Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

BMC Medical Genetics

Research Article

Etienne Nel¹  Monika Esser²  Marlo Möller³  Eric Banda³  Paul D. van Helden³  Annika Neethling³  Glynis Johnson³  Brigitte Glanzmann³  Eileen G. Hoal³  Michael Urban³  Craig Kinnear³  Glenda Durrheim³  Mardelle Schoeman³  Nikola Schlechter³ 

[1] Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa;National Health Laboratory Service, Immunology Unit, Division of Medical Microbiology, Department of Pathology, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa;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, 8000, Cape Town, South Africa;

关键词: Trichohepatoenteric syndrome;    Primary immunodeficiency diseases;    Exome;    Consanguineous;    Next generation sequencing;    Sanger sequencing;   

DOI  :  10.1186/s12881-017-0388-5

 received in 2016-07-18, accepted in 2017-03-02,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundTrichohepatoenteric 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.MethodsWhole 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.ResultsExome 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.ConclusionsWES 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.

【 授权许可】

CC BY   
© The Author(s). 2017