Nonsyndromic hearing impairment (NSHI) is one of the most heterogeneous trait known with 103 identified genes. It is hypothesized that many NSHI genes remain to be discovered due to the many different processes that can malfunction within the inner ear and cause hearing impairment. To date, most NSHI gene identification studies have been performed in families ascertained in Europe and Asia with the greatest number of findings in NSHI families from the Middle East and the Indian Subcontinent. To get a complete picture of the genes and variants involved in NSHI, it is essential to perform gene identification in understudied populations, e.g. sub-Saharan Africans. Despite many identified NSHI genes, only GJB2 and GJB6 have been systematically studied in sub-Saharan Africans. Other studies in sub-Saharan Africans have only reported novel variants in known NSHI genes. Additionally, NSHI is understudied in African-Americans and little is known about the genetic etiology of NSHI in this population. Therefore, little is known about the allelic architecture and frequency of NSHI pathogenic variants in populations of sub-Saharan African ancestry. Our preliminary study of 10 NSHI families from Cameroon using the OtoSCOPE sequencing array demonstrated that ~30% of NSHI genes in Cameroon are either not present in other populations or have yet to be identified. However, this estimate of 30% may be low due to the limited geographical region of study subject ascertainment. A recent study of 51 hearing impaired African-Americans using OtoSCOPE demonstrated that 74% of the study subjects did not have a variant in a known NSHI gene. We estimate that known pathogenic variants in NSHI genes only explain ~4.1% of autosomal recessive (AR)NSHI in African-Americans, which is the most common form of NSHI. To identify novel NSHI genes that are important to individuals of African ancestry, we will collect 125 families that segregate early-onset (<6 years of age) ARNSHI, 510 early-onset NSHI probands and 500 controls from Cameroon, Rwanda, South Africa (Xhosa-Bantu ancestry) and Sudan. This will be the largest study of NSHI to date in sub-Saharan Africans. Exome and whole genome sequencing, filtering approaches, rare variant aggregate association analysis and bioinformatic evaluation will be used to find genes containing pathogenic NSHI variants. These genes will be followed-up with functional and expression studies. The identification of novel NSHI genes in the sub-Saharan African population will give us a better insight into the genetic etiology of hearing impairment. Improved knowledge of genes and proteins that are essential to the auditory process will aid in the development of therapeutic interventions and genetic screening protocols for early diagnosis of NSHI. This study has high public health significance, in particular for minority populations, since it will improve genetic screening and in the future prediction of cochlear implant and treatment outcomes in sub-Saharan Africans, African-Americans and Hispanic-Americans of African descent.
Although hearing impairment (HI) is the most common sensory deficit in the world little is known about the genetic etiology of HI in sub-Saharan Africans and individuals of African descent. Studying the genetics of HI in sub-Saharan Africans will provide a better understanding of the mechanism of hearing and will greatly aid in the development of treatment strategies for HI. Additionally, identification of variants involved in HI in sub-Saharan Africans is highly beneficial for genetic screening so that HI can be diagnosed and intervention can occur at a young age to maximize a child?s cognitive, social-emotional, speech and language development.
