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.