Application of Whole Exome Sequencing in Congenital Secretory Diarrhea Diagnosis.
Application of Whole Exome Sequencing in Congenital Secretory Diarrhea Diagnosis.
复制标题
整个外显子组测序在先天性分泌性腹泻诊断中的应用。
DOI：
10.1097/mpg.0000000000002258
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发表时间：
2019-06
影响因子：
2.9
通讯作者：
Cerezo CS
中科院分区：
文献类型：
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作者：
Gupta A;Sanville J;Menz T;Warner N;Muise AM;Fiedler K;Martín MG;Padbury J;Phornphutkul C;Sanchez-Esteban J;Cerezo CS
方法和结果在多伦多患病儿童医院应用基因组学中心对患者、父母和2名健康兄弟姐妹进行外显子组测序，发现148,943个变异，其中739个被预测为罕见、编码和破坏性的。用VarSeq软件(Golden Helix)进行常染色体隐性遗传建模，共鉴定出4个纯合子隐性，28个复合杂合子，没有高质量的从头变异。其中一个纯合子隐性变异是在一个已知的导致分泌性钠腹泻的基因上，SLC9A3编码NHE3。在这个先证者中，发现了一种新的纯合子突变(D405G NHE3)，而父母和未受影响的兄弟姐妹都是杂合携带者。这种变体不存在于公共数据库中，并被多种算法预测为有害的(3)。此外，D405G NHE3在许多物种中都是保守的，并且位于先前报道的几个致病变异体的跨膜区内(图1)。有趣的是，SLC9A3的纯合子区域没有在LCSH区域或SNP阵列中被鉴定。
METHODS AND RESULTSWhole exome sequencing was performed at the Center for Applied Genomics at the Hospital for Sick Children, Toronto, on the patient, parents, and 2 healthy siblings revealing 148,943 variants, 739 of which were predicted to be rare, coding, and damaging. Autosomal recessive inheritance modeling was carried out using VarSeq software (Golden Helix) identifying 4 homozygous recessive, 28 compound heterozygous, and no high-quality de novo variants. One of the homozygous recessive variants is in a gene known to cause secretory sodium diarrhea, SLC9A3 encoding NHE3. In this proband, a novel homozygous change (D405G NHE3) was identified, whereas both parents and unaffected siblings were heterozygous carriers. This variant is not present in public databases and is predicted to be deleterious by multiple algorithms (3). In addition, D405G NHE3 is conserved across many species and is within the transmembrane region close to several previously reported pathogenic variants (Fig. 1). Interestingly, the region of homozygosity of SLC9A3 was not identified in an LCSH region or on SNP array.