Browsing by Author "Chimusa Emile"

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    Open Access
    Genetics of hearing impairment and peripheral neuropathy in Mali
    (2023) Yalcouye, Abdoulaye; Wonkam, Ambroise; Chimusa Emile
    Background Hearing impairment (HI), the most common sensory disturbance, affects about 1 in 1000 living newborns globally. Its incidence is reported higher in sub-Saharan African (SSA) populations. HI is caused by environmental and genetics factors. In many developing countries, environmental factors are reported to be the most prevalent aetiologies while genetic causes are predominant in the developed countries. Over 50% of congenital HI has a genetic origin with more than 120 genes identified to date. Despite this large number of known genes, only GJB2 (OMIM: 121011) and GJB6 (OMIM: 604418) are systematically studied in SSA populations for which the prevalence of HI-causal variants is insignificant. Charcot-Marie-Tooth disease (CMT), is the most common inherited peripheral neuropathy (IPN) with a high clinical and genetic heterogeneity and over 100 genes are related to CMT, mostly in populations of Caucasian ancestry. Yet, despite being described more than 130 years ago, there remains a paucity of information on its global prevalence and genetic epidemiology due largely to challenges in diagnosis, especially in countries with limited resources. Over 90% of CMT are caused by mutations in PMP22 (OMIM: 601097), GJB1 (OMIM: 304040), MFN2 (OMIM: 608507), MPZ (OMIM: 159440) genes. HI is the common audiological symptom associated with CMT and is caused by several genes including PMP22 and GJB1. HI and IPN are inherited in autosomal (dominant and recessive), X-linked, and mitochondrial transmission. However, the genetic epidemiology of these diseases are largely unknown in Africa, and have not been investigated in Mali where consanguineous marriage is a common practice that may increase recessive conditions.
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    Open Access
    Human host and malaria parasite genome variations to susceptibility to malaria
    (2023) Hordofa, Hundaol; Dandara, Collet; Chimusa Emile
    Background: Inter-ethnic differences in response to medication can be explained through population structure as observed from genetic variants affecting drug metabolism. Antimalarial drugs are used in populations carrying different profiles of genetic variability. However, there is limited information on the distribution of genetic variants of pharmacogenomics importance in African populations. Aims: We set out to determine whether there are differences in the pharmacogenetic profiles when comparing populations residing in malaria endemic and non-endemic areas. Methodology: Genome-wide genotype datasets (n=13, 447) from four malaria endemic African populations, including Mali, Kenya, Gambia, and Malawi, which were part of the MalariaGEN consortium, were accessed. As comparator, reference datasets of global populations comprising of 20 ethnic groups (n~5,000) from African Genome Variation Project (AGVP) and 1000 Genome consortium project were accessed, considering their malaria epidemiology. Pharmacogenes that are verified from databases such as PharmVar and PharmGKB, and nomenclature sites for uridine 5'-diphospho-glucuronosyltransferases (UGT), solute carrier (SLC) transporters, ATP-binding cassette (ABC) transporters, thiopurine Smethyl transferase (TPMT), and N-acetyltransferases (NAT) were used. Pharmacogenes reported to affect antimalarial drugs were noted and their distribution analysed. Single nucleotide polymorphisms (SNPs) that map to pharmacogenes were retrieved from dbSNP databases and used in the comparison of the populations from malaria endemic and nonendemic regions, through population structure evaluation using pharmacogenes variants. As part of confirmation, genotyping for CYP2C8 SNPs was carried out in native South African population groups, which we have access to our laboratory. CYP2C8 is particularly interesting because of its central involvement in the metabolism of some of the major antimalarial drugs. Results: There were quantitative and qualitative differences in the distribution of pharmacogenes variants when comparing populations from malaria endemic regions to those from non-endemic regions. For instance, the analysis of the minor allele frequency (MAF) proportion of all pharmacogenes variants obtained from the databases revealed that a high proportion of common variants (MAF > 0.05) of pharmacogenes were higher in the four African population from malaria endemic areas (MAF proportion > 50%) compared with world populations from malaria non-endemic areas (MAF proportion < 50%). There were a disproportionately higher number of variants in cytochrome P450 enzymes such as CYP2A13 and CYP2F1 in the malaria endemic populations (> 80%) compared to non-endemic populations (< 65%). Further analysis based on antimalarial specific pharmacogenes variants showed that UGT1A9 had the highest proportion of variants (> 80%) in the malaria endemic populations. The ABC drug transporters such as ABCC4, ABCC1 and ABCC2 were found to have a higher proportion of pathogenic SNPs in populations of the four malaria endemic areas (> 50%) compared with those from non-endemic areas (< 30%). Principal component analysis (PCA) based on pharmacogenes variants also showed clear differentiation into different population. Moreover, four CYP2C8 variants (rs11572103T>A (*2), rs11572101A>G, rs11572100T>C and rs1926705C>T), characterized in South Africans, were found to have III statistically significant difference (p-value < 0.05) in allele frequency when compared with global populations. Conclusions: The findings from this study revealed the profiles of pharmacogenes variants in populations from malaria endemic and non-endemic geographical regions. The variants in CYP2A13, CYP2F1, and UGT1A9 were found in higher proportions in populations from malaria endemic areas compared to non-malaria endemic areas. This suggests that pharmacogenetic testing for patients based on antimalarial pharmacogenes having a higher proportion of variants in malaria endemic areas (e.g., UGT1A9) may be necessary. Moreover, a high frequency in the functional variant of CYP2C8, rs11572103T>A (*2), was found in the South African population. This may also have relevance for future consideration of pharmacogenetic testing for a person traveling to malaria endemic areas from non-endemic areas, such as South Africa. Future studies should be done using large scale sequencing datasets from malaria endemic areas and assess the effect of common variants of antimalarial pharmacogenes on the safety and efficacy of currently used antimalarial drugs.
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    Open Access
    The genetics of non-syndromic hearing impairment in South Africa
    (2023) Manyisa, Noluthando; Wonkam, Ambroise; Chimusa Emile
    Hearing impairment (HI) is a sensory disorder resulting in the partial or complete disability to perceive sound in the better-hearing ear. It is defined as the inability to hear better than 25dB in the better-hearing ear. Subsequently, it is considered disabling when a child cannot perceive sound better the 30dB, in the better hearing ear, and an adult cannot perceive sound better than 40dB, in the better hearing ear. Hearing impairment may result from genetic, environmental, or unknown factors. The connexin gene, GJB2, is the prevalent gene resulting in congenital HI in most children with European, North American, and East Asian ancestry. Apart from the founder mutations present in GJB2 in Morocco, Ghana and Senegal, the prevalent causative genes resulting in congenital HI in African populations are yet to be fully elucidated. Congenital Hearing impairment in South Africa (RSA), has been estimated to have an incidence rate of 5.5 per 1000 live births, which is 5 times higher than the birth incidence in high-income countries (approximately 1 to 2 per 1000 live births). Patients are generally diagnosed late with HI, at approximately 3 years old, and the most prevalent environmental factors associated with HI in RSA are middle ear infections, with several reports implicating ototoxicity as a cause of HI. Variants in connexin genes i.e. GJB2 associated with HI have been shown to be irrelevant in the Black South African populations, and the limited genetic studies have identified private mutations in selected families. However, the full extent of prevalent genes associated with HI in the South African populations is still to be investigated. Methods and results Through a systematic review, we investigated the state of HI research in South Africa was established. Though studies have been performed since the 1960s, the results showed that genetics of HI in South Africa was not well explored. Universal new-born hearing screening is ideal in detecting congenital HI, but it is currently not standard practice in the country. However, with the advent of modern technology, HI screening may be more accessible to patients through community health workers. Patients who fail the repeated screenings may then be referred for further audiometry testing. This may positively impact the identification of patients with HI and assist with the necessary interventions. We also collaboratively worked to establish the first disease ontology for HI to further allow standardised and harmonised language surrounding HI. This provides the scalability and interoperability of research going forward. It will allow for all stakeholders in HI research to use the same terminology when discussing HI. In order to address the dearth of genetics research regarding non-syndromic HI, patients presenting with putative genetic HI were recruited from schools of the deaf across South Africa and two hospitals in Cape Town. The patients were recruited along with their family members, both with and without HI, and their DNA was extracted from whole blood. Twenty-seven families segregating non-syndromic HI, consisting of 65 affected and 35 unaffected individuals were subjected to whole exome sequencing (WES). The HI was resolved in 20 families (74%), and pathogenic variants were identified in the genes: WFS1 (c.A2141), MITF (cT918A), ADGRV1(c.G564T, c.A17450G, c.A11298C), PDSS1(c.C641T, NEU1(c.C1069T, c.G754C), c.G727A), TBC1D24(c.G1514A), MYO15A(c.C1378T, TMPRSS3(c.205+6t>A), c.9303+5G>A, c.G6634A), USH2A(c.T9437A, c.G2990T, c.G101A), STRC(c.G225A, c.C4057T, c.G4655C, c.C4351T, c.G4403A), P2RX2(c.G1064A, c.C1187G), OTOG(c.C2525A, c.G3143A, c.G916A), LHFPL5(c.621delC), TRIOBP(c.C3133T, c.C4298T), SLC26A4(c.T94C, c.T716A), GJB2(c.35delG), REST(c.G1244C), CRYM(c.*6_*2delACAAA), CDH23(c.T1585C, c.G8230A), FGFR2(c.1297+10G>C), MYO7A(c.6255delC). The pathogenic variants presented 8 autosomal dominant alleles and 12 autosomal recessive alleles Five families presented with pathogenic or likely pathogenic variations associated with Usher Syndrome and the remaining 14 families presented with pathogenic variations associated with non-syndromic HI. One family presented with putative pathogenic variations in NEU1, which is a gene associated with Sialidosis. We specifically investigated, in greater detail, a dominant novel variation in REST, present in one family, which encodes a transcription factor, that was identified using whole exome sequencing. This gene was previously suspected to be associated with hearing impairment only once, in an American family. The variation was absent in the unaffected South African family members, unrelated patients, and unaffected controls. In vitro cell-based studies indicated that the variation results in the loss of nuclear exclusivity of REST. Luciferase assays indicated that the mutant was unable to repress the expression of one of its target genes, whereas the wild-type effectively inhibited the expression of the target. Conclusions This thesis successfully performed the following investigations: 1) development of the first Hearing Impairment Ontology worldwide, 2) review the genetic profile of HI in South Africa, 3) used WES to find known and novel variants in established HI genes, and 4) confirmed REST as a novel HI gene. Future work will focus on sequencing all the remaining samples and identifying their putative causative mutations. Further work includes feedbacking the results of the genetic testing to the patients and their families. The data will contribute to improving the HI-genes pairs' curation in Africa, and globally.