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Simple Summary: The prevalence of GJB2-related (MIM: 121011) congenital non-syndromic hearing impairment (NSHI) accounts for close to 50% in populations of Asian and European ancestry. However, in sub-Saharan Africa, except for Ghana, previous data showed that the prevalence of GJB2-associated NSHI is close to zero. To investigate the contribution of GJB2 mutations in autosomal recessive NSHI in Senegal, we screened 129 affected and 143 unaffected individuals from 44 multiplex families, 9 sporadic cases, and 148 hearing controls with no personal or family history of hearing impairment, by targeted gene sequencing. We identified three pathogenic GJB2 variants in 34% (n = 15/44) of multiplex families, of which 80% (n = 12/15) were consanguineous. The most common variant, GJB2: c.94C>T: p.(Arg32Cys), accounted for 27.3% (n = 12/44) of familial cases. We also identified the previously reported "Ghanaian" founder variant, GJB2: c.427C>T: p.(Arg143Trp), in four multiplex Senegalese families. Relatively high allele frequencies of c.94C>T. and c.427C>T variants were observed among the screened hearing controls: 1% (n = 2/148 ∗ 2), and 2% (n = 4/148 ∗ 2), respectively. No GJB6-D13S18 deletion was identified in any of the hearing-impaired participants. The data suggest that GJB2: c.94C>T: p.(Arg32Cys) should be routinely tested in NSHI in Senegal. This study aimed to investigate GJB2 (MIM: 121011) and GJB6 (MIM: 604418) variants associated with familial non-syndromic hearing impairment (HI) in Senegal. We investigated a total of 129 affected and 143 unaffected individuals from 44 multiplex families by segregating autosomal recessive non-syndromic HI, 9 sporadic HI cases of putative genetic origin, and 148 control individuals without personal or family history of HI. The DNA samples were screened for GJB2 coding-region variants and GJB6-D3S1830 deletions. The mean age at the medical diagnosis of the affected individuals was 2.93 ± 2.53 years [range: 1–15 years]. Consanguinity was present in 40 out of 53 families (75.47%). Variants in GJB2 explained HI in 34.1% (n = 15/44) of multiplex families. A bi-allelic pathogenic variant, GJB2: c.94C>T: p.(Arg32Cys) accounted for 25% (n = 11/44 families) of familial cases, of which 80% (n = 12/15) were consanguineous. Interestingly, the previously reported "Ghanaian" founder variant, GJB2: c.427C>T: p.(Arg143Trp), accounted for 4.5% (n = 2/44 families) of the families investigated. Among the normal controls, the allele frequency of GJB2: c.94C>T and GJB2: c.427C>T was estimated at 1% (2/148 ∗ 2) and 2% (4/148 ∗ 2), respectively. No GJB6-D3S1830 deletion was identified in any of the HI patients. This is the first report of a genetic investigation of HI in Senegal, and suggests that GJB2: c.94C>T: p.(Arg32Cys) and GJB2: c.427C>T: p.(Arg143Trp) should be tested in clinical practice for congenital HI in Senegal. [ABSTRACT FROM AUTHOR]

Genome-wide association studies for severe malaria (SM) have identified 30 genetic variants mostly located in non-coding regions. Here, we aimed to identify potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium (LD) with the malaria-associated genetic variants. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing five ATP2B4 SNPs in LD with rs10900585. We found significant associations between SM and rs10900585 and our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we demonstrated that both individual SNPs and the combination of SNPs had regulatory effects. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Our data demonstrate that severe malaria-associated genetic variants alter the expression of ATP2B4 encoding a plasma membrane calcium-transporting ATPase 4 (PMCA4) expressed on red blood cells. Altering the activity of this regulatory element affects the risk of SM, likely through calcium concentration effect on parasitaemia. [ABSTRACT FROM AUTHOR]