Connexin Genes Variants Associated with Non-Syndromic Hearing Impairment: A Systematic Review of the Global Burden.

Mutations 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.

Enhancing Genetic Medicine: Rapid and Cost-Effective Molecular Diagnosis for a GJB2 Founder Mutation for Hearing Impairment in Ghana.

In Ghana, gap-junction protein ß 2 (GJB2) variants account for about 25.9% of familial hearing impairment (HI) cases. The GJB2-p.Arg143Trp (NM_004004.6:c.427C>T/OMIM: 121011.0009/rs80338948) variant remains the most frequent variant associated with congenital HI in Ghana, but has not yet been investigated in clinical practice. We therefore sought to design a rapid and cost-effective test to detect this variant. We sampled 20 hearing-impaired and 10 normal hearing family members from 8 families segregating autosomal recessive non syndromic HI. In addition, a total of 111 unrelated isolated individuals with HI were selected, as well as 50 normal hearing control participants. A restriction fragment length polymorphism (RFLP) test was designed, using the restriction enzyme NciI optimized and validated with Sanger sequencing, for rapid genotyping of the common GJB2-p.Arg143Trp variant. All hearing-impaired participants from 7/8 families were homozygous positive for the GJB2-p.Arg143Trp mutation using the NciI-RFLP test, which was confirmed with Sanger sequencing. The investigation of 111 individuals with isolated non-syndromic HI that were previously Sanger sequenced found that the sensitivity of the GJB2-p.Arg143Trp NciI-RFLP testing was 100%. All the 50 control subjects with normal hearing were found to be negative for the variant. Although the test is extremely valuable, it is not 100% specific because it cannot differentiate between other mutations at the recognition site of the restriction enzyme. The GJB2-p.Arg143Trp NciI-RFLP-based diagnostic test had a high sensitivity for genotyping the most common GJB2 pathogenic and founder variant (p.Arg143Trp) within the Ghanaian populations. We recommend the adoption and implementation of this test for hearing impairment genetic clinical investigations to complement the newborn hearing screening program in Ghana. The present study is a practical case scenario of enhancing genetic medicine in Africa.

A cross-sectional comparative study of perceived stigma between patients with epilepsy and patients living with HIV/AIDS in Accra, Ghana.

BACKGROUND: Health-related stigma is a great challenge to the treatment of diseases. In epilepsy like other conditions, it causes affected individuals to conceal their illness. In this study, we described stigma perceived by patients with epilepsy at the Korle Bu Teaching Hospital (KBTH), a tertiary referral facility, and the Accra Psychiatry Hospital in Ghana (APH). We then compared the perception of stigma in patients with epilepsy to stigma perceived by persons living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) (PLWHA), a chronic communicable disease stigmatized in Ghana. METHODS: A total of 351 patients with epilepsy were recruited from both sites by systematic random sampling and interviewed. The Kilifi Stigma Scale for Epilepsy was used to determine individual patient's stigma score. Statistical analysis was done using multiple logistic regression analysis to control for the effect of measured independent variables that were significant on univariate analysis: age, gender, marital status, income, type of epilepsy, and the frequency of seizures, on the outcome variable. Comparative analysis of the mean stigma score in patients with epilepsy and persons living with HIV/AIDS was done using the Student's t-test and Mann-Whitney U test (Wilcoxon rank sum test). RESULTS: The presence of perceived stigma using the Kilifi Stigma Score Estimation was 32.02% (62), 33.33% (49), and 28.88% (54) among respondents from KBTH, APH, and PLWHA respectively. Results from Wilcoxon rank sum test showed that the median stigma score between the three groups was significant; KBTH and APH (p-value; 0.0258), KBTH and PLWHA (p-value; 0.00001), and APH and PLWHA (p-value; 0.0000). Age (<40 years), seizure frequency, ethnic group (Ewe and Guan), and being divorced showed high odds for perceived stigma among KBTH patients with epilepsy. Having tertiary education led to lower odds for perceived stigma in epilepsy for APH patients with epilepsy. CONCLUSION: This study showed that epilepsy is associated with a high stigma perception. The perceived stigma was greater than stigma in PLWHAs in Accra. Stigma was affected by unemployment, ethnicity (Ewe and Guan), and uncontrolled seizures. Increasing age reduced perceived stigma and the management of patients with epilepsy in a psychiatric facility might have impacted negatively on the perceived stigma.