The implementation and utility of clinical exome sequencing in a South African infant cohort.

Genetic disorders are significant contributors to infant hospitalization and mortality globally. The early diagnosis of these conditions in infants remains a considerable challenge. Clinical exome sequencing (CES) has shown to be a successful tool for the early diagnosis of genetic conditions, however, its utility in African infant populations has not been investigated. The impact of the under-representation of African genomic data, the cost of testing, and genomic workforce shortages, need to be investigated and evidence-based implementation strategies accounting for locally available genetics expertise and diagnostic infrastructure need to be developed. We evaluated the diagnostic utility of singleton CES in a cohort of 32 ill, South African infants from two State hospitals in Johannesburg, South Africa. We analysed the data using a series of filtering approaches, including a curated virtual gene panel consisting of genes implicated in neonatal-and early childhood-onset conditions and genes with known founder and common variants in African populations. We reported a diagnostic yield of 22% and identified seven pathogenic variants in the NPHS1, COL2A1, OCRL, SHOC2, TPRV4, MTM1 and STAC3 genes. This study demonstrates the utility value of CES in the South African State healthcare setting, providing a diagnosis to patients who would otherwise not receive one and allowing for directed management. We anticipate an increase in the diagnostic yield of our workflow with further refinement of the study inclusion criteria. This study highlights important considerations for the implementation of genomic medicine in under-resourced settings and in under-represented African populations where variant interpretation remains a challenge.

Heterozygote to homozygote related living donor liver transplantation in maple syrup urine disease: a case report.

Liver transplantation is an accepted treatment modality in the management of MSUD. To our knowledge, ours is only the second successful case to date of a patient with MSUD receiving an allograft from an RLD who is a heterozygous carrier for the disease. In view of the worldwide shortage of available organs for transplantation, heterozygote to homozygote transplantation in the setting of MSUD may provide a viable alternative for those awaiting transplantation. We report on the case of a two-yr-old infant with MSUD, who received a left lateral segment (segments II and III) liver transplant from his mother, a heterozygote carrier of one of the three abnormal genes implicated in MSUD. Post-operative BCAA levels normalized in our patient and remained so on an unrestricted protein diet and during times of physiological stress. To date, this is only the second case of a successful RLD liver transplant in a child with MSUD. Preliminary results indicate that RLD liver transplants are at least equivalent to deceased donor liver transplants in the treatment of MSUD, although longer term follow-up is required. Heterozygote to homozygote RLD transplant in patients with MSUD presents a new pool of potential liver donors.

Paediatric liver transplantation in Johannesburg revisited: 59 transplants and challenges met.

BACKGROUND: A paediatric liver transplant programme was started at the Wits Donald Gordon Medical Centre, Johannesburg, South Africa (SA), in November 2005. We reported on the first 29 patients in 2012. Since then we have performed a further 30 transplants in 28 patients, having met the major challenge of donor shortage by introducing a living related donor programme and increasing the use of split liver grafts. OBJECTIVE: To review the Wits Donald Gordon Medical Centre paediatric liver transplant programme to date. We describe how the programme has evolved and specifically compare the outcomes of the first cohort with the most recent 28 patients. METHODS: Case notes of all paediatric liver transplants performed between 14 November 2005 and 30 June 2014 were retrospectively reviewed. Data were analysed for age and weight at transplantation, indication and type of graft. Morbidity and mortality were documented, specifically biliary and vascular complications. Comparison was made between Era 1 (November 2005 - October 2012) and Era 2 (November 2012 - June 2014). RESULTS: A total of 59 transplants were performed in 57 patients. Age at transplantation ranged from 9 months to 213 months (mean 82.39 months) and weight ranged from 5 kg to 62 kg (mean 21 kg). A total of 23 whole livers, 10 reduced-size grafts, 14 split liver grafts and 12 living donor liver transplants (LDLTs) were performed. Eight patients were referred with fulminant hepatic failure (FHF), all in Era 2. Of these, three patients were successfully transplanted. Of the 57 patients, 45 are alive and well with actuarial 1-year patient and graft survival of 85% and 84% and 5-year patient and graft survival of 78% and 74%, respectively. Sixteen (25.42%) biliary complications occurred in 15 of our 59 transplants. Seven patients developed significant vascular complications. Comparing Era 1 with Era 2, mean age at transplant decreased from 100.86 months to 64.73 months, mean weight from 25.2 kg to 16.9 kg, and type of graft utilised changed with a trend away from the use of whole livers and reduced-sized grafts to split livers and segment 2,3 LDLT grafts. CONCLUSION: Initially limited by a shortage of donor organs, we aggressively explored optimal utilisation, splitting liver grafts from deceased donors as often as possible and establishing an LDLT programme. This increased access to donor livers allowed us to include patients with FHF and to perform retransplantation in recipients with early graft failure. It remains to offer liver transplantation to the entire paediatric community in SA, in conjunction with the only other established paediatric liver transplant unit, at Red Cross War Memorial Children's Hospital in Cape Town.