Targeted genomic enrichment and massively parallel sequencing identifies novel nonsyndromic hearing impairment pathogenic variants in Cameroonian families.

In sub-Saharan Africa GJB2-related nonsyndromic hearing impairment (NSHI) is rare. Ten Cameroonian families was studied using a platform (OtoSCOPE®) with 116 genes. In seven of 10 families (70%), 12 pathogenic variants were identified in six genes. Five of the 12 (41.6%) variants are novel. These results confirm the efficiency of comprehensive genetic testing in defining the causes of NSHI in sub-Saharan Africa.

Phenotypic and allelic distribution of the ABO and Rhesus (D) blood groups in the Cameroonian population.

Data on blood group phenotypes are important for blood transfusion programs, for disease association and population genetics studies. This study aimed at reporting the phenotypic and allelic distribution of ABO and Rhesus (Rh) groups in various ethnolinguistic groups in the Cameroonians. We obtained ABO and Rhesus blood groups and self-identified ethnicity from 14,546 Cameroonian students. Ethnicity was classified in seven major ethnolinguistic groups: Afro-Asiatic, Nilo-Saharan, Niger-Kordofanian/West Atlantic, Niger-Kordofanian/Adamawa-Ubangui, Niger-Kordofanian/Benue-Congo/Bantu/Grassfield, Niger-Kordofanian/Benue-Congo/Bantu/Mbam and Niger-Kordofanian/Benue-Congo/Bantu/Equatorial. ABO allelic frequencies were determined using the Bernstein method. Differences in phenotypic distribution of blood groups were assessed using the chi-square test; a P value <0.05 being considered as statistically significant. The frequencies of the antigens of blood groups O, A, B and AB were 48.62%, 25.07%, 21.86% and 4.45%, respectively. Rhesus-positive was 96.32%. The allelic frequencies of O, A and B genes were 0.6978, 0.1605 and 0.1416, respectively. Phenotypic frequencies of the blood groups in the general study population and in the different ethnolinguistic groups were in agreement with Hardy-Weinberg equilibrium expectations (P > 0.05). The frequencies of O, A, and B blood phenotypes were significantly lower, respectively, in the Nilo-Saharan group (P = 0.009), the Niger-Kordofanian/Benue-Congo/Bantu groups (P = 0.021) and the Niger-Kordofanian/West-Atlantic group. AB blood group was most frequent in the Niger-Kordofanian/Adamawa-Ubangui group (P = 0.024). Our study provides the first data on ethnic distribution of ABO and Rhesus blood groups in the Cameroonian population and suggests that its general profile is similar to those of several sub-Saharan African populations. We found some significant differences in phenotypic distribution amongst major ethnolinguistic groups. These data may be important for blood donor recruitment policy and blood transfusion service in Cameroon.

Sickle cell disease: new opportunities and challenges in Africa.

Sickle cell disease (SCD) is one of the most common genetic causes of illness and death in the world. This is a review of SCD in Africa, which bears the highest burden of disease. The first section provides an introduction to the molecular basis of SCD and the pathophysiological mechanism of selected clinical events. The second section discusses the epidemiology of the disease (prevalence, morbidity, and mortality), at global level and within Africa. The third section discusses the laboratory diagnosis and management of SCD, emphasizing strategies that been have proven to be effective in areas with limited resources. Throughout the review, specific activities that require evidence to guide healthcare in Africa, as well as strategic areas for further research, will be highlighted.

Burden, genotype and phenotype profiles of adult patients with sickle cell disease in Cape Town, South Africa.

BACKGROUND: An exponential increase in the number of sickle cell disease (SCD) patients in paediatric services in Cape Town, South Africa, has been reported. The trend in adult/adolescent services has not been investigated. OBJECTIVES: To evaluate epidemiological trends of SCD and the profile of patients affected by SCD attending the Haematology Clinic at Groote Schuur Hospital (GSH), Cape Town. METHODS: (i) A retrospective review of the number of SCD patients over the past 20 years; (ii) a cross-sectional analysis of clinical and haematological characteristics of SCD patients; and (iii) molecular analysis of the haemoglobin S mutation, the haplotype in the ß-globin-like genes cluster, the 3.7 kb α-thalassaemia gene deletion and 19 selected single-nucleotide polymorphisms (SNPs) associated with fetal haemoglobin (HbF) levels. RESULTS: From 1995 to 2016, 81 adolescent/adult patients with SCD were registered, mostly originating from other African countries (n=61, 75.3%). There was an increase of over 200% in new cases (n=47) during the last quarter of the two decades investigated. Data from 34 of 58 regular attendees (58.6%) were analysed. The mean age of the patients was 26.1 years (standard deviation (SD) 9.8), and 70.6% were male. With the exception of four patients with sickle/ß-thalassaemia, all the patients had SCD (haemoglobin SS). The co-inheritance of a single 3.7 kb α-globin deletion was found in 42.3% of cases (n=11). The Bantu haplotype was the most observed (65.4% of chromosomes). Most HbF-promoting SNPs were not associated with variable levels of haematological indices. CONCLUSIONS: There is an increasing burden of adult SCD patients at GSH. National health and academic institutions need to adapt policies and healthcare professional training accordingly.

Disease burden and the role of pharmacogenomics in African populations.

BACKGROUND: The burden of communicable and non-communicable diseases in Sub-Saharan Africa poses a challenge in achieving quality healthcare. Although therapeutic drugs have generally improved health, their efficacy differs from individual to individual. Variability in treatment response is mainly because of genetic variants that affect the pharmacokinetics and pharmacodynamics of drugs. METHOD: The intersection of disease burden and therapeutic intervention is reviewed, and the status of pharmacogenomics knowledge in African populations is explored. RESULTS: The most commonly studied variants with pharmacogenomics relevance are discussed, especially in genes coding for enzymes that affect the response to drugs used for HIV, malaria, sickle cell disease and cardiovascular diseases. CONCLUSIONS: The genetically diverse African population is likely to benefit from a pharmacogenomics-based healthcare approach, especially with respect to reduction of drug side effects, and separation of responders and non-responders leading to optimized drug choices and doses for each patient.

Beta-globin gene haplotypes and selected Malaria-associated variants among black Southern African populations.

Partial carrier-resistance to Plasmodium falciparum malaria conferred by the sickle cell (HbS) mutation has resulted in the local amplification and positive selection of sickle cell disease (SCD) in malaria-endemic regions and particularly in sub-Saharan Africa (SSA). The present study investigated the ß-globin gene haplotypes, and selected malaria-associated variants among three cohorts of Bantu-speaking individuals from Malawi, Zimbabwe and South Africa compared with reports with data from others SSA populations. The data suggest a south-ward frequency decrease of malaria-associated variants in SSA linked to the evolutionary dynamics of various African populations' genomes through selective pressure of malaria. These selected genomics differences, positive selection of SCD in malaria-endemic regions among 'Bantus' from various part of Africa emphasise the evidence of the dissociation between genetics, anthropology and culture. The present study also showed a relatively prevalent Benin haplotype, which is mostly found in West Africa, among Southern African Blacks and very low Bantu haplotype, which could suggest a major migration route, of Southern Africa Bantu, along the African west coast, post-occurrence of the Sickle cell mutation, which date remain to be fully elucidated.

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.

The epidemiology of stroke in sickle cell patients in Yaounde, Cameroon.

BACKGROUND AND PURPOSE: Stroke, a severe and recurrent but preventable complication of sickle cell disease (SCD), has not been well studied in Cameroon. To obtain baseline data towards the development of a national stroke prevention programme in SCD, we studied a sample of sickle cell patients with the aim of determining stroke prevalence, clinical presentation and management practices. PATIENTS AND METHODS: Homozygous sickle cell patients in two centres in Yaounde were screened for stroke, in a cross-sectional study. Stroke was diagnosed clinically and confirmed where possible with brain computerized tomography. The National Institutes of Health Stroke Score (NIHSS) and modified Rankin scale (mRS) were used to assess stroke severity. Management practices were noted from patient charts. RESULTS: One hundred and twenty patients aged 7 months to 35 years (mean age 13.49+/-8.79 years) were included. Eight cases of stroke (mean age 16.6+/-11.2 years) were identified, giving a stroke prevalence of 6.67%. Cerebral infarction was thrice as common as cerebral hemorrhage and clinical presentation was classical. Cerebral infarction was more frequent in patients aged below 20 years and hemorrhage in those above 20 (p=0.11). The annual recurrence rate was 25%. Missed diagnosis rate by attending physician was 25%. The NIHSS and mRS showed high stroke severity. Stroke management practices were insufficient and no patient received any form of stroke prophylaxis. CONCLUSION: Stroke prevalence and presentation in sickle cell patients in Yaounde is similar to that observed in developed countries, but the wide management gap calls for rapid action. Our situation is ideal for the study of the natural history of stroke in sickle cell disease.

Pyle metaphyseal dysplasia in an African child: Case report and review of the literature.

Pyle disease (OMIM 265900), also known as metaphyseal dysplasia, is a rare autosomal recessive disorder with no known gene mutation. We report a case of Pyle disease in a 7-year-old African boy of mixed ancestry who presented with finger and wrist fractures following minor trauma. The radiological findings revealed abnormally broad metaphyses of the tubular bones, known as Erlenmeyer-flask bone deformity, and mild cranial sclerosis, both hallmarks of the condition. We report the first case in a patient with African ancestry, which could help in the gene discovery of this rare autosomal recessive skeletal dysplasia with unknown mutations.

No evidence for clinical utility in investigating the connexin genes GJB2, GJB6 and GJA1 in non-syndromic hearing loss in black Africans.

BACKGROUND: Deafness is the most common sensory disability in the world. Globally, mutations in GJB2 (connexin 26) have been shown to play a major role in non-syndromic deafness. Two other connexin genes, GJB6 (connexin 30) and GJA1 (connexin 43), have been implicated in hearing loss, but these genes have seldom been investigated in black Africans. We aimed to validate the utility of testing for GJB2, GJB6 and GJA1 in an African context. METHODS: Two hundred and five patients with non-syndromic deafness from Cameroon and South Africa had the full coding regions of GJB2 sequenced. Subsequently, a carefully selected subset of 100 patients was further sequenced for GJB6 and GJA1 using Sanger cycle sequencing. In addition, the large-scale GJB6-D3S1830 deletion was investigated. RESULTS: No pathogenic mutations that could explain the hearing loss were detected in GJB2, GJB6 or GJA1, and the GJB6-D3S1830 deletion was not detected. There were no statistically significant differences in genomic variations in these genes between patients and controls. A comprehensive literature review supported these findings. CONCLUSION: Mutations in GJB2, GJB6 and GJA1 are not a major cause of non-syndromic deafness in black Africans and should not be investigated routinely in clinical practice.

Beta-cell crosstalk: a further dimension in the stimulus-secretion coupling of glucose-induced insulin release.

Pancreatic beta-cells are connected by gap junction channels made of a connexin protein, referred to as Cx36. Through these channels, beta-cells are coupled to each other, i.e. exchange cytoplasmic ions and small metabolites. Previous experiments have indicated that these exchanges are important for coordinating the function of individual cells within pancreatic islets, particularly with regard to glucose-induced insulin secretion. Advances in molecular biology, genetics and mouse transgenic approaches allow now for a direct experimental testing of this mechanism in vitro as well as in vivo. Recent experiments in rodent and culture models suggest that connexin-dependent cell-to-cell crosstalk is a significant player in the multifactorial regulation of insulin secretion and, possibly, of other beta-cell functions, such as growth. Elucidating the still obscure mechanism whereby connexin signalling exerts this influence will provide insights on the contribution of direct cell-to-cell interactions in the physiological regulation of beta-cell life. The presence of Cx36 within human pancreatic islets, raises the further challenge to determine whether a dysfunction of connexin signaling may contribute to the pathophysiology of beta-cell dysfunctions in type I and/or type II diabetes. Efforts to understand the functions of beta-cell connexins are also a prerequisite for the engineering of surrogate cells and their proper tridimensional packaging, which are instrumental for the future implementation of a replacement cell therapy in diabetic patients.

High-grade intra-epithelial neoplasia and prostate cancer in Dibombari, Cameroon.

High-grade prostatic intra-epithelial neoplasia (HGPIN) occurs a decade earlier in men of African descent in the US and Brazil, compared to white men. Prostate cancer incidence and mortality is worse in the African-American than in US white men. Sub-Saharan Africa was thought to be a low incidence area. This disparity has been attributed to lifestyle factors such as diet. We report the results of prostatic biopsies, from an ongoing national prostate cancer survey. One hundred and eleven men aged 40 y and over were recruited for medical interview (AUA symptom score), prostate specific antigen (PSA) assay and digital rectal examination (DRE). Between six and 10 cores of random digitally guided needle biopsies were performed on 24 subjects that had either suspicious prostates on digital rectal examination +/ or PSA > or =4 ng/ml. All lesions of the prostate were described on routine histopathology. The Gleason score and proportion of tissue involved with cancer, was determined. Eight men had benign prostatic hyperplasia (BPH), six had cancer, another six had low grade intra-epithelial neoplasia, two had HGPIN, there was one case of BPH and chronic prostatitis and one case of chronic prostatitis only. The cancer patients were aged 58-75 y (mean 66.93 y). Gleason scores ranged from 5 to 9, there was one score of 3. Cancer made up 20-80% tissue samples. HGPIN was found in two cases (mean age 58 y). Significant prostate cancer and the pre-cancerous lesion HGPIN exist in Dibombari, Cameroon. The purported low incidence of prostate cancer may reflect cultural and economic barriers to health care.

Peripartum cardiomyopathy and familial dilated Cardiomyopathy: a tale of two cases.

Peripartum cardiomyopathy (PPCM) is a form of pregnancyrelated heart failure that is associated with considerable morbidity and mortality. Most patients present with acute postpartal heart failure that otherwise resembles the clinical presentation of dilated cardiomyopathy (DCM). There is increasing recognition that PPCM may be due to genetic factors in a significant proportion of cases. There is evidence that at least 7% of cases of PPCM may be part of the spectrum of familial DCM. We report on two cases of PPCM, with relatives demonstrating familial DCM, both patients displaying autosomal dominant patterns of inheritance, and showing severe cardiomyopathy among proband and affected relatives. Family screening for familial DCM should be indicated in all cases of unexplained PPCM.

Association between biological markers of sickle cell disease and cognitive functioning amongst Cameroonian children.

BACKGROUND: Some of the major complications of sickle cell disease (SCD) occur in the brain and apart from overt stroke, patients also present with cognitive impairments. We sought to evaluate the prevalence of cognitive deficits as well as their biological predicting factors in young SCD patients in Cameroon. METHODS: The cognitive performances of Cameroonian SCD young patients were evaluated using a neuropsychological test battery assessing four domains of cognitive functioning (executive functions, attention, memory, and sensory-motor skills) previously adapted and normalized on healthy subjects in Yaoundé. FINDINGS: Up to 37.5% of the 96 SCD patients aged 6 to 24 years (M = 13.5, SD = 4.9) had mild-to-severe cognitive deficits. The cognitive deficits tend to increase with age. There was a significant effect of SCD on executive functions and attention, whereas SCD patients performed as well as controls on memory and sensory-motor skills tests. Structural equation models showed a significant association between (a) severe anemia and lower executive functioning, (b) low fetal hemoglobin levels and lower executive functioning and attention, (c) history of cerebrovascular accidents and lower performances in executive functioning, sensory-motor skills, and memory, (d) pathological electroencephalogram and lower attention, and (e) abnormal Transcranial Doppler and lower memory. CONCLUSION: SCD patients in Cameroon presented a very high prevalence of cognitive deficits, with a specific impairment of executive functions and attention. Routine neuropsychological evaluation for early detection of cognitive deficits in SCD patients could represent a cost-effective tool to implement in resource-limited contexts such as in sub-Saharan Africa.

Capacity-building in human genetics for developing countries: initiatives and perspectives in sub-Saharan Africa.

BACKGROUND: Stakeholders who are committed to bridge the gap in genetics services need to be aware of current initiatives in sub-Saharan Africa. METHODS: We reviewed selected experiences from African geneticists that led to specific recommendations. RESULTS: The initiation of prenatal diagnosis of sickle cell anaemia founded the first medical genetic service in Cameroon. There remains a need for international collaborative effort to overcome the lack of human, technical and financial resources around the practice of medical genetics in Africa. The African Society of Human Genetics, Wellcome Trust and NIH have recently proposed a model on how to fully engage Africa in genomics. It includes a 'Health and disease' phase I: use of the case-control design to study genetic and epidemiological determinants of 7 important diseases in Africa, and a 'Genetic variation' phase II: comprehensive documentation of genetic variations in 100 carefully selected ethnic groups across Africa. The strategy would require the development of: (1) clinical phenotyping centres, (2) molecular phenotyping centres, (3) genotyping and sequencing capability, (4) data centres, and (5) a bio-repository in Africa. CONCLUSIONS: Governments and international health agencies need to recognise that genetics is important to the global medical community. The initiatives of African geneticists need advocacy and encouragement from the international community.

Pediatric urolithiasis in sub-saharan Africa: a comparative study in two regions of Cameroon.

OBJECTIVE: To determine the composition of caculi and the predisposing factors for stone nucleation and growth in children from two regions of Cameroon. METHODS: This was a cross-sectional study involving 21 children, 17 from the northern and 4 from the southern region, over a 6-year period. Data on age, diet, residence, clinical presentation, location of stone, and results of stone analysis were collated following a preestablished proforma. A computerized analysis of the data was carried out. The constituents of stone sections and nidus were assembled so as to determine the principal causes of stone nucleation and growth. RESULTS: Pediatric urolithiasis was more common in the northern Sahelian belt of Cameroon. Males and rural dwellers were more commonly affected. Endemic (bladder) stone disease was found in the majority of the patients. All stones were mixed. The most frequent constituents of the stones were ammonium urate, struvites, and whewellite in descending order of percentage mean volume per stone. The nidus was available for study in only 10 stones, and its composition revealed heterogeneity of causes of nucleation. The commonest cause for stone formation and growth were infection and hyperuricosuria (malnutrition). CONCLUSIONS: Pediatric bladder stone disease is not uncommon in northern Cameroon. Many factors combined to predispose to stone nucleation and growth, but the level of socioeconomic development was preponderant. Stone composition indicated that urolithiasis in children was a heterogeneous disorder, but hyperuricosuria, insufficient diuresis, and infection associated with malnutrition seemed to be the most common causes.