Implications of direct-to-consumer whole-exome sequencing in South Africa

This editorial examines a number of vitally important ethical, legal and scientific concerns that have to be addressed to ensure proper and ethical implementation of direct-to-consumer whole-exome sequencing in South Africa. Individuals taking part in this endeavour must be fully informed of the positive and negative sequelae

Genetic factors influencing inhibitor development in a cohort of South African Haemophilia A patients

Haemophilia A (HA) is a an X-linked bleeding disorder that manifests due to a mutation in the F8 gene encoding the coagulation factor VIII (FVIII) protein. Therapeutic management of HA involves intravenous FVIII infusions which are either plasma derived or recombinant concentrates that are administered to prevent or manage bleeding episodes promptly. A critical complication of repeated FVIII replacement therapy is the production of FVIII neutralising inhibitors which affect the coagulation potential of the replacement therapy, thus compromising the ability to manage bleeding episodes. The genetic and environmental factors predisposing to inhibitor development remain uncertain, and require improved understanding to provide optimal patient care and surveillance. The study firstly aimed to characterise a cohort of South African HA patients in terms of clinical severity, ethnicity, int22 mutation status and inhibitor development; secondly, to explore whether the genetic factors (clinical severity, ethnicity, int22 mutation status, F8 gene haplotype) influence inhibitor development. A total of 229 probands who had diagnostic HA testing at the Molecular Genetics Laboratory, Division of Human Genetics, of the National Health Laboratory Services (NHLS) and School of Pathology, University of the Witwatersrand, Johannesburg, were included in the study. The majority of patients (91%) in the cohort had severe HA. There were a similar proportion of black and white patients in the cohort. There was a 13% incidence of inhibitor development in the cohort of which 72% were black and 28% were white patients. To investigate the influence of genetic factors on inhibitor development only the probands with known inhibitor status were included (n=216). It was established that 36% (77/216) of patients were int22 positive of which 20% (15/77) were reported to be inhibitor positive while 10% (14/139) of the int22 negative patients (n=139) were shown to be inhibitor positive. Therefore, the int22 positive patients had a two-fold higher incidence of inhibitor development than int22 negative patients. F8 gene haplotype analysis revealed that the H1 and H2 haplotypes were the most common in the cohort while the H3 and H5 haplotypes were only reported in black patients. Black patients were shown to have a higher prevalence of inhibitor development within each haplotype, thus suggesting that factors other than F8 gene haplotype are important in inhibitor development. Overall, black int22 positive probands had a significantly higher prevalence (p=0.04) of inhibitor development than white int22 positive and negative patients in the cohort which is suggestive that ethnicity and F8 gene mutation may play a more major role in inhibitor development compared to F8 gene haplotype. Hence, there is a need to identify other genetic factors that may predispose HA patients to inhibitor development

Implications of direct-to-consumer whole-exome sequencing in South Africa

Next-generation sequencing (NGS) has truly transformed human genetics and is now an integral discovery tool in the field. Whole-exome sequencing (WES) – an NGS application focused on the proteincoding regions of the human genome – has already bridged the bench-to-bedside divide internationally and is offered as a clinical test by several accredited laboratories. Clinical WES is not currently offered in South Africa (SA) for a number of reasons, including technological constraints, insufficient storage for the resulting large datasets, ethical considerations and limitations of our understanding of the impact of human genetic variants on health and in terms of clinical utility. The historical under-representation of individuals of black African descent in genomics research further complicates the interpretation of results obtained from WES data in black Africans. Concurrently, the application of WES for preventive healthcare in seemingly healthy individuals is progressing rapidly. WES offered as a direct-to-consumer (DTC) genetic test to healthy individuals in aid of wellness and future disease risk prediction raises many critical considerations, some of which were highlighted previously in the SAMJ by the Southern African Society for Human Genetics. This topic is currently back in the headlines as local health insurance company Discovery Health launched their suite of personalised medicine products, which includes WES.[5-7] This offering is presented in partnership with US-based company Human Longevity, Inc. (HLI) under the leadership of J Craig Venter.http://www.samj.org.zaam2017Immunolog

Implications of direct-to-consumer whole-exome sequencing in South Africa

Next-generation sequencing (NGS) has truly transformed human genetics and is now an integral discovery tool in the field. Whole-exome sequencing (WES) – an NGS application focused on the proteincoding regions of the human genome – has already bridged the bench-to-bedside divide internationally and is offered as a clinical test by several accredited laboratories. Clinical WES is not currently offered in South Africa (SA) for a number of reasons, including technological constraints, insufficient storage for the resulting large datasets, ethical considerations and limitations of our understanding of the impact of human genetic variants on health and in terms of clinical utility. The historical under-representation of individuals of black African descent in genomics research further complicates the interpretation of results obtained from WES data in black Africans. Concurrently, the application of WES for preventive healthcare in seemingly healthy individuals is progressing rapidly. WES offered as a direct-to-consumer (DTC) genetic test to healthy individuals in aid of wellness and future disease risk prediction raises many critical considerations, some of which were highlighted previously in the SAMJ by the Southern African Society for Human Genetics. This topic is currently back in the headlines as local health insurance company Discovery Health launched their suite of personalised medicine products, which includes WES.[5-7] This offering is presented in partnership with US-based company Human Longevity, Inc. (HLI) under the leadership of J Craig Venter.http://www.samj.org.zaam2017Immunolog