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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Consanguineous; Exome; Next generation sequencing; Primary immunodeficiency diseases; Sanger sequencing; Trichohepatoenteric syndrome.

Fig. 1

Multigeneration pedigree of the Trichohepatoenteric syndrome family

Fig. 2

Clinical features of the proband. a Hyperpigmentation of the trunk. b Exfoliating rash present at the feet of the proband. c Prominent forehead with triangular appearance of the face. d Chest X-ray showing extensive bilateral bronchopneumonia

Fig. 3

ClustalW multiple sequence alignment showing the highly conserved position of the c.4507C > T (p.1053R > C) mutation in TTC37

Fig. 4

Validation of the mutation using Sanger sequencing. The proband (indicated by the black arrow) and affected deceased brother are homozygous for TTC37 c.4507C > T (p.1503R > C), while both unaffected parents as well as the unaffected sibling are heterozygotes