Browsing by Department "Division of Human Genetics"
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- ItemOpen AccessA cost effective RFLP method to genotype Solute carrier organic anion 1B1 (SLCO1B1) c.1929A>C (p.Leu643Phe, rs34671512); a variant with potential effect on rosuvastatin pharmacokinetics(BioMed Central, 2018-06-14) Soko, Nyarai D; Masimirembwa, Collen; Dandara, ColletObjective: This study describes a restriction fragment polymorphism protocol for rapidly screening the polymorphism SLCO1B1 c.1929A>C in genomic DNA samples. The polymorphism SLCO1B1 c.1929A>C has been associated with increased activity resulting in increased hepatic uptake of drugs. Currently SLCO1B1 c.1929A>C is genotyped using direct sequencing techniques and 5′ nuclease based assays which can be cost prohibiting in resource limited settings. The aim of this study therefore was to design and validate a cost effective RFLP for genotyping the SLCO1B1 c.1929A>C polymorphism. This study was designed to investigate the effect of the polymorphism SLCO1B1 c.1929A>C on interindividual variability in rosuvastatin pharmacokinetics in healthy volunteers of African descent. Results We describe a restriction fragment length polymorphism method to genotype SLCO1B1 c.1929A>C polymorphism using the restriction enzyme Ase1. A student’s t test with Welch correction was used to establish association between the SLCO1B1 c.1929A>C variant and rosuvastatin exposure. The frequency of the SLCO1B1 c.1929C allele amongst Zimbabweans was 6%. The SLCO1B1 c.1929C allele was associated with a 75% reduction (P < 0.001) in rosuvastatin exposure when compared to individuals carrying the wild type SLCO1B1 c.1929A allele. Polymorphism c.1929A>C may therefore play a significant role in rosuvastatin response. The RFLP method is quick and cost effective.
- ItemOpen AccessA molecular approach to Huntington disease in Southern Africa(1990) Greenberg, Leslie J H L
- ItemOpen AccessAge Estimate of GJB2-p.(Arg143Trp) Founder Variant in Hearing Impairment in Ghana, Suggests Multiple Independent Origins across Populations(2022-03-21) Aboagye, Elvis Twumasi; Adadey, Samuel Mawuli; Esoh, Kevin; Jonas, Mario; de Kock, Carmen; Amenga-Etego, Lucas; Awandare, Gordon A; Wonkam, AmbroiseGap junction protein beta 2 (GJB2) (connexin 26) variants are commonly implicated in non-syndromic hearing impairment (NSHI). In Ghana, the GJB2 variant p.(Arg143Trp) is the largest contributor to NSHI and has a reported prevalence of 25.9% in affected multiplex families. To date, in the African continent, GJB2-p.(Arg143Trp) has only been reported in Ghana. Using wholeexome sequencing data from 32 individuals from 16 families segregating NSHI, and 38 unrelated hearing controls with the same ethnolinguistic background, we investigated the date and origin of p.(Arg143Trp) in Ghana using linked markers. With a Bayesian linkage disequilibrium gene mapping method, we estimated GJB2-p.(Arg143Trp) to have originated about 9625 years (385 generations) ago in Ghana. A haplotype analysis comparing data extracted from Ghanaians and those from the 1000 Genomes project revealed that GJB2-p.(Arg143Trp) is carried on different haplotype backgrounds in Ghanaian and Japanese populations, as well as among populations of European ancestry, lending further support to the multiple independent origins of the variant. In addition, we found substantial haplotype conservation in the genetic background of Ghanaian individuals with biallelic GJB2- p.(Arg143Trp) compared to the GJB2-p.(Arg143Trp)-negative group with normal hearing from Ghana, suggesting a strong evolutionary constraint in this genomic region in Ghanaian populations that are homozygous for GJB2-p.(Arg143Trp). The present study evaluates the age of GJB2-p.(Arg143Trp) at 9625 years and supports the multiple independent origins of this variant in the global population.
- ItemOpen AccessAPOE, PCSK9, and CETP genetic variants as potential biomarkers of dyslipidaemia in black South Africans with Type 2 Diabetes Mellitus(2018) Evans, Jonathan; Dandara, ColletDyslipidaemia is a commonly encountered clinical condition and is a major risk factor for cardiovascular diseases. Although there are many factors associated with dyslipidaemia, a strong genetic component is evident. Apolipoprotein E (APOE), proprotein convertase subtilisin/kexin type 9 (PCSK9), and cholesteryl ester transfer protein (CETP) are key regulators of plasma cholesterol levels. Thus, genetic variation in the genes coding for these proteins contributes to dyslipidaemia. In this study, a cohort of black South African Type 2 Diabetes Mellitus (T2DM) patients was characterized for mutations in genes coding for APOE, PCSK9, and CETP, and the possible effects of these variants on their lipid profiles was evaluated. Participants (n=417) were recruited from the Chris Hani Baragwaneth Hospital Diabetes Clinic, Johannesburg from whom blood samples were obtained for DNA extraction. The cohort was further stratified into two groups; individuals on statin treatment (Sim+, n=291), and the second that was not on treatment (Sim-, n=87). Lipid profiles were determined by enzymatic methods. DNA was genotyped for APOE, PCSK9, and CETP variants using PCRRFLP and Sanger sequencing. Analysis of the effects of the genetic variants was carried out in two ways. Firstly, for all the participants combined, and then by separating those on statin treatment from those without (Sim+ vs. Sim-). Genotype and allele frequencies were calculated followed by genotype-phenotype correlations with lipid profiles. Univariate analysis showed a significant association between the APOE4 isoform and lower HDL-c levels in the combined cohort (p=0.034). The effects were more pronounced in the Sim- group (p=0.004) but were absent in the Sim+ group. Contrary to above, APOE2 was significantly associated with lower total cholesterol (TC) (p< 0.001) and lower LDL-c (p< 0.001) when compared to APOE3 in the combined cohort. Upon analysing treatment groups, the correlations were observed in the Sim+ group (p=0.027 and p=0.003, respectively), while there were no observed correlations in the Sim- group. The CETP rs34065661C/G and G/G genotypes were significantly associated with increased HDL-c levels (p=0.017; when applying a dominant genetic model) in the combined cohort, as well as in the Sim+ group (p=0.026). Multivariate analysis, using a generalized linear model, confirmed associations between APOE rs429358C and lower HDL-c (OR=0.881, p=1.64e04), and APOE rs7412T and decreased LDL-c (OR=0.759, p=0.012). No significant associations were observed for PCSK9 polymorphisms. We report significant associations between APOE and CETP genetic variations and altered lipid levels in this black South African T2DM population. These genetic variants could be biomarkers for dyslipidaemia among Africans. However, it is imperative that the APOE, PCSK9, and CETP genes are fully characterized for additional polymorphisms in order to come up with a better genetic profile that explains the variance in lipid levels observed in the black South African population. The impact of these genetic variants could be relevant to other black African populations as well.
- ItemOpen AccessAssociation of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in Cameroon(Public Library of Science, 2014) Wonkam, Ambroise; Bitoungui, Valentina J Ngo; Vorster, Anna A; Ramesar, Raj; Cooper, Richard S; Tayo, Bamidele; Lettre, Guillaume; Ngogang, JeanneBACKGROUND: Genetic variation at loci influencing adult levels of HbF have been shown to modify the clinical course of sickle cell disease (SCD). Data on this important aspect of SCD have not yet been reported from West Africa. We investigated the relationship between HbF levels and the relevant genetic loci in 610 patients with SCD (98% HbSS homozygotes) from Cameroon, and compared the results to a well-characterized African-American cohort. Methods and FINDINGS: Socio-demographic and clinical features were collected and medical records reviewed. Only patients >5 years old, who had not received a blood transfusion or treatment with hydroxyurea were included. Hemoglobin electrophoresis and a full blood count were conducted upon arrival at the hospital. RFLP-PCR was used to describe the HBB gene haplotypes. SNaPshot PCR, Capillary electrophoresis and cycle sequencing were used for the genotyping of 10 selected SNPs. Genetic analysis was performed with PLINK software and statistical models in the statistical package R. Allele frequencies of relevant variants at BCL11A were similar to those detected in African Americans; although the relationships with Hb F were significant (p <.001), they explained substantially less of the variance in HbF than was observed among African Americans (∼ 2% vs 10%). SNPs in HBS1L-MYB region ( HMIP ) likewise had a significant impact on HbF, however, we did not find an association between HbF and the variations in HBB cluster and OR51B5/6 locus on chromosome 11p, due in part to the virtual absence of the Senegal and Indian Arab haplotypes. We also found evidence that selected SNPs in HBS1L-MYB region ( HMIP ) and BCL11A affect both other hematological indices and rates of hospitalization. CONCLUSIONS: This study has confirmed the associations of SNPs in BCL11A and HBS1L-MYB and fetal haemoglobin in Cameroonian SCA patients; hematological indices and hospitalization rates were also associated with specific allelic variants.
- ItemOpen AccessAssociation of variants in APOL1, MYH9 and HMOX1 WITH micro-Albuminuria among Sickle Cell disease patients from Cameroon(2016) Geard, Amy; Wonkam, Ambroise; Chimusa, Emile RIntroduction: Sickle Cell Disease (SCD) is a monogenic, multi-organ hemoglobinopathy disorder that is highly prevalent in Africa, with nearly 300 000 newborn cases per year. The underlying pathophysiological mechanism of the disease involves alteration of the normal soft and biconcave disc shape of erythrocytes, to that of a rigid crescent. These abnormal red blood cells cause vaso-occlusion and intravascular hemolysis, resulting in a variety of clinical manifestations, including acute pain crises, anemia, and damage to various organs. Kidney disease is a clinical proxy of severity, developing only in a subset of patients, and is subject to modification by genetic variations. Indeed, reports have shown significant association between proteinuria and specific genetic variants in MYH9 and APOL1, and between estimated Glomerular Filtration Rate (eGFR) and End Stage Kidney Disease (ESKD) with HMOX1 variants among adult African Americans affected by SCD. However, the association between these variants and micro-albuminuria, a primary indicator of renal dysfunction, has not been investigated, nor has any study of these variants been performed among SCD patients in Africa. Aim: The aim of this study was to investigate the association of targeted single nucleotide polymorphisms (SNPs) in APOL1, MYH9 and HMOX1, as well as a 5' promoter dinucleotide repeat in HMOX1, with micro-albuminuria among SCD patients from Cameroon; and to compare the results to that from a cohort of non-SCD Cameroonian individuals affected by ESKD.
- ItemOpen AccessBi-Allelic Novel Variants in CLIC5 Identified in a Cameroonian Multiplex Family with Non-Syndromic Hearing Impairment(2020-10-23) Wonkam-Tingang, Edmond; Schrauwen, Isabelle; Esoh, Kevin K; Bharadwaj, Thashi; Nouel-Saied, Liz M; Acharya, Anushree; Nasir, Abdul; Adadey, Samuel M; Mowla, Shaheen; Leal, Suzanne M; Wonkam, AmbroiseDNA samples from five members of a multiplex non-consanguineous Cameroonian family, segregating prelingual and progressive autosomal recessive non-syndromic sensorineural hearing impairment, underwent whole exome sequencing. We identified novel bi-allelic compound heterozygous pathogenic variants in CLIC5. The variants identified, i.e., the missense [NM_016929.5:c.224T>C; p.(L75P)] and the splicing (NM_016929.5:c.63+1G>A), were validated using Sanger sequencing in all seven available family members and co-segregated with hearing impairment (HI) in the three hearing impaired family members. The three affected individuals were compound heterozygous for both variants, and all unaffected individuals were heterozygous for one of the two variants. Both variants were absent from the genome aggregation database (gnomAD), the Single Nucleotide Polymorphism Database (dbSNP), and the UK10K and Greater Middle East (GME) databases, as well as from 122 apparently healthy controls from Cameroon. We also did not identify these pathogenic variants in 118 unrelated sporadic cases of non-syndromic hearing impairment (NSHI) from Cameroon. In silico analysis showed that the missense variant CLIC5-p.(L75P) substitutes a highly conserved amino acid residue (leucine), and is expected to alter the stability, the structure, and the function of the CLIC5 protein, while the splicing variant CLIC5-(c.63+1G>A) is predicted to disrupt a consensus donor splice site and alter the splicing of the pre-mRNA. This study is the second report, worldwide, to describe CLIC5 involvement in human hearing impairment, and thus confirms CLIC5 as a novel non-syndromic hearing impairment gene that should be included in targeted diagnostic gene panels.
- ItemOpen AccessBiomedical research, a tool to address the health issues that affect African populations(BioMed Central Ltd, 2013) Peprah, Emmanuel; Wonkam, AmbroiseTraditionally, biomedical research endeavors in low to middle resources countries have focused on communicable diseases. However, data collected over the past 20years by the World Health Organization (WHO) show a significant increase in the number of people suffering from non-communicable diseases (e.g. heart disease, diabetes, cancer and pulmonary diseases). Within the coming years, WHO predicts significant decreases in communicable diseases while non-communicable diseases are expected to double in low and middle income countries in sub-Saharan Africa. The predicted increase in the non-communicable diseases population could be economically burdensome for the basic healthcare infrastructure of countries that lack resources to address this emerging disease burden. Biomedical research could stimulate development of healthcare and biomedical infrastructure. If this development is sustainable, it provides an opportunity to alleviate the burden of both communicable and non-communicable diseases through diagnosis, prevention and treatment. In this paper, we discuss how research using biomedical technology, especially genomics, has produced data that enhances the understanding and treatment of both communicable and non-communicable diseases in sub-Saharan Africa. We further discuss how scientific development can provide opportunities to pursue research areas responsive to the African populations. We limit our discussion to biomedical research in the areas of genomics due to its substantial impact on the scientific community in recent years however, we also recognize that targeted investments in other scientific disciplines could also foster further development in African countries.
- ItemOpen AccessA candidate gene analysis of arrhythmogenic right ventricular cardiomyopathy (ARVC)(2006) Du Preez, Janine; Mayosi, Bongani MHeart failure is a major public health problem throughout the world. In South Africa 17% of mortality is attributed to cardiovascular disease (CVD). Heart failure may be either ischemic or non-ischemic in origin. A significant proportion of non-ischemic heart failur is due to cardiomyopathy. There are currently five types of cardiomyopathy recognised, of which arrhythmogenic right ventricular cardiomyopathy (ARVC) is one. ARVC is familial in 30 to 50% of cases and it is inherited in an autosomal dominant or an autosomal recessive manner. Twelve chromosomal loci have been linked to ARVC and six genes have been identified. In 2004 Asano and colleagues reported a mouse model of ARVC that established LAMRI and CBX5 as candidate genes for the human form of ARVC.
- ItemOpen AccessCase report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation(2015) Abrams, ElaineBackgroundEfavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children.Case presentationFour black African children, between the ages of 4 and 8years presenting between 1 and 20months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60mg/L, 5–15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation.ConclusionEfavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate.
- ItemOpen AccessChemotherapeutic drugs, 5-fluorouracil and cisplatin, differentially affect exprssion of drug metabolising enzyme genes in an oesophageal cancer cell line(2014) Hassen, Naseeha; Dandara, Collet; Mowla, Shaheen; Parker, M ICancer is a leading cause of death worldwide. Oesophageal cancer in particular is the sixth most common cause of cancer deaths globally and its incidence and mortality rates in Southern Africa are among the highest in the world. One of the major challenges with cancer treatment is the vast variability in patient response to chemotherapy, which is predominantly due to genetic variability. The most relevant genes in this context encode the CYP and GST drug metabolising enzymes (DMEs) as these enzymes metabolise up to 90% of clinically-prescribed medication. Patients are also exposed to a variety of other compounds that along with chemotherapeutic drugs may alter DME gene expression. Changes in DME gene expression influence the therapeutic outcomes for patients; thus, understanding the effects of drugs and compounds on the expression of DMEs is crucial for the advancement of personalised medicine. The aim of this study was to determine the effects of two commonly-used chemotherapeutic drugs, as well as a CYP-inducing compound, on the differential expression of four pharmacogenetically relevant DME-encoding genes, CYP1A1, 1A2, 1B1 and GSTP1, in a human oesophageal cancer cell line.
- ItemOpen AccessA clinical and molecular investigation of two families with Simpson-Golabi-Behmel syndrome(2014) Pretorius, Careni Elizabeth; Fieggen, Karen; Beighton, PeterIncludes abstract (p. 30-32). Includes bibliographical references.
- ItemOpen AccessThe co-inheritance of alpha-thalassemia and sickle cell anemia is associated with better hematological indices and lower consultations rate in Cameroonian patients and could improve their survival(Public Library of Science, 2014) Rumaney, Maryam Bibi; Bitoungui, Valentina Josiane Ngo; Vorster, Anna Alvera; Ramesar, Raj; Kengne, Andre Pascal; Ngogang, Jeanne; Wonkam, AmbroiseBACKGROUND: Co-inheritance of α-thalassemia was reported to be associated with a delayed age of disease onset among Cameroonian Sickle Cell Anemia (SCA) patients. The present study aimed to explore the correlation between α-thalassemia, hematological indices, and clinical events in these patients. Methods and FINDINGS: We studied 161 Cameroonian SCA patients and 103 controls (59.1% HbAA) with median ages of 17.5 and 23 years. RFLP-PCR was used to confirm SCA genotype and to describe haplotypes in the HBB-like genes cluster. Multiplex Gap-PCR was performed to investigate the 3.7 kb α-globin gene deletions. SNaPshot PCR, capillary electrophoresis and cycle sequencing were used for the genotyping of 10 SNPs in BCL11A , HMIP1/2 , OR51B5/6 and HBG loci, known to influence HbF levels. Generalised linear regression models adjusted for age, sex and SNPs genotypes was used to investigate effects of α-thalassemia on clinical and hematological indices. The median rate of vaso-occlusive painful crisis and hospitalisations was two and one per year, respectively. Stroke was reported in eight cases (7.4%). Benin haplotype was the most prevalent (66.3%; n = 208 chromosomes). Among patients, 37.3% ( n = 60) had at least one 3.7 kb deletion, compared to 10.9% ( n = 6) among HbAA controls (p<0.001). Among patients, the median RBC count increased with the number of 3.7 kb deletions [2.6, 3.0 and 3.4 million/dl, with no, one and two deletions (p = 0.01)]. The median MCV decreased with the number of 3.7 kb deletion [86, 80, and 68fl, with no, one and two deletions (p<0.0001)], as well as median WBC counts [13.2, 10.5 and 9.8×10 9 /L (p<0.0001. The co-inheritance of α-thalassemia was associated with lower consultations rate (p = 0.038). CONCLUSION: The co-inheritance of α-thalassemia and SCA is associated with improved hematological indices, and lower consultations rate in this group of patients. This could possibly improve their survival and explain the higher proportion of α-thalassemia among patients than controls.
- ItemOpen AccessCommon ABCA4 mutations in South Africans: frequencies, pathogenicity and genotype-phenotype correlations(2010) Nossek, C; Ramesar, Rajkumar; Greenberg, Jacquie
- ItemOpen AccessComputational selection and prioritization of candidate genes for Fetal Alcohol Syndrome(BioMed Central Ltd, 2007) Lombard, Zane; Tiffin, Nicki; Hofmann, Oliver; Bajic, Vladimir; Hide, Winston; Ramsay, MicheleBACKGROUND:Fetal alcohol syndrome (FAS) is a serious global health problem and is observed at high frequencies in certain South African communities. Although in utero alcohol exposure is the primary trigger, there is evidence for genetic- and other susceptibility factors in FAS development. No genome-wide association or linkage studies have been performed for FAS, making computational selection and -prioritization of candidate disease genes an attractive approach. RESULTS: 10174 Candidate genes were initially selected from the whole genome using a previously described method, which selects candidate genes according to their expression in disease-affected tissues. Hereafter candidates were prioritized for experimental investigation by investigating criteria pertinent to FAS and binary filtering. 29 Criteria were assessed by mining various database sources to populate criteria-specific gene lists. Candidate genes were then prioritized for experimental investigation using a binary system that assessed the criteria gene lists against the candidate list, and candidate genes were scored accordingly. A group of 87 genes was prioritized as candidates and for future experimental validation. The validity of the binary prioritization method was assessed by investigating the protein-protein interactions, functional enrichment and common promoter element binding sites of the top-ranked genes. CONCLUSION: This analysis highlighted a list of strong candidate genes from the TGF-beta, MAPK and Hedgehog signalling pathways, which are all integral to fetal development and potential targets for alcohol's teratogenic effect. We conclude that this novel bioinformatics approach effectively prioritizes credible candidate genes for further experimental analysis.
- ItemOpen AccessConnexin Genes Variants Associated with Non-Syndromic Hearing Impairment: A Systematic Review of the Global Burden(2020-10-28) Adadey, Samuel Mawuli; Wonkam-Tingang, Edmond; Twumasi Aboagye, Elvis; Nayo-Gyan, Daniel Wonder; Boatemaa Ansong, Maame; Quaye, Osbourne; Awandare, Gordon A.; Wonkam, AmbroiseMutations in connexins are the most common causes of hearing impairment (HI) in many populations. Our aim was to review the global burden of pathogenic and likely pathogenic (PLP) variants in connexin genes associated with HI. We conducted a systematic review of the literature based on targeted inclusion/exclusion criteria of publications from 1997 to 2020. The databases used were PubMed, Scopus, Africa-Wide Information, and Web of Science. The protocol was registered on PROSPERO, the International Prospective Register of Systematic Reviews, with the registration number “CRD42020169697”. The data extracted were analyzed using Microsoft Excel and SPSS version 25 (IBM, Armonk, New York, United States). A total of 571 independent studies were retrieved and considered for data extraction with the majority of studies (47.8% (n = 289)) done in Asia. Targeted sequencing was found to be the most common technique used in investigating connexin gene mutations. We identified seven connexin genes that were associated with HI, and GJB2 (520/571 publications) was the most studied among the seven. Excluding PLP in GJB2, GJB6, and GJA1 the other connexin gene variants (thus GJB3, GJB4, GJC3, and GJC1 variants) had conflicting association with HI. Biallelic GJB2 PLP variants were the most common and widespread variants associated with non-syndromic hearing impairment (NSHI) in different global populations but absent in most African populations. The most common GJB2 alleles found to be predominant in specific populations include; p.Gly12ValfsTer2 in Europeans, North Africans, Brazilians, and Americans; p.V37I and p.L79Cfs in Asians; p.W24X in Indians; p.L56Rfs in Americans; and the founder mutation p.R143W in Africans from Ghana, or with putative Ghanaian ancestry. The present review suggests that only GJB2 and GJB3 are recognized and validated HI genes. The findings call for an extensive investigation of the other connexin genes in many populations to elucidate their contributions to HI, in order to improve gene-disease pair curations, globally.
- ItemOpen AccessCorrection to: Digital messaging to support control for type 2 diabetes (StAR2D): a multicentre randomised controlled trial(2022-04-13) Farmer, A; Bobrow, K; Leon, N; Williams, N; Phiri, E; Namadingo, H; Cooper, S; Prince, J; Crampin, A; Besada, D; Daviaud, E; Yu, L-M; N’goma, J; Springer, D; Pauly, B; Tarassenko, L; Norris, S; Nyirenda, M; Levitt, NCorrection to: Digital messaging to support control for type 2 diabetes (StAR2D): a multicentre randomised controlled trial, available at: https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-021-11874-7.
- ItemOpen AccessCraniosynostosis in a South Africa population(2021) Crous, Ilse; Fieggen, KarenBackground: Craniosynostosis refers to the premature fusion of calvarial bones which lead to restricted growth potential. Compensatory growth occurs in the dimensions not restricted by fusion and causes progressive distortion in the skull shape. The majority of craniosynostosis cases occur in isolation and are so called non-syndromic craniosynostosis. In about 30 % of all cases, anomalies are noted along with the craniosynostosis, often defining a described and recognised syndrome. The aim is to delineate the phenotype observed in a South African population. Methods: In this descriptive study, hospital records for the preceding five years were retrospectively reviewed to describe the profile of patients with craniosynostosis seen at the Red Cross War Memorial Children's Hospital in Cape Town. In addition to the retrospective review, a sub cohort of patients were prospectively phenotyped. The patients were subdivided into three groups namely: non-syndromic craniosynostosis, syndromic craniosynostosis and craniosynostosis with additional features. The last group included patients who had additional malformations or clinical findings without a syndromic diagnosis. The prevalence of phenotypic findings, teratogen exposure, birth complications, congenital malformations, surgical interventions and results of genetic testing in this cohort is described. Descriptive statistical analysis was used. Results: A total of 47 children with craniosynostosis were included in this study. Twenty-five individuals of the cohort were male, and one patient has a disorder of sexual development. Eighteen patients had non-syndromic synostosis. Twelve of these had sagittal type synostosis and five had metopic type synostosis with one unspecified. Thirteen had syndromic synostosis. Eight were clinically diagnosed with Crouzon syndrome of which three were molecularly confirmed. Four patients had Apert syndrome and one had Pfeiffer syndrome, these were clinically diagnosed without molecular confirmation. Sixteen patients had craniosynostosis with some additional findings but no syndromic diagnosis. The suture involved in the majority of patients was the sagittal suture. Ten patients had an additional structural brain abnormality and 13 had signs of raised intracranial pressure. The average age at confirmation of diagnosis of craniosynostosis by CT scan was 22.5 months (SD = 31.4, range: 0.1 – 140.9). Thirty of the 47 patients had craniosynostosis surgery. The average age of surgery was 22.4 months (SD = 19; range: 5-79). The anthropometric, phenotype and developmental features indicate that this is a highly heterogenous group of disorders. Conclusion: Craniosynostosis has been widely reported worldwide, especially in individuals of European descent with only a few reports on craniosynostosis in South African or African populations. Knowledge of the phenotypic spectrum will aid in understanding and documenting this group of disorders in our local population. This study also highlights that this is a complex condition best managed by a multidisciplinary team that should include a medical geneticist. The recognition of specific craniosynostosis syndromes together with appropriate molecular testing can be cost effective even in a limited resource setting and aid in accurate prognosis and recurrence risk information for families.
- ItemOpen AccessDelineation of the genetic causes of complex epilepsies in South African pediatric patients(2023) Esterhuizen, Alina; Ramesar, Rajkumar; Wilmshurst JoanneBackground Sub-Saharan Africa bears the highest burden of epilepsy worldwide. A proportion is presumed to be genetic, but this aetiology is buried under the burden of infections and perinatal insults, in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs), are most severely affected by this diagnostic gap, as the rate of actionable findings is highest in DEE-associated genes. This research study investigated the genetic architecture of epilepsy in South African (SA) children clinically diagnosed with DEE, highlighting the clinical utility of informative genetic findings and relevance to precision medicine for DEEs in a resource-constrained setting. Methods A group of 234 genetically naïve SA children with drug-resistant epilepsy and a diagnosis or suspicion of DEE, were recruited between 2016 and 2019. All probands were genetically tested using a DEE gene panel of 71 genes. Of the panel-negative probands, 78 were tested with chromosomal microarray and 20 proband/parent trios underwent exome sequencing. Statistical comparison of electroclinical features in children with and without candidate variants was performed to identify characteristics most likely predictive of a positive genetic finding. Results Pathogenic/likely pathogenic (P/LP) variants were identified in 41/234(17.5%) * probands. Of these, 29/234(12.4%) * were sequence variants in epilepsy-associated genes and 12/234(5.1%) * were genomic copy number variants (CNVs). Sixteen variants of uncertain significance (VUS) were detected in 12 patients. Of the 41 children with P/LP variants, 26/234(11%) had variants supporting precision therapy. Multivariate regression modelling highlighted neonatal or infantile-onset seizures with movement abnormalities and attention difficulties as predictive of a positive genetic finding. This, coupled with an emphasis on precision medicine outcomes, was used to propose the pragmatic “Think-Genetics” decision tree for early recognition of a possible genetic aetiology, pragmatic testing, and multidisciplinary consultation. Conclusion The findings presented here emphasise the relevance of an early genetic diagnosis in DEEs and highlight the importance of access to genetic testing. The “Think-Genetics” strategy was designed for early recognition, appropriate interim management, and genetic testing for DEEs in resource constrained settings. The outcomes of this study emphasise the pressing need for augmentation of the local genetic laboratory services, to incorporate gene panels and exome sequencing. *These percentages were rounded off to whole numbers in the published articles included in this thesis (i.e., rounded off to 18%, 12% and 5%, respectively).
- ItemOpen AccessDental implications of genetic and congenital intellectual disabilities in Cape Town(2018) Roberts, Tina Sharon; Beighton, Peter; Stephen, LXGIntroduction Intellectual disability (ID) is a common and significant problem which has many social, financial, medical and dental implications in South Africa. The severity of the ID varies, ranging from mild to profound impairment and numerous environmental and genetic factors play a role in the aetiology. Oral health is crucial to the overall health and well-being of children with ID. The dental problems of children with ID may be overshadowed by their intellectual dysfunction, and in some instances, by syndromic manifestations. These dental abnormalities may be unnoticed or considered of lesser importance than systemic health issues. There is a paucity of information in both the international and local scientific literature regarding the dental needs, the dental management implications and barriers to oral care pertaining to children with ID. For these reasons, the principal focus of this thesis is the identification, documentation and analysis of the dental abnormalities a group of children with ID in Cape Town, South Africa. Methodology A total of 206 children with ID were assessed during the investigation; 157 children at six Special Educational Facilities (SE Facilities) and 49 at the Red Cross Children’s Hospital (RXH) in Cape Town. The children were referred to the author by the Medical Genetics team of the University of Cape Town. This clinical study was based on a cross-sectional, quantitative, exploratory, descriptive design. When appropriate, clinical photographs and panorex radiographs were obtained. Signed permission for these records were granted by the parents or legal caregivers. Results The frequency of unmet dental disorders among children with ID both at the SE Facilities and RXH was high: dental caries (67% and 84%); gingival disease (69% and 86%); missing teeth (46% and 51%); malocclusion (30% and 66%); structural tooth abnormalities (7.5% and 38%). Based on clinical observation, forty-three percent of children at the SE Facilities had abnormalities of the jaw and midface that required surgical intervention. Dental fillings were present in only 8% of children at the SE Facilities and 12% of children at the RXH. Many parents and caregivers of children with ID experienced difficulty attending dental clinics. Financial and psychosocial issues were the key barriers that prevented their children from accessing dental services. Conclusions Intellectual disability varies in complexity and affects several South African children. Oral health plays a significant role in the general health and well-being of children with ID. The prevalence of unmet dental needs among children with ID is high, and in South Africa, the limited financial resources dedicated to primary and specialized oral health care may preclude access of many affected children to the required dental services. Furthermore, psychosocial factors such as violence, limited finance, and logistical problems such as transport may also impact on the high frequency of dental disease in this country. The common occurrence of unmet basic and specialized dental need reported in this study reflects the plight of children with ID in the context of dental management. The possible challenges faced by affected children in the maintenance of acceptable levels of oral health together with those encountered by oral healthcare professionals in the management of dental problems are complex yet integral to patients’ quality of life. This study aims to heighten the awareness of the importance of oral health among children with ID in South Africa.