Michael Urban’s research while affiliated with National Health Laboratory Service and other places

Purpose Limited data exist on managing hereditary breast cancer in low‐ middle‐income countries (LMICs). We assessed proband and cascade genetic testing, and risk‐reducing measures in a South African regional breast cancer service. Methods We analysed records from 534 consecutive female probands receiving genetic counselling for breast cancer and their 115 relatives who attended genetic counselling. Demographic and clinical data, family pedigrees and genetic test data were collated from hospital clinical records, regional laboratory data, screening appointments and radiological records. Results Test uptake in probands was high (86.9%), although cost was a deterrent in some. There were 83 (19.6%) probands who tested positive, and 45.0% of them had one or more family members have testing. This resulted in 9.2% of relatives (first‐ to third‐degree) having cascade testing. Family testing was associated with a stronger family history of cancer, female gender and being a first‐degree relative (uptake was 25.6% in female first‐degree relatives). Risk‐reducing mastectomy was accepted by 52.6% of eligible female family members, while mammographic surveillance (30%) and bilateral salpingo‐oophorectomy (15.4%) were less frequent. Conclusion Genetic testing was well accepted by probands, but uptake was low in family members. Overall, one family member carrying a pathogenic variant was identified for every 13 probands receiving genetic counselling and for every 11 probands tested. Risk‐reducing measures were taken up by over half of those eligible. Limited uptake of cascade testing and variable uptake of risk‐reducing options impacted the programme. To our knowledge, this is the first study in Africa of the real‐world effectiveness of a breast cancer genetic service.

Purpose Breast cancer (BC) is the commonest cancer in South African women. A proportion are associated with a pathogenic or likely pathogenic (P/LP) variant in a BC susceptibility gene. Clinical guidelines for genetic testing are used to optimise variant detection while containing costs. We assessed the detection rate in women of diverse ancestries who met the South African National Department of Health (NDOH) testing guidelines, and analysed relationships between testing criteria, participant characteristics and presence of a BRCA1/2 P/LP variant. Methods Records from 376 women with BC who met NDOH criteria and had genetic testing were included. Demographic, clinical and test result data were collated to describe detection rates according to criteria met, and a multivariate analysis conducted to find variables most frequently associated with a P/LP variant. Results P/LP variant prevalence in women meeting NDOH testing criteria was 19.9% (75/376). Women meeting ≥ 2 guideline criteria were over twice as likely to have a P/LP variant (OR 2.27, 95%CI 1.27–4.07, p = 0.006), highlighting the guidelines’ capacity to stratify risk. Family history (OR 1.97; 95%CI 1.05–3.70, p = 0.03) and Black African ancestry (OR 2.58; 95%CI 1.28–5.18, p < 0.01) were independently associated with having a BRCA1/2 P/LP variant when controlling for other variables. Notably, although Black African participants were less likely to report a family history, those that did had higher odds of a P/LP variant in BRCA1/2. Conclusion These results demonstrate the usefulness of the NDOH guidelines in women of diverse ancestries and provide insight into the factors associated with P/LP variants in understudied African populations.

Concurrent testing of numerous genes for hereditary breast cancer (BC) is available but can result in management difficulties. We evaluated use of an expanded BC gene panel in women of diverse South African ancestries and assessed use of African genomic data to reclassify variants of uncertain significance (VUS). A total of 331 women of White, Black African, or Mixed Ancestry with BC had a 9‐gene panel test, with an additional 75 genes tested in those without a pathogenic/likely pathogenic (P/LP) variant. The proportion of VUS reclassified using ClinGen gene‐specific allele frequency (AF) thresholds or an AF > 0.001 in nonguidelines genes in African genomic data was determined. The 9‐gene panel identified 58 P/LP variants, but only two of the P/LP variants detected using the 75‐gene panel were in confirmed BC genes, resulting in a total of 60 (18.1%) in all participants. P/LP variant prevalence was similar across ancestry groups, but VUS prevalence was higher in Black African and Mixed Ancestry than in White participants. In total, 611 VUS were detected, representing 324 distinct variants. 10.8% (9/83) of VUS met ClinGen AF thresholds in genomic data while 10.8% (26/240) in nonguideline genes had an AF > 0.001. Overall, 27.0% of VUS occurrences could potentially be reclassified using African genomic data. Thus, expanding the gene panel yielded few clinically actionable variants but many VUS, particularly in participants of Black African and Mixed Ancestry. However, use of African genomic data has the potential to reclassify a significant proportion of VUS.

Primary immunodeficiency disorders (PIDs) are inborn errors of immunity (IEI) that cause immune system impairment. To date, more than 400 single-gene IEI have been well defined. The advent of next generation sequencing (NGS) technologies has improved clinical diagnosis and allowed for discovery of novel genes and variants associated with IEI. Molecular diagnosis provides clear clinical benefits for patients by altering management, enabling access to certain treatments and facilitates genetic counselling. Here we report on an 8-year experience using two different NGS technologies, namely research-based WES and targeted gene panels, in patients with suspected IEI in the South African healthcare system. A total of 52 patients’ had WES only, 26 had a targeted gene panel only, and 2 had both panel and WES. Overall, a molecular diagnosis was achieved in 30% (24/80) of patients. Clinical management was significantly altered in 67% of patients following molecular results. All 24 families with a molecular diagnosis received more accurate genetic counselling and family cascade testing. Results highlight the clinical value of expanded genetic testing in IEI and its relevance to understanding the genetic and clinical spectrum of the IEI-related disorders in Africa. Detection rates under 40% illustrate the complexity and heterogeneity of these disorders, especially in an African population, thus highlighting the need for expanded genomic testing and research to further elucidate this.

Background: The X-linked recessive primary immunodeficiency disease (PIDD) Wiskott-Aldrich syndrome (WAS) is identified by an extreme susceptibility to infections, eczema and thrombocytopenia with microplatelets. The syndrome, the result of mutations in the WAS gene which encodes the Wiskott-Aldrich protein (WASp), has wide clinical phenotype variation, ranging from classical WAS to X-linked thrombocytopaenia and X-linked neutropaenia. In many cases, the diagnosis of WAS in first affected males is delayed, because patients may not present with the classic signs and symptoms, which may intersect with other thrombocytopenia causes. Case presentation: Here, we describe a three-year-old HIV negative boy presenting with recurrent infections, skin rashes, features of autoimmunity and atopy. However, platelets were initially reported as normal in numbers and morphology as were baseline immune investigations. An older male sibling had died in infancy from suspected immunodeficiency. Uncertainty of diagnosis and suspected severe PIDD prompted urgent further molecular investigation. Whole exome sequencing identified c. 397 G > A as a novel hemizygous missense mutation located in exon 4 of WAS. Conclusion: With definitive molecular diagnosis, we could target treatment and offer genetic counselling and prenatal diagnostic testing to the family. The identification of novel variants is important to confirm phenotype variations of a syndrome.

Background: Neural tube defects (NTDs) are an important category of birth defect, but surveillance remains inadequate in South Africa. Objectives: To assess the identification of NTDs at a tertiary hospital using a range of prenatal, perinatal and postnatal data sources, and to estimate the impact of prenatal diagnosis and birth prevalence for the referral area. Methods: Cases of anencephaly, encephalocele and spina bifida (SB) in a 6-year period were retrospectively identified from 5 data sources covering prenatal, perinatal and postnatal care. These were cross-correlated to avoid duplicate entries and to determine the contribution of different data sources. Details of prenatal diagnosis and termination of pregnancy (TOP) were obtained for 10 years, and birth prevalence over 2 years. Results: During a 6-year period 195 NTDs were identified at a Western Cape Province tertiary hospital. These included 59 (30%) cases of anencephaly, 28 (14%) of encephalocele and 108 (55%) of SB. The majority of NTDs (71%) were detected prenatally, although SB was less commonly diagnosed prenatally than cranial defects (56% v. 88%; p<0.001). Of SB cases ascertained pre- or postnatally, 57% of patients were born alive and 50% discharged alive, but 72% of survivors had not been diagnosed prenatally. Women receiving prenatal diagnosis of any type of NTD before 24 weeks' gestation were nearly always offered TOP, and the majority accepted termination after non-directive counselling. For SB, later prenatal diagnosis was associated with much lower termination rates because the option was less often offered (51% v. 100%; p<0.001), and perhaps less often accepted (57% v. 78%; p=0.06). The estimated NTD birth prevalence for the referral area was 0.76 - 0.80 per 1 000 live births, but perhaps up to 1.18 per 1 000 when considering under-referral of lethal cranial lesions from rural areas. Conclusions: A substantial number of NTDs can be ascertained from a tertiary hospital environment if multiple data sources are used, even though adding data from the Perinatal Problem Identification Program for outlying health facilities increases detection of lethal defects. Hospital-based surveillance can be considered, especially for SB. Prenatal diagnosis was fairly common and pregnancy termination was often offered and accepted if detected before 24 weeks' gestation. A regional prenatal ultrasound programme, predominantly based in primary care but with ready access to a tertiary centre, can be quite effective, although limited or delayed access to prenatal diagnosis must be addressed.

Two of the most common cancers are breast cancer and colorectal cancer. Up to 10% of cases of each are associated with a high risk of recurrence in an affected individual, or of occurrence in biological relatives. This results from the presence of an underlying mutation (or 'pathogenic variant') in a high-penetrance gene. Such cases are typically associated with an autosomal dominant pattern of inheritance, although this may not be obvious in the family history. Genetic testing can identify many (but not all) of these cases, and should be offered to those whose family history or clinical features suggest a high risk. Although testing for certain risk genes (e.g. BRCA1 or BRCA2) has been available for years, the advent of next-generation sequencing gene panels' now allows for simultaneous testing of many more genes at lower cost. This allows for more frequent detection of pathogenic variants in underlying genes than in the past, but also makes interpretation more complex. An index of suspicion for genetic cancers and appropriate referral to a genetics health professional are increasingly important.

Two of the most common cancers are breast cancer and colorectal cancer. Up to 10% of cases of each are associated with a high risk of recurrence in an affected individual, or of occurrence in biological relatives. This results from the presence of an underlying mutation (or ‘pathogenic variant’) in a high-penetrance gene. Such cases are typically associated with an autosomal dominant pattern of inheritance, although this may not be obvious in the family history. Genetic testing can identify many (but not all) of these cases, and should be offered to those whose family history or clinical features suggest a high risk. Although testing for certain risk genes (e.g. BRCA1 or BRCA2) has been available for years, the advent of next-generation sequencing ‘gene panels’ now allows for simultaneous testing of many more genes at lower cost. This allows for more frequent detection of pathogenic variants in underlying genes than in the past, but also makes interpretation more complex. An index of suspicion for genetic cancers and appropriate referral to a genetics health professional are increasingly important.

While individual primary immunodeficiency diseases (PIDs) are rare, collectively they represent a significant burden of disease. Recent estimates show that about one million people in Africa suffer from a PID. However, data from African PID registries reflect only a small percentage of the estimated prevalence. This disparity is partly due to the lack of PID awareness and the masking of PIDs by the endemic pathogens. Over three million tuberculosis (TB) cases were reported in Africa in 2016, with many of these from southern Africa. Despite concerted efforts to address this high burden of disease, the underlying genetic correlates of susceptibility to TB remain poorly understood. High penetrance mutations in immune system genes can cause PIDs that selectively predispose individuals to TB and other mycobacterial diseases. Additionally, the identification of individuals at a heightened risk of developing TB or of presenting with severe or disseminated TB due to their genetic ancestry is crucial to promote a positive treatment outcome. The screening for and identification of PID mutations in TB-endemic regions by next-generation sequencing (NGS) represents a promising approach to improve the understanding of what constitutes an effective immune response to TB, as well as the range of associated PIDs and phenotypes.