Genetics of schizophrenia in the South African Xhosa.

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.

Strengthening human genetics research in Africa: report of the 9th meeting of the African Society of Human Genetics in Dakar in May 2016.

The 9th meeting of the African Society of Human Genetics, in partnership with the Senegalese Cancer Research and Study Group and the Human Heredity and Health in Africa (H3Africa) Consortium, was held in Dakar, Senegal. The theme was Strengthening Human Genetics Research in Africa. The 210 delegates came from 21 African countries and from France, Switzerland, UK, UAE, Canada and the USA. The goal was to highlight genetic and genomic science across the African continent with the ultimate goal of improving the health of Africans and those across the globe, and to promote the careers of young African scientists in the field. A session on the sustainability of genomic research in Africa brought to light innovative and practical approaches to supporting research in resource-limited settings and the importance of promoting genetics in academic, research funding, governmental and private sectors. This meeting led to the formation of the Senegalese Society for Human Genetics.

Le 9ème congrès de la Société Africaine de Génétique Humaine, en partenariat avec le Groupe d'Etude et de Recherche sur le Cancer (GERC) et le Consortium H3Africa, s'est tenu à Dakar, au Sénégal. Le thème était «Renforcer la recherche en Génétique Humaine en Afrique¼. Les 210 participants sont venus de 21 pays africains et de six non africains. L'objectif était de valoriser la génétique et la génomique à travers l'Afrique avec comme but ultime d'améliorer la santé des populations, et de promouvoir les carrières des jeunes chercheurs Africains. Une session sur la pérennité de la recherche génomique a révélé des approches innovantes et pratiques supportant la recherche dans des contextes de ressources limitées et l'importance de promouvoir la formation universitaire en génétique, le financement de la recherche par les gouvernements et le privé. Ce congrès conduisit à la création de la Société Sénégalaise de Génétique Humaine.

Promoter region variation in NFE2L2 influences susceptibility to ototoxicity in patients exposed to high cumulative doses of cisplatin.

Ototoxicity is a disabling reaction to cisplatin chemotherapy. Much of the inter-individual variability in the development of hearing impairment among cisplatin-receiving patients has not been fully accounted for. In particular, little is known about the pharmacogenomics of cisplatin-induced ototoxicity. This study sought to investigate the role of variation in five candidate genes in a cohort of South African cancer patients. Five variants within the candidate genes were genotyped in 214 patients, of which SLC22A2 rs316019 and NFE2L2 rs6721961 associated with reduced rates of ototoxicity. In the patients who were exposed to cumulative cisplatin doses ⩾200 mg m-2 (n=113), the variant rs6721961 associated with ototoxicity according to three different grading scales of hearing loss (ASHA, P=0.005; Chang, P=0.028; CTCAE, P=0.004). The NFE2L2 promotor variant rs6721961 may therefore be protective against hearing loss in cisplatin-receiving cancer patients.

Inherited retinal disorders in South Africa and the clinical impact of evolving technologies.

Retinal degenerative disorders (RDDs) encompass a group of inherited diseases characterised by vision loss. The genetic and clinical complexity poses a challenge in unravelling the molecular genetic aetiology of this group of disorders. Furthermore, the population diversity in South Africa (SA) presents researchers with a particularly complicated task. Rapid advances in the development of cutting-edge technological platforms over the past two decades, however, have assisted in overcoming some of the challenges. The RDD research team has utilised these escalating technologies, which has facilitated a corresponding increase in molecular diagnoses. A biorepository has been established and comprises ~3 200 patient DNA samples archived with many forms of RDD (including retinitis pigmentosa, macular dystrophies, Stargardt disease, Leber congenital amaurosis, Usher syndrome and Bardet Biedl syndrome). A comprehensive review is presented of the SA journey spanning 25 years, into elucidating the molecular genetic basis of various forms of RDD in SA.

Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type); mutation analysis in eight affected South African families.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMD-JL), type 1 is an autosomal recessive disorder which has been identified in more than 30 affected children in the Afrikaans-speaking community of South Africa. Sequencing of B3GALT6 revealed a specific mutation, c.235A > G, in homozygous form in four families, while three others were compound heterozygotes for this mutation in combination with the c.200C > T mutation. In addition, a proband from one family carried the c.16C > T mutation combined with c.200C > T. In a series of five Iranian persons, mutations in B3GALT6 have been implicated in a syndrome characterised by skeletal abnormalities with intellectual disability, bone and connective tissue fragility. Other mutations in B3GALT6 resulted in the classical SEMD-JL phenotype in seven Japanese families and in a syndrome which has been likened to a progeroid form of Ehlers-Danlos syndrome (EDS). It is evident that there is considerable intragenic heterogeneity in B3GALT6. One of the mutations, c.200C > T, in the affected South Africans was also present in one of the Japanese persons and the respective phenotypes were identical. The multiplicity of allelic mutations and the phenotypic differences in the affected persons supports the concept that a spectrum of connective tissue disorders is programmed by mutations in B3GALT6.

Identification of new cases of early-onset colorectal cancer with an MLH1 epimutation in an ethnically diverse South African cohort.

Lynch syndrome, characterized by young-onset microsatellite unstable colorectal, endometrial and other cancers, is caused by germline mutations of the mismatch repair genes, most commonly MLH1, MSH2 and MSH6. Constitutional MLH1 epimutations, which manifest as soma-wide methylation and transcriptional silencing of a single allele, have been identified in a subset of patients with a Lynch syndrome phenotype in the absence of a mismatch repair mutation. This study aimed to determine if MLH1 epimutations predispose to the development of young-onset colorectal cancer in an ethnically diverse population of South African subjects. A total of 122 index cases with a diagnosis of colorectal cancer below 50 years of age, who had tested negative for a definitive pathogenic mutation of the key mismatch repair genes, were screened for constitutional MLH1 methylation in their leukocyte DNA. Monoallelic MLH1 epimutations were identified in two sporadic cases (1.6%): a male of black African descent and an Asian Indian female. Few alleles were affected by methylation in the female, indicating mosaicism. These cases provide further evidence of the aetiological role for MLH1 epimutations in cancer development and the requirement for sensitive molecular screening techniques to identify mosaic epimutations. Furthermore, while this mechanism is rare, it affects patients of multiple ethnic origins.

Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters.

Lynch Syndrome (LS) is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, hMLH1, hMSH2 and hMSH6. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. The influence of environmental factors on extracolonic cancer risk in LS patients has not been investigated thus far. The aim of this study was to investigate some of these factors in South African females carrying the hMLH1 c.C1528T mutation and their mutation-negative relatives. Data were collected from 87 mutation-positive females and 121 mutation-negative female relatives regarding age, cancer history, hormonal contraceptive use, parity, duration of breast feeding, height, weight and age at first birth, last birth, menarche and menopause. Influence of these factors on cancer risk was analysed by mixed-effects generalised linear models. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females versus 7% (8/121) of mutation-negative females, (P = 0.0279, adjusted for age and relatedness between women). Breast cancer was the most common extracolonic cancer. An association was found for oral contraceptive use and extracolonic cancer risk in mutation-negative females only. No association was found for any of the other risk factors investigated, when adjusted for age. This might be due to the scarcity of extracolonic cancers in our data. Future knowledge on the influence of additional environmental factors on cancer risk in LS females can lead to evidence-based lifestyle advice for mutation carriers, thereby complementing the prevention strategies available today. In addition, it can contribute to an integrated model of cancer aetiology. Therefore, this study should be taken as a thrust for further research.

Advancing public health genomics in Africa through prospective cohort studies.

Human genomic studies have revolutionised science in high-income countries through large cohort studies (on the order of 100,000+ participants) which examine a multitude of risk factors. Yet Africa, with the most genetically diverse population in the world, large burdens of communicable and non-communicable diseases, and unique environments and risk factors, has no such large studies which comprehensively examine multiple interacting risk factors for disease. We argue that establishing such studies is overdue. Scientific discoveries from large cohort studies can drive innovation, foster training and local capacity building, and provide vital evidence for public health decision making. Furthermore, evidence from studies in Africa could provide insights to disease processes relevant to other populations around the globe. The enormous potential for genetic and epidemiologic discovery in Africa should not continue to go untapped. Combining powerful genomic tools with epidemiology through large cohort studies could dramatically advance public health in Africa.

Mobile colonoscopic surveillance provides quality care for hereditary nonpolyposis colorectal carcinoma families in South Africa.

BACKGROUND: It is difficult to provide a colonoscopic surveillance service for at-risk family members with hereditary nonpolyposis colorectal carcinoma when many of those family members live in a remote area of South African far from endoscopic services. A mobile surveillance programme was established to service these individuals. OBJECTIVE: The aim of this study was to compare the quality of the mobile service to that provided in established endoscopy units. METHOD: Ninety-one asymptomatic subjects with known disease-causing mutations underwent 259 colonoscopies. Of these, 171 colonoscopies were performed by a mobile colonoscopy service in small rural hospitals and 88 in established endoscopy units. The quality of the colonoscopic services was measured by completion rate, the rate of detection of colonoscopic abnormalities, histopathological analyses of biopsies, surgical intervention and colorectal cancer deaths. RESULTS: The caecum was reached in 96% of all colonoscopies. A significant lesion was detected in 8.8% of colonoscopies. There was no difference in the rate of complete colonoscopy and detection rate of lesions in the established units and the mobile service (both P = 0.6). The rate of detection of early adenocarcinomas was similar (P = 0.17). The colonoscopic screening/surveillance programme meets international standards with a high accuracy (95.75%) and negative predictive value (100%). CONCLUSION: The mobile service provides access to colonoscopy in remote areas without compromising the quality of service.

A computer-based register for inherited retinal dystrophies in Southern Africa.

A genetic register for inherited retinal degenerative disorders (RDDs) has been established at the Division of Human Genetics, UCT Medical School, Cape Town, South Africa. The primary role of the register is to monitor the progress of molecular research and to facilitate the efficient delivery of services, including genetic counselling, to respective family members and new patients. The database currently holds information on 1829 subjects. The RDD-specific breakdown of the data are presented.

LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13).

Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 in 4000, RP can be inherited in X-linked, autosomal dominant or autosomal recessive modes. The RP13 locus for autosomal dominant RP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP family. Using a positional cloning and candidate gene strategy, we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families. Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree, and four additional mutations have been identified in other unrelated adRP families. The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional significance is associated with this part of the protein. These mutations in this ubiquitous and highly conserved splicing factor offer compelling evidence for a novel pathway to retinal degeneration.

Diverse prevalence of large deletions within the OA1 gene in ocular albinism type 1 patients from Europe and North America.

Ocular albinism type 1 (OA1) is an X-linked disorder mainly characterized by congenital nystagmus and photodysphoria, moderate to severe reduction of visual acuity, hypopigmentation of the retina, and the presence of macromelanosomes in the skin and eyes. We have previously isolated the gene for OA1 and characterized its protein product as melanosomal membrane glycoprotein displaying structural and functional features of G protein-coupled receptors. We and others have identified mutations of various types within the OA1 gene in patients with this disorder, including deletions and splice site, frameshift, nonsense, and missense mutations. However, different prevalences of large intragenic deletions have been reported, ranging from 10% to 50% in independent studies. To determine whether these differences might be related to the geographic origin of the OA1 families tested, we performed a further extensive mutation analysis study leading to the identification of pathogenic mutations in 30 unrelated OA1 patients mainly from Europe and North America. These results, together with our earlier mutation reports on OA1, allow us to resolve the apparent discrepancies between previous studies and point to a substantial difference in the frequency of large intragenic deletions in European (<10%) compared with North American (>50%) OA1 families. These observations and our overall refinement of point mutation distribution within the OA1 gene have important implications for the molecular diagnosis of OA1 and for the establishment of any mutation detection program for this disorder.

Molecular genetics improves the management of hereditary non-polyposis colorectal cancer.

BACKGROUND: The syndrome of hereditary non-polyposis colorectal cancer (HNPCC) can be diagnosed fairly accurately using clinical criteria and a family history. Identifying HNPCC helps to prevent large-bowel cancer, or allows cancer to be treated at an early stage. Once the syndrome has been diagnosed a family member's risk can be judged approximately from a family tree, or it can now be predicted accurately if the causative mutation is known. OBJECTIVE: This study involved attempts to improve the management of a family with HNPCC over a period of 10 years. Clinical diagnostic criteria, colonoscopic surveillance, surgical treatment, genetic counselling, molecular genetic research, and finally predictive genetic testing were applied as they evolved during this time. SUBJECTS AND METHODS: A rural general practitioner first noted inherited large-bowel cancer in the family and began screening subjects as they presented, using rigid sigmoidoscopy at the local hospital. At the time that the disorder was recognised as being HNPCC (1987), screening by means of colonoscopy at our university hospital was aimed primarily at first-degree relatives of affected individuals. After realising how many were at risk, screening was brought closer to the family. A team of clinicians and researchers visited the local hospital to identify and counsel those at risk and to perform screening colonoscopy. Family members were recruited for research to find the gene and its mutation that causes the disease, to develop an accurate predictive test and to reduce the number of subjects undergoing surveillance colonoscopies. RESULTS: There are approximately 500 individuals in this family. In the 10 years of this study the number of subjects who have been counselled for increased genetic risk or who have requested colonoscopic surveillance for HNPCC in this kindred has increased from 20 to 140. After the causative mutation was found in the hMLH1 gene on chromosome 3, a test for it has reduced the number of subjects who need screening colonoscopy by over 70%. A protocol has been devised to inform family members, to acquire material for research in order to provide genetic counselling for (pre-test and post-test) risk, and to test for the mutation. Eventually, identifying those with the mutation should focus surveillance accurately. CONCLUSIONS: The benefits of restricting screening to subjects with the mutation that causes colorectal cancer and of performing operations to prevent cancer are hard to measure accurately. However, it is likely that at least half the family members will be able to avoid colonoscopic screening, some deaths from cancer should be prevented, and the cost of preventing and treating cancer in the family should fall substantially.

X-linked late-onset sensorineural deafness caused by a deletion involving OA1 and a novel gene containing WD-40 repeats.

We have identified a novel gene, transducin (beta)-like 1 (TBL1), in the Xp22.3 genomic region, that shows high homology with members of the WD-40-repeat protein family. The gene contains 18 exons spanning approximately 150 kb of the genomic region adjacent to the ocular albinism gene (OA1) on the telomeric side. However, unlike OA1, TBL1 is transcribed from telomere to centromere. Northern analysis indicates that TBL1 is ubiquitously expressed, with two transcripts of approximately 2.1 kb and 6.0 kb. The open reading frame encodes a 526-amino acid protein, which shows the presence of six beta-transducin repeats (WD-40 motif) in the C-terminal domain. The homology with known beta-subunits of G proteins and other WD-40-repeat containing proteins is restricted to the WD-40 motif. Genomic analysis revealed that the gene is either partly or entirely deleted in patients carrying Xp22.3 terminal deletions. The complexity of the contiguous gene-syndrome phenotype shared by these patients depends on the number of known disease genes involved in the deletions. Interestingly, one patient carrying a microinterstitial deletion involving the 3' portion of both TBL1 and OA1 shows the OA1 phenotype associated with X-linked late-onset sensorineural deafness. We postulate an involvement of TBL1 in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype.

Refinement of the RP17 locus for autosomal dominant retinitis pigmentosa, construction of a YAC contig and investigation of the candidate gene retinal fascin.

The RP17 locus for autosomal dominant retinitis pigmentosa has previously been mapped to chromosome 17q by linkage analysis. Two unrelated South African families are linked to this locus and the identification of key recombination events assigned the RP17 locus to a 10 cM interval on 17q22. The work reported here refines the mapping of the locus from a 10 cM to a 1 cM interval between the microsatellite markers D17S1604 and D17S948. A physical map of this interval was constructed using information from the Whitehead/MIT YAC contig WC 17.8. Sequence-tagged site (STS) content mapping of seven overlapping YACs from this contig was employed in order to build the map. A BAC library was screened to cover a gap in the YAC contig and two positive BACs were identified. Intragenic polymorphisms in the retinal fascin gene provided evidence for the exclusion of this candidate as the RP17 disease gene.

Stickler-like syndrome due to a dominant negative mutation in the COL2A1 gene.

The type II collagenopathies include a wide spectrum of phenotypes ranging from mild spondylo epiphyseal dysplasia (SED) to severe achondrogenesis/hypochondrogenesis. Several attempts have been made at providing phenotype-genotype correlations in this group of disorders. In this report we discuss a South African family in which four members have a phenotype resembling Stickler syndrome type 1. Ocular problems and conductive deafness predominate, while skeletal changes resemble those of a mild form of multiple epiphyseal dysplasia (MED). In distinction to the classical form of Stickler syndrome, the affected persons have stubby digits. DNA analysis of the exons of the COL2A1 gene documented a C-T transversion in exon 39, resulting in an Arg704Cys substitution in the triple helical domain of the type II collagen peptide; this nontermination mutation may be indicative of further heterogeneity in the Stickler group of disorders or of a new syndrome amongst the type II collagenopathies.