Healthcare Utilization 12 Months Prior to Fatal and Non-fatal Suicidal Behaviour in Cape Town, South Africa.

The purpose of this study was to characterize healthcare use for general care and mental health one year before suicidal behavior among individuals with fatal and non-fatal suicidal behavior (NFSB) in Cape Town, South Africa. We linked electronic health records of 484 participants from a case series of 93 completed suicides on whom forensic autopsies were performed at a mortuary in Cape Town, between August 2014 and January 2016; and 391 patients admitted to hospital following NFSB between June 2014 and March 2015, and between August 2015 and August 2017. Time from last healthcare visit to date of suicidal behavior (fatal or non-fatal) was calculated, and Kaplan Meier curves were used to compare the differences by psychiatric diagnoses and study group. Overall, 64.5% of completed suicides and 65.9% of NFSB patients sought general healthcare in the year before suicidal behavior. Most of these visits occurred at hospital outpatient clinics (40.8%) and primary healthcare facilities (31.3%). The prevalence of preexisting psychiatric diagnoses and the use of mental healthcare services was lower for individuals who completed suicide compared to NFSB patients. Common reasons for a healthcare visit among individuals who completed suicide were chronic disease and assault; and psychiatric illness (depression, bipolar, and/or substance use disorders), chronic disease and HIV among NFSB patients. A large proportion of individuals with fatal and NFSB interacted with the healthcare system before suicidal behavior. These findings suggest opportunities for suicide prevention at primary healthcare facilities, antiretroviral treatment centers and emergency departments.HIGHLIGHTSHealthcare access is common among individuals with fatal and NFSB in the year before suicidal behavior.The prevalence of mental disorder diagnoses is higher among NFSB patients than among individuals who completed suicide.A greater proportion of NFSB patients accessed mental healthcare services compared to individuals who completed suicide.

Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up.

ABSTRACT: The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33-0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non-colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32-0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non-colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62-1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non-colorectal cancer cancers for patients with LS. PREVENTION RELEVANCE: Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers. See related Spotlight, p. 557.

Organophosphate pesticide exposure as a risk factor for attempted suicide in Cape Town, South Africa: A case-control study.

Pesticides are a commonly used agent for suicide in many Low- and Middle-Income countries (LMICs). However, accumulating evidence suggests that exposure to organophosphate (OP) pesticide may also increase the risk of suicide. We conducted a hospital-based case-control study to investigate whether prior household, garden or occupational OP exposure were associated with attempted suicide using conditional logistic regression modeling. Participants who attempted suicide with any means and were admitted to two Western Cape Province hospitals in South Africa were compared to a sample of controls matched by age, sex and time of admission with unrelated conditions, between August 2015 and August 2017. The means of attempted suicide was not recorded. OP exposure was determined by dialkyl phosphate (DAP) metabolites detected in hair and by environmental and occupational history. Approximately 85% of participants reported using pesticides in the home or garden and 15% of participants reported current or past occupational exposure while working on a farm. Attempted suicide was not associated with reported home or garden OP use (Odds ratio [OR] = 0.59, 95%CI 0.33-1.04), hair DAP metabolites (OR = 1.00, 95%CI 0.98-1.02) or current or past agricultural work (OR = 1.08, 95%CI 0.62-1.87), but was associated with hazardous drinking and unemployment with no household income. We found no evidence that attempted suicide was associated with environmental or occupational pesticide use in an urban South African population attending an emergency center.

Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa.

The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.

Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.

More than two decades ago, a recessive syndromic phenotype affecting kidneys, eyes, and ears, was first described in the endogamous Afrikaner population of South Africa. Using whole-exome sequencing of DNA from two affected siblings (and their carrier parents), we identified the novel RRM2B c.786G>T variant as a plausible disease-causing mutation. The RRM2B gene is involved in mitochondrial integrity, and the observed change was not previously reported in any genomic database. The subsequent screening revealed the variant in two newly presenting unrelated patients, as well as two patients in our registry with rod-cone dystrophy, hearing loss, and Fanconi-type renal disease. All patients with the c.786G>T variant share an identical 1.5 Mb haplotype around this gene, suggesting a founder effect in the Afrikaner population. We present ultrastructural evidence of mitochondrial impairment in one patient, to support our thesis that this RRM2B variant is associated with the renal, ophthalmological, and auditory phenotype.

Whole-exome sequencing in an Afrikaner family with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) has considerable heritability, with genome-wide association studies indicating that multiple common genetic variants contribute to risk. Less work has been undertaken to assess the contribution of rare variation in the development of this complex disorder, particularly in isolated populations. Using whole-exome sequencing (WES), the aim of this study was to identify rare, potentially damaging variants contributing to risk for BD in the Afrikaner population. METHODS: WES was performed on eight Afrikaner family members, five affected and three unaffected. The analyses focused on i) the identification of rare, damaging variation, and ii) the molecular pathways in which these rare variants play a role using in silico prediction tools such as wANNOVAR and KOBAS 3.0. RESULTS: Two rare and potentially damaging missense variants in FAM71B and SLC26A9 were shared by affected family members but were absent in unaffected members. In addition, variants in genes that play a role in pathways involved in signal transduction and synaptic transmission were shared by the five affected individuals. LIMITATIONS: Two main limitations affect this study: the limited number of cases and controls, and the fact that whole-exome sequencing can only capture a small fragment of the genome which may harbor mutations. CONCLUSION: This is the first WES study of BD in an Afrikaner family, and findings suggest that novel candidate genes may contribute to risk for BD in this population. Future work in larger samples of this population as well as in other populations is needed to fully investigate the role of the candidate genes found here.

Building Skills and Resources for Genomics, Epigenetics, and Bioinformatics Research for Africa: Report of the Joint 11th Conference of the African Society of Human Genetics and 12th H3Africa Consortium, 2018.

The 11th Congress of the African Society of Human Genetics (AfSHG) was held from September 16, 2018 to September 21, 2018, in conjunction with the 12th Human Heredity and Health in Africa (H3Africa) Consortium meeting in Kigali, Rwanda. The event was organized by the AfSHG in partnership with the Rwanda Society of Human Genetics and the University of Rwanda. A 2-day workshop on the application of next-generation sequencing technologies for analyzing monogenic disease in African populations was organized as part of the conference (September 22, 2018-September 23, 2018, Kigali, Rwanda). The theme of the conference was "Building skills and resources for genomics, epigenetics and bioinformatics research for Africa." The conference served as a platform to bring together members from country-specific Societies of Human Genetics, including Rwanda, Cameroon, Democratic Republic of Congo, Egypt, Mali, Senegal, and South Africa, and included 435 delegates from 38 countries, including 29 African countries that attended the conference. A major topic of discussion was how to bridge the gap between the emerging knowledge on genomics and Omics in African populations. The importance of understanding the role of genetic variation in disease causation and susceptibility among Africans was a constant theme during the meeting, as was the need to develop research infrastructure and resources to enhance healthcare systems, so that they are not left behind in the genomic revolution. It was concluded that there is a need to inspire more African scientists to train and work as investigators, clinicians, and genetic counselors in the field of human genetics in Africa. Local investments, and South-South and South-North collaboration were identified as the key drivers for the successful implementation of research and development on the continent.

Developing a Road Map to Spread Genomic Knowledge in Africa: 10th Conference of the African Society of Human Genetics, Cairo, Egypt.

The tenth conference of the African Society of Human Genetics was held in Egypt with the theme "Human Genetics and Genomics in Africa: Challenges for Both Rare and Common Genetic Disorders." Current research was presented, and we discussed visions for the future of genomic research on the African continent. In this report, we summarize the presented scientific research within and relevant to Africa as presented by both African and non-African scientists. We also discuss the current situation concerning genomic medicine and genomic research within the continent, difficulties in implementing genetic services and genomic medicine in Africa, and a road map to overcome those difficulties and meet the needs of the African researchers and patients.

Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma.

PURPOSE: To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma. DESIGN: Case series. PARTICIPANTS: Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma. METHODS: We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography. MAIN OUTCOME MEASURES: IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings. RESULTS: We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula. CONCLUSIONS: IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype-phenotype correlations.

Molecular Diagnosis of Inherited Retinal Diseases in Indigenous African Populations by Whole-Exome Sequencing.

Purpose: A majority of genes associated with inherited retinal diseases (IRDs) have been identified in patients of European origin. Indigenous African populations exhibit rich genomic diversity, and evaluation of reported genetic mutations has yielded low returns so far. Our goal was to perform whole-exome sequencing (WES) to examine variants in known IRD genes in underrepresented African cohorts. Methods: Whole-exome sequencing was performed on 56 samples from 16 families with diverse IRD phenotypes that had remained undiagnosed after screening for known mutations using genotyping-based microarrays (Asper Ophthalmics). Variants in reported IRD genes were identified using WES and validated by Sanger sequencing. Custom TaqMan assays were used to screen for identified mutations in 193 unrelated indigenous Africans with IRDs. Results: A total of 3494 variants were identified in 217 known IRD genes, leading to the identification of seven different mutations (including six novel) in six genes (RHO, PRPF3, PRPF31, ABCA4, CERKL, and PDE6B) in six distinct families. TaqMan screening in additional probands revealed identical homozygous CERKL and PDE6B variants in four more patients. Conclusions: This is the first report of WES of patients with IRDs in indigenous African populations. Our study identified genetic defects in almost 40% of the families analyzed, significantly enhancing the molecular diagnosis of IRD in South Africa. Thus, WES of understudied cohorts seems to present an effective strategy for determining novel mutations in heterogeneous retinal diseases.

Minimum information required for a DMET experiment reporting.

AIM: To provide pharmacogenomics reporting guidelines, the information and tools required for reporting to public omic databases. MATERIAL & METHODS: For effective DMET data interpretation, sharing, interoperability, reproducibility and reporting, we propose the Minimum Information required for a DMET Experiment (MIDE) reporting. RESULTS: MIDE provides reporting guidelines and describes the information required for reporting, data storage and data sharing in the form of XML. CONCLUSION: The MIDE guidelines will benefit the scientific community with pharmacogenomics experiments, including reporting pharmacogenomics data from other technology platforms, with the tools that will ease and automate the generation of such reports using the standardized MIDE XML schema, facilitating the sharing, dissemination, reanalysis of datasets through accessible and transparent pharmacogenomics data reporting.

A Founder Mutation in MYO7A Underlies a Significant Proportion of Usher Syndrome in Indigenous South Africans: Implications for the African Diaspora.

PURPOSE: Research over the past 25 years at the University of Cape Town has led to the identification of causative mutations in 17% of the 1416 families in the Retinal Degenerative Diseases (RDD) biorepository in South Africa. A low rate of mutation detection has been observed in patients of indigenous African origin, hinting at novel genes and mutations in this population. Recently, however, data from our translational research program showed two unrelated indigenous African families with Usher syndrome (USH), with the same homozygous MYO7A mutation. Therefore, the extent to which this mutation contributes toward the disease burden in South Africa was investigated. METHODS: Cohorts of unrelated indigenous South African probands with different RDD diagnoses were tested for the MYO7A c.6377delC mutation. Familial cosegregation analysis was performed for homozygous probands, clinical data were evaluated, and SNP haplotypes were analyzed. RESULTS: This homozygous MYO7A mutation underlies a remarkable 43% of indigenous African USH cases investigated in this study, the majority of which (60%) were diagnosed clinically with Type 2 USH. All homozygotes shared a common haplotype. This mutation does not appear to cause nonsyndromic vision loss. CONCLUSIONS: Of interest is the origin of this common mutation relevant to the Bantu population migration into southern Africa. Further investigation of the phenotype may elucidate the disease biology, and perhaps reveal a larger cohort with the same mutation, with which to assess the impact of environmental and genetic modifiers and evaluate therapeutic trials.

Obesity, Aspirin, and Risk of Colorectal Cancer in Carriers of Hereditary Colorectal Cancer: A Prospective Investigation in the CAPP2 Study.

PURPOSE: In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This prospective study investigated the association between body mass index and cancer risk in patients with Lynch syndrome (LS). PATIENTS AND METHODS: Participants with LS were recruited to the CAPP2 study, in which they were randomly assigned to receive aspirin 600 mg per day or aspirin placebo, plus resistant starch 30 g per day or starch placebo (2 × 2 factorial design). Mean intervention period was 25.0 months, and mean follow-up was 55.7 months. RESULTS: During follow-up, 55 of 937 participants developed CRC. For obese participants, CRC risk was 2.41× (95% CI, 1.22 to 4.85) greater than for underweight and normal-weight participants (reference group), and CRC risk increased by 7% for each 1-kg/m(2) increase in body mass index. The risk of all LS-related cancers in obese people was 1.77× (95% CI, 1.06 to 2.96; P = .03) greater than for the reference group. In subgroup analysis, obesity was associated with 3.72× (95% CI, 1.41 to 9.81) greater CRC risk in patients with LS with MLH1 mutation, but no excess risk was observed in those with MSH2 or MSH6 mutation (P = .5). The obesity-related excess CRC risk was confined to those randomly assigned to the aspirin placebo group (adjusted hazard ratio, 2.75; 95% CI, 1.12 to 6.79; P = .03). CONCLUSION: Obesity is associated with substantially increased CRC risk in patients with LS, but this risk is abrogated in those taking aspirin. Such patients are likely to benefit from obesity prevention and/or regular aspirin.

Exploring researchers' experiences of working with a researcher-driven, population-specific community advisory board in a South African schizophrenia genomics study.

BACKGROUND: Community engagement within biomedical research is broadly defined as a collaborative relationship between a research team and a group of individuals targeted for research. A Community Advisory Board (CAB) is one mechanism of engaging the community. Within genomics research CABs may be particularly relevant due to the potential implications of research findings drawn from individual participants on the larger communities they represent. Within such research, CABs seek to meet instrumental goals such as protecting research participants and their community from research-related risks, as well as intrinsic goals such as promoting the respect of participants and their community. However, successful community engagement depends on the degree to which CABs legitimately represent and engage with communities targeted for research. Currently, there is little literature describing the use of CABs in genomics research taking place in developing countries, and even less in the field of genomics research relating to mental illness. The aim of this article is to describe and consider the contributions made by a researcher-driven, population-specific CAB in a genomics of schizophrenia research project taking place in South Africa, from the perspective of the research team. DISCUSSION: Four broad discussion topics emerged during the CAB meetings namely: 1) informed consent procedures, 2) recruitment strategies, 3) patient illness beliefs and stigma experiences, and 4) specific ethical concerns relating to the project. The authors consider these discussions in terms of their contributions to instrumental and intrinsic goals of community engagement. The CAB gave valuable input on the consent processes and materials, recruitment strategies and suggested ways of minimizing the potential for stigma and discrimination. All of these contributions were of an instrumental nature, and helped improve the way in which the research took place. In addition, and perhaps more importantly, the CAB made a unique and important contribution relating to intrinsic functions such as promoting the respect and dignity of research participants and their community. This was particularly evident in ensuring sensitivity and respect of the community's traditional beliefs about schizophrenia and its treatment, and in this way promoting a respectful relationship between the research team and the participants.

Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes.

PRPF8-retinitis pigmentosa is said to be severe but there has been no overview of phenotype across different mutations. We screened RP patients for PRPF8 mutations and identified three new missense mutations, including the first documented mutation outside exon 42 and the first de novo mutation. This brings the known RP-causing mutations in PRPF8 to nineteen. We then collated clinical data from new and published cases to determine an accurate prognosis for PRPF8-RP. Clinical data for 75 PRPF8-RP patients were compared, revealing that while the effect on peripheral retinal function is severe, patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. We also noted that prognosis for PRPF8-RP differs with different mutations, with p.H2309P or p.H2309R having a worse prognosis than p.R2310K. This correlates with the observed difference in growth defect severity in yeast lines carrying the equivalent mutations, though such correlation remains tentative given the limited number of mutations for which information is available. The yeast phenotype is caused by lack of mature spliceosomes in the nucleus, leading to reduced RNA splicing function. Correlation between yeast and human phenotypes suggests that splicing factor RP may also result from an underlying splicing deficit.

Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics.

Africa is the ultimate source of modern humans and as such harbors more genetic variation than any other continent. For this reason, studies of the patterns of genetic variation in African populations are crucial to understanding how genes affect phenotypic variation, including disease predisposition. In addition, the patterns of extant genetic variation in Africa are important for understanding how genetic variation affects infectious diseases that are a major problem in Africa, such as malaria, tuberculosis, schistosomiasis, and HIV/AIDS. Therefore, elucidating the role that genetic susceptibility to infectious diseases plays is critical to improving the health of people in Africa. It is also of note that recent and ongoing social and cultural changes in sub-Saharan Africa have increased the prevalence of non-communicable diseases that will also require genetic analyses to improve disease prevention and treatment. In this review we give special attention to many of the past and ongoing studies, emphasizing those in Sub-Saharan Africans that address the role of genetic variation in human disease.

The extracolonic cancer spectrum in females with the common 'South African' hMLH1 c.C1528T mutation.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease, characterized by the occurrence of predominantly colon and endometrial cancer and, less frequently, cancer of the small bowel, stomach, hepatobiliary tract, ureter, renal pelvis, ovaries and brain. The phenotypic diversity may partially be explained by allelic heterogeneity. The aim of this study was to investigate the frequency of extracolonic cancers in a cohort of females sharing the same c.C1528T disease-predisposing mutation in the hMLH1 gene. Data on cancer history were obtained from 87 mutation-positive females and 121 mutation-negative sisters, as a control group. Testing for microsatellite instability (MSI) and expression of the wild-type hMLH1 allele was performed on extra-colonic tumour tissue blocks of mutation-positive individuals. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females vs. 7% (8/121) of mutation-negative females (P = 0.10). Multiple primary cancers occurred at a significantly higher incidence in the first group. Breast cancer, which was the most frequent extra-colonic cancer in mutation positive females (53%), occurred at a young age, and occurred bilaterally in two out of seven cases. Involvement of the hMLH1 gene was confirmed in five out of seven cases of breast cancer, two cases of endometrial cancer, one case of ovarian cancer and one case of renal cell carcinoma, by detecting immunohistochemical compromise of the gene product. Although the study might not have been adequately statistically powered (to provide a significant P value), the noteworthy findings in this study include the confirmation of a range of Lynch II type cancers in a cohort we previously thought was wholly predisposed to Lynch I features, and a confirmation of breast cancer as part of the spectrum of Lynch syndrome cancers affecting women.

Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease.

Genetically determined Alzheimer's disease (AD) is virtually unknown in Africa. We report clinicopathological findings and a presenilin 1 (PS1) mutation associated with early-onset AD in a large Xhosa family from Southern Africa. Twelve individuals spanning four generations were affected, four of whom underwent clinical and psychometric evaluation. Their phenotype was characterized by memory impairment beginning in the early part of the fifth decade, with progressive dementing illness lasting 6-7 years that did not appear to be modified by the presence of an apolipoprotein E (APOE)-epsilon 4 allele. Initial linkage-based analysis using known DNA markers suggested allele cosegregation with a locus on chromosome 14. Direct sequencing of the PS1 gene disclosed a novel I143M (ATT to ATG at nucleotide 677) mutation that lies in a cluster in the second transmembrane domain of the protein. Examination of the proband's brain at autopsy revealed severe AD pathology characterized by neuronal loss, abundant beta amyloid (A beta) neuritic plaques (A beta 42) and neurofibrillary degeneration extending into the brainstem. The phenotype of the I143M mutation was clearly associated with a high degree of neurofibrillary change compared with early-onset sporadic AD cases. Although sporadic cases of AD do exist in African populations, our study confirms the existence of early-onset familial AD among indigenous Southern Africans.