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The genetics of non-syndromic hearing impairment in South Africa
Get PDFHearing 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
Whole exome sequencing to investigate genetic variants of non-syndromic hearing impairment in a population of African ancestry
Get PDFIntroduction: Hearing impairment occurs when a child has hearing loss greater than 30dB in their better hearing ear and an adult cannot detect sound lower than 40dB in the better hearing ear. It is a common sensory disorder that affecting approximately 360 million worldwide, with an incidence of 6 in 1000 live births in developing countries such as those in Sub-Saharan Africa. 50 % of hearing impairment, in developed countries, is due to genetic factors, with 70% of genetic hearing impairment being classified as non-syndromic hearing impairment, which occurs when the hearing impairment presents with no other clinical manifestations. Hearing impairment is associated with over 150 genes, of which two connexin genes, GJB2 and GJB6, are the most prevalent genes associated with hearing impairment in European, Asian and North American of European ancestries populations. These genes have however been shown to be insignificant causes of Hearing Impairment in African populations. Aim: The aim of this study is to determine the rates for putative pathogenic variants in 172 hearing impairment associated genes, among Cameroonian patients affected by hearing impairment, and non-hearing-impaired controls. Methods: Patients and controls Patients were recruited from various schools of the Deaf and Ear, Nose and Throat (ENT) clinics in Cameroon. The patients were examined by qualified medical geneticists and ophthalmologist and detailed family history and medical history was obtained from the patients and their parents. 19 patients, who were negative for GJB2 and GJB6 mutations and presented with putative non-syndromic hearing impairment, were selected from a cohort of 582 patients for the present study. The control population consisted of 130 ethnically matched groups without any personal or familial history of hearing impairment. The controls were recruited from Yaoundé Central Hospital and Laquintinie Hospital in Cameroon. Whole exome sequencing DNA was extracted from whole blood using the salting out procedure and the Puregene Blood kit®. The DNA was subjected to spectrometry and gel electrophoresis to determine the quantity and quality of the DNA samples. The samples were then subjected to whole exome sequencing on the Illumina platform using the Nextera Rapid Capture Exome Kit at an average read depth of 30X, whereby only 18 patients were successfully sequenced. The exomes were then subjected to FastQC and SolexaQC++ for quality control measures and aligned to the hg19 reference genome using GATK and VariantMetaCaller. Bioinformatics analysis Variant annotation was performed using Annovar and the annotated variants were filtered based in rarity and pathogenicity. Tests for genetic differentiation and principle component analysis was performed on the combined patient exomes and combine control exomes. The first principle component analysis included data from African populations from the 1000 Genomes Phase 3 as well as six control samples from the Democratic Republic of Congo; and the second principle component analysis analysed on the Cameroonian patients and control population. Population structure analysis was followed by protein-protein interaction analysis using custom python and R script and pathway enrichment analysis using Enrichr combined with a second custom R script. The proportion of derived and ancestral alleles was computed by downloading the SNP ancestral alleles from Ensembl and verifying the presence of the SNPs in dbSNP database. The combined patient and control exomes were annotated using the VCFtools “fillOaa” script. The ancestral alleles were computed by dividing the number of times the alternative allele matched the ancestral allele with the number of copies of all the alternative alleles across all samples at the particular position. The ancestral alleles were categorised into six bins, based on their minor allele frequency, in the patient and control populations and this was used to contrast their proportions of derived and ancestral alleles. Furthermore, the proportion of ancestral and derived alleles in hearing impairment associated genes was computed at SNP based level for the Cameroonian population and contrasted with population from the Democratic Republic of Congo. Variants validation by Sanger sequencing Primers were designed to amplify the fragment surrounding the purported SNPs in MYO15A, MYO3A, and COL9A3 as well as for the fragments surrounding the population specific SNPs in VTN, RPL3L and DHRS4L2. Polymerase chain reaction was performed for the MYO15A, and MYO3A fragments. This was followed by purification of the PCR products and direct cycle Sanger sequencing of the PCR products. The sequencing products were then purified through ethanol precipitation and the fragments were suspended in HiDi Formamide and run on the capillary electrophoresis. The variants in MYO3A, MYO15A and COL9A3 were viewed in Integrated Genomics Viewer using the Bam files as well. Results Putative deleterious variants Single nucleotide polymorphism (SNPs) in MYO3A, MYO15A and COL9A3, were filtered out as putative causative mutations for three, four and two patients respectively. Direct Sanger Sequencing and viewing the patients BAM files did not confirm the presence of any of these putative pathogenic in the patients. Variations in USH2A, HSD17B4 and MYO1A were also filtered out but these variants were not considered disease causing, after a careful genotype to phenotypes correlations. Population genetics variants differentiations At a population level, specific variations were identified in FOXD4L2, DHRS2L6, RPL3L and VTN. Significant genetic differentiation was shown to exist between the control population and the patients’ population with regard to specific variants in VTN and RPL3L; furthermore, it was shown that these variants in VTN and RPL3L interact with other hearing impairment associated proteins with evidences that that VTN is hub protein for a hearing impairment associated pathway along with nine other genes. Conversely, this was not the case for variants described in FOXD4L2 and DHRS2L6. In known hearing Impairment genes, the proportion of ancestral alleles was lowest for the patients’ population for variations with minor allele frequencies between 0.0 and 0.1. The proportion of derived and ancestral alleles was also shown to differ between the Cameroonian and the population from the Democratic Republic of Congo, indication possible regional differences in aetiology of Hearing impairment amongst multiple African populations. Discussion Low putative pathogenic variants in known hearing impairment genes among Africans The low pick up rate for putative pathogenic variants in our patients follows a similar trend observed in the African American populations, with hearing impairment, as well as data from targeted exome sequencing from South African and Nigerian populations. This result is also in agreeance with other studies that interrogated hearing impairment in African populations utilising other means besides next generation sequencing. This result also highlights the importance of validating any results obtained from next generation sequencing through traditional approaches such as Sanger Sequencing or viewing the BAM files on IGV, specifically in African population, poorly represented in Exome databases. Bioinformatics Analysis Exhibited some Specific Variants among Cameroonian Protein-protein interactions and enrichment analysis indicated that VTN and RPL3L, and their interacting proteins, are significantly associated with osteoclast differentiation, which is associated with hearing impairment in osteogenesis imperfecta. VTN was further shown as a hub protein of a protein subnetwork, along ATPB2. The presence of a second protein acting as a hub protein may account for why aberrations in VTN have not been associated with a disease; whereby ATPB2 may ameliorate the pathogenic phenotype that ought to be observed in the presence of null mutations in VTN. Evolutionary adaptation of human hearing Data indicates the patient population carried a higher proportion of derived alleles in known hearing impairment genes, at low minor allele frequencies; possibly indicating, the interactive modifiers capacities of multiple hearing impairment genes, or alternatively, the polygenetic nature of hearing impairment in some patients. The proportion of ancestral and derived alleles was contrasted in the Cameroonian and the population from the Democratic Republic of Congo and it indicated that the variations that may result in hearing impairment in the one population may not be the same variations that result in hearing impairment in the other population Due to this, it is necessary to determine the causative variants resulting in disease in each of these populations independently. Conclusion and perspectives The results support a low pick up rate of putative variants in 172 known genes in groups of Cameroonian patients with HI, underscoring the current Targeted panel sequencing for HI may not be relevant for some African populations. The result also support the need of confirmation of variants found in WES, as well careful genotype to phenotypes correlations, particularly among African, whose sequences exome is relatively low in Exomes databases, and as a result could lead to more false positive results. Population genetic analysis has provided novel insight in the genetic architecture of HI among this group of Africans; particularly, the differential frequencies of ancestral alleles vs derived alleles in HI genes among patients vs controls underline the possibility of multigenic influence on the phenotype of Hearing Impairment that have not been well investigated, and may also signal evolutionary enrichment of some variants of HI genes in the populations as the result of natural selections, that deserve further investigation. The result supports the need of intensive familial studies in multiple African populations in order to unravel the novel genes and those variants that are relevant in clinical practice for people of African ancestry
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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