Principal Investigator:

Scientific Description:

HI-GENES Africa Project Summary/Abstract Despite a large number of identified genes, only GJB2 and GJB6 have been systematically studied in sub-Saharan Africans, for which prevalence of NSHI-causal variants is close to zero and we estimate known NSHI genes only explain ~4.1% of autosomal recessive (AR) NSHI in African-Americans. In the current project called HI-GENES Africa, referring to Hearing Impairment Genetics Studies in Africa, we propose to use Whole genome sequencing (WES), to study to date, the largest sample of sub-Saharan Africans from Cameroon, Mali, Ghana, and South Africa with prelingual ARNSHI in order to identify novel NSHI genes and to better understand the genetic etiology of NSHI in African populations. Aim 1) Ascertain families and probands with early-onset NSHI from Cameroon, Mali, Ghana, and South Africa. We will ascertain 125 families that segregate early-onset (<6 years of age) ARNSHI. For each family multiple affected (at least two per family) and unaffected members will be ascertained. Additionally, 500 probands with early-onset HI (<6 years of age) with strong evidence of having ARNSHI will be ascertained. The probands and family members will be carefully evaluated by clinical and audiometric testing to rule out syndromic HI and HI due to infectious and ototoxic exposures. Aim 2) Generate next generation sequence data on hearing-impaired family members. For each family, we will exome-sequence (including the mitochondrial genome) samples, from two affected family members, and follow up variants segregating in their parents and at least one non-affected sibling and a control non- affected population. We anticipate from previous experience that for ~5% of the families (n=~8) a causal variant will not be identified using exome sequencing, due to insufficient read depth or variant is in non-coding region. These families will be followed-up by generating whole genome sequence (WGS) data that also help to identify copy number variants. Aim 3) Analyze sequence data to identify novel NSHI genes. Using Variant Mendelian Tools we will annotate the identified variants and analyze rare variants (allele frequency<0.005 according to the ExAC database and sequencing data from Cameroon, Mali, Ghana, and South Africa Controls). Bioinformatic evaluation using multiple tools will be used to predict which variants are deleterious. Segregation of rare damaging variants will be tested in families. Given the large sample size there is a very high probability of identifying a number of novel NSHI genes in multiple families. HI-GENES Africa 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.

Lay Description:

Hearing impairment remains the most disabling congenital disease, with higher burden in Africa. Congenital hearing impairment occurs in 6 per 1000 new-born in Africa. Early diagnosis and interventions for children with hearing impairment is recommended to maximise their cognitive, social-emotional, speech and language development. Half of congenital hearing impairment cases have a genetic aetiology, of which 70% are isolated and referred as non-syndromic (NS).

Despite a large number of identified genes, only two (GJB2 and GJB6) have been systematically studied in sub-Saharan Africans, for which prevalence of NSHI (non syndromic hearing impairment)-causal variants is close to zero. We estimated that known NSHI genes only explain ~4.1% of NSHI in African-Americans.

The HI-GENES Africa programme proposes to use whole genome sequencing (WES), to study the largest sample of sub-Saharan Africans from Cameroon, Mali, Ghana, and South Africa with prelingual NSHI, in order to identify novel NSHI genes and to better understand the genetic aetiology of NSHI in African populations. We will also engage policies makers, and support groups on psychosocial challenges experienced by families and people living with HI.

HI-GENES Africa has high public health significance, since it will specifically improve genetic diagnosis, and future prediction of treatment outcomes in sub-Saharan Africans, and people of African descent. The research vision of HI-GENES Africa is to become the network that facilitates diagnosis, care, and quality of life of people living with hearing impairment, aligned with best standards.