综合征。该突变被多个预测模型确定为有害。蛋白建模表明，该突变有可能通过构象变化、干扰蛋白的包装或蛋白界面的变化，导致 SKIV2L 结构的不稳定性。
THE 综合征在新生儿期可表现出广泛的临床特征。WES 是先天性腹泻患者的重要诊断工具，可促进各种表现出非典型特征的疾病的诊断。
