The contribution of GJB4 and GJC3 gene variants to hearing impairment in Africa has not yet been studied. Here, we investigated the contribution of these genes to autosomal recessive non-syndromic hearing impairment in Ghanaian children. Hearing-impaired children from 141 simplex and 59 multiplex families were enrolled from 11 schools for the deaf in Ghana. The coding regions of GJB4 and GJC3 were amplified, sequenced, and analyzed for the study participants previously found to be negative for GJB2 and GJB6 variants. Seven GJB4 and one GJC3 variants were identified. One out of the seven GJB4 variants was classified as likely pathogenic, while the others were either benign or synonymous. The likely pathogenic variant (p.Asn119Thr/rs190460237) was predicted to be likely associated with hearing impairment. We modeled the wild-type and mutant proteins of this variant (p.Asn119Thr) to evaluate the effect of the mutation on protein structure and ligand-binding properties. The mutant and not the wild type had the potential to bind N-Ethyl-5ʹ-Carboxamido Adenosine (DB03719) which was due to a slight structural change that was observed. No clinically relevant variant was identified in the GJC3 gene. We report for the first time a likely pathogenic GJB4 variant that may be associated with non-syndromic hearing impairment in Ghana; the finding will add to the body of evidence of the contribution of GJB4 to hearing impairment cases around the world.

Impact statement

Although connexins are known to be the major genetic factors associated with HI, only a few studies have investigated GJB4 and GJC3 variants among hearing-impaired patients. This study is the first to report GJB4 and GJC3 variants from an African HI cohort. We have demonstrated that GJB4 and GJC3 genes may not contribute significantly to HI in Ghana, hence these genes should not be considered for routine clinical screening in Ghana. However, it is important to study a larger population to determine the association of GJB4 and GJC3 variants with HI.

中文翻译：

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加纳非综合征性听力障碍中的 GJB4 和 GJC3 变异。

GJB4和GJC3基因变异对非洲听力障碍的影响尚未得到研究。在这里，我们研究了这些基因对加纳儿童常染色体隐性非综合征性听力障碍的影响。加纳 11 所聋哑学校招收了来自 141 个单一家庭和 59 个混合家庭的听障儿童。对之前发现GJB2和GJB6变体呈阴性的研究参与者的GJB4和GJC3编码区进行了扩增、测序和分析。鉴定出 7 个GJB4和 1 个GJC3变体。七个GJB4变体中有一个被归类为可能致病，而其他变体要么是良性的，要么是同义的。预测可能的致病性变异 (p.Asn119Thr/rs190460237) 可能与听力障碍有关。我们对该变体 (p.Asn119Thr) 的野生型和突变蛋白进行了建模，以评估突变对蛋白质结构和配体结合特性的影响。突变体而非野生型有可能结合 N-Ethyl-5ʹ-Carboxamido Adenosine (DB03719)，这是由于观察到了轻微的结构变化。 GJC3基因中未发现临床相关变异。我们首次报告了一种可能与加纳非综合征性听力障碍相关的致病性GJB4变异；这一发现将为GJB4对世界各地听力障碍案件的贡献提供更多证据。

 影响报告

尽管已知连接蛋白是与 HI 相关的主要遗传因素，但只有少数研究调查了听力受损患者的GJB4和GJC3变异。这项研究首次报告了来自非洲 HI 队列的GJB4和GJC3变异。我们已经证明， GJB4和GJC3基因可能对加纳的 HI 没有显着影响，因此不应考虑将这些基因用于加纳的常规临床筛查。然而，重要的是研究更大的人群以确定GJB4和GJC3变异与 HI 的关联。