Kinnear Craig, Glanzmann Brigitte, Banda Eric, Schlechter Nikola, Durrheim Glenda, Neethling Annika, Nel Etienne, Schoeman Mardelle, Johnson Glynis, van Helden Paul D, Hoal Eileen G, Esser Monika, Urban Michael, Möller Marlo
SA MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, P.O. Box 241, Cape Town, 8000, South Africa.
Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
BMC Med Genet. 2017 Mar 14;18(1):26. doi: 10.1186/s12881-017-0388-5.
Trichohepatoenteric syndrome (THE-S) or phenotypic diarrhoea of infancy is a rare autosomal recessive disorder characterised by severe infantile diarrhoea, facial dysmorphism, immunodeficiency and woolly hair. It was first described in 1982 in two infants with intractable diarrhoea, liver cirrhosis and abnormal hair structure on microscopy. We report on two siblings from a consanguineous family of Somali descent who, despite extensive clinical investigation, remained undiagnosed until their demise. The index patient died of fulminant cytomegalovirus pneumonitis at 3 months of age.
Whole exome sequencing (WES) was performed on a premortem DNA sample from the index case. Variants in a homozygous recessive state or compound heterozygous state were prioritized as potential candidate variants using TAPER™. Sanger sequencing was done to genotype the parents, unaffected sibling and a deceased sibling for the variant of interest.
Exome sequencing identified a novel homozygous mutation (c.4507C > T, rs200067423) in TTC37 which was confirmed by Sanger sequencing in the index case. The identification of this mutation led to the diagnosis of THE-S in the proband and the same homozygous variant was confirmed in a male sibling who died 4 years earlier with severe chronic diarrhoea of infancy. The unaffected parents and sister were heterozygous for the identified variant.
WES permitted definitive genetic diagnosis despite an atypical presentation in the index case and suggests that severe infection, likely secondary to immunodeficiency, may be a presenting feature. In addition definitive molecular diagnosis allows for genetic counseling and future prenatal diagnosis, and demonstrates the value of WES for post-mortem diagnosis of disorders with a non-specific clinical presentation in which a Mendelian cause is suspected.
毛发肝肠综合征（THE-S）或婴儿期表型腹泻是一种罕见的常染色体隐性疾病，其特征为严重的婴儿腹泻、面部畸形、免疫缺陷和卷发。1982年首次在两名患有顽固性腹泻、肝硬化且显微镜下毛发结构异常的婴儿中被描述。我们报告了一对来自索马里裔近亲家庭的兄弟姐妹，尽管进行了广泛的临床检查，但在他们去世前仍未确诊。索引患者在3个月大时死于暴发性巨细胞病毒肺炎。
对索引病例的尸前DNA样本进行全外显子组测序（WES）。使用TAPER™将纯合隐性状态或复合杂合状态的变异作为潜在候选变异进行优先排序。对父母、未受影响的兄弟姐妹和已故兄弟姐妹进行桑格测序，以确定感兴趣变异的基因型。
外显子组测序在TTC37中鉴定出一个新的纯合突变（c.4507C>T，rs200067423），索引病例中的该突变经桑格测序得以证实。该突变的鉴定导致先证者被诊断为THE-S，并且在一名4年前死于严重婴儿慢性腹泻的男性兄弟姐妹中也证实了相同的纯合变异。未受影响的父母和姐妹为所鉴定变异的杂合子。
尽管索引病例表现不典型，但WES仍实现了明确的基因诊断，并表明严重感染可能是一个首发特征，这可能继发于免疫缺陷。此外，明确的分子诊断有助于进行遗传咨询和未来的产前诊断，并证明了WES对于具有非特异性临床表现且怀疑为孟德尔病因的疾病进行死后诊断的价值。
