Etiologies of Early-Onset Hearing Impairment in Rwanda

<b>Background:</b> Over three-quarters of the people living with hearing impairment (HI) live in low- and middle-income countries. However, Rwanda has limited data on the clinical profile of HI. <b>Aim:</b> We used community-based nationwide recruitment of participants to determine the etiology of early-onset (<7 years of age) HI in Rwanda. <b>Methods:</b> Participants were included after clinical examination, including audiological assessment by pure tone audiometry and/or auditory brainstem response. DNA was extracted from peripheral blood, and the entire coding region of <i>GJB2</i> was interrogated using Sanger sequencing. Multiplex PCR and Sanger sequencing were used to analyze the prevalence of the <i>GJB6</i>-D3S1830 deletion. <b>Results:</b> The participants were recruited from seven inclusive schools, one university teaching hospital, and four independent communities nationwide. We reviewed the clinical histories of 422 individuals affected by early-onset HI from 348 families and found that 21.18% (<i>n</i> = 89/422) was linked to early childhood meningitis infection while 51.23% (<i>n</i> = 216/422) was categorized as unknown HI etiology. Because of putative genetic causes, 82/348 (23.6%) families were reviewed and identified for genetic testing. Within the 82 families with potential genetic causes, 122 individuals were affected by HI, and 205 were unaffected. The male/female ratio of those enrolled for genetic investigations was 0.79 (<i>n</i> = 145/182). The mean age of diagnosis of HI was 4.3 ± 2.6 years. Most cases (89.36%, <i>n</i> = 109/122) reviewed were prelingual. Pedigree analysis suggested autosomal recessive inheritance in 46.3% (<i>n</i> = 38/82) of families. Most HI participants from familial cases had nonsyndromic HI (94.2%, <i>n</i> = 115/122). Waardenburg syndrome was found in three participants out of seven participants who presented with syndromic HI, while three other participants manifested signs of Usher syndrome and one with suspected Noonan syndrome. Molecular analysis did not find pathogenic variants in <i>GJB2</i> or <i>GJB6</i>-D3S1830 deletion in any of the probands tested (<i>n</i> = 27/122; 22.13%) or 100 non-affected control participants. <b>Conclusions:</b> This study revealed an overall late diagnosis (mean at 4.3 years) of HI in Rwanda. Most cases were of unknown origin or putative environmental origin (76.4%), with meningitis predominating as the acquired cause of early-onset HI. Among cases of putative genetic etiology, nonsyndromic HI accounted for the large majority (94.2%). However, <i>GJB2</i> and <i>GJB6</i> pathogenic variants were not identified in the screened proportion of the cohort. This study calls for the implementation of neonatal hearing screening as well as reinforcement of immunization programs to reduce the burden of acquired early-onset HI in Rwanda. Additional genomic studies, ideally using exome sequencing for familial cases, are needed.