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

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.

Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.

BACKGROUND: In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately ad 1700 and segregating the same KCNQ1 mutation (A341V). METHODS AND RESULTS: The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking beta-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (< or =440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7+/-4 versus 13+/-9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. CONCLUSIONS: KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.

Long QT syndrome in South Africa: the results of comprehensive genetic screening.

Congenital long QT syndrome (cLQTS) is a genetic disorder predisposing to ventricular arrhythmia, syncope and sudden death. Over 700 different cLQTS-causing mutations in 13 genes are known. The genetic spectrum of LQTS in 44 South African cLQTS patients (23 known to carry the South African founder mutation p.A341V in KCNQ1) was established by screening for mutations in the coding regions of KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A, the most frequently implicated cLQTS-causing genes (five-gene screening). Fourteen disease-causing mutations were identified, eight (including the founder mutation) in KCNQ1, five in KCNH2 and one in KCNE1. Two mutations were novel. Two double heterozygotes were found among the 23 families (8.5%) carrying the founder mutation. In conclusion, cLQTS in South Africa reflects both a strong founder effect and a genetic spectrum similar to that seen in other populations. Consequently, five-gene screening should be offered as a standard screening option, as is the case internationally. This will disclose compound and double heterozygotes. Fivegene screening will most likely be even more informative in other South African sub-populations with a greater genetic diversity.

Does pregnancy increase cardiac risk for LQT1 patients with the KCNQ1-A341V mutation?

OBJECTIVES: The purpose of this study was to assess the pregnancy-related cardiovascular risk in LQT1 patients. BACKGROUND: Only 1 study addressed this issue in genotyped patients and reported that the highest risk is for LQT2 patients. METHODS: This case-control study, performed in a cohort of patients from 22 families affected by LQT1 and all sharing the common KCNQ1-A341V mutation, involved 36 mutation carriers and 24 of their unaffected sisters for a total of 182 pregnancies. RESULTS: There were 3 (2.6%) cardiac events (2 cardiac arrests) in the 115 LQT1 pregnancies. Because they occurred only among the 27 mothers with previous symptoms, all off-therapy, the risk for symptomatic patients is 11%, but decreases to 0 in symptomatic patients treated with beta-blockers. Carriers and control subjects did not differ for the incidence of miscarriage (10% vs. 15%). Cesarean sections (C-sections), elective or owing to fetal distress, were performed more often in carriers than in non-carriers (27% vs. 14%). Beta-blocker therapy did not influence the prevalence of fetal distress. Among the infants born to carriers, all those with fetal distress were carriers of the A341V mutation (10 of 10, 100%). Among the offspring of the carriers, 48 of 92 (52%) were mutation carriers, and of those, 15% died suddenly at age 14 +/- 6 years. CONCLUSIONS: Women affected by the common KCNQ1-A341V mutation are at low risk for cardiac events during pregnancy and without excess risk of miscarriage; their infants delivered by C-section because of fetal distress are extremely likely to also be mutation carriers. Beta-blockers remain recommended. These conclusions likely apply to most LQT1 patients.