TY  - JOUR
AU  - Oluwole, Oluwafemi G.
AU  - James, Kili
AU  - Wonkam, Ambroise
PY  - 2025
DA  - 2025/06/26
TI  - The Identification and Classification of Novel Genetic Variants in the <i>MCPH1</i> Gene Suggest Association with Non-Syndromic Hearing Impairment
JO  - OBM Genetics
SP  - 299
VL  - 09
IS  - 02
AB  - Human mouse orthologous hearing impairment genes were investigated in African patients for causal variants. A homozygous mutation in exon 13 of the microcephalin1 (MCPH1) gene, which encodes the BRCA1-carboxyl terminal 2 domain (BRCT2), was reported in non-syndromic hearing impairment (NSHI). The present study aims to investigate further the emerging roles of MCPH1 in the genetics of NSHI in African patients in the new and larger cohorts. This study screened multiplex families and isolated cases, including 90 patients and 212 controls from Cameroon (n = 106) and South Africa (n = 106) using the Sanger sequencing technique with PCR. Subsequently, computational analyses were conducted to assess the level of relevance of the gene and the effects of genetic variations within it. The estimated mode of inheritance for the familial cases was 34.8% autosomal recessive, 34.8% autosomal dominant, 21.74% mitochondrial, and 8.66% X-linked. Four rare missense variants and seven novel variants were identified in the MCPH1 gene. The homozygous variants MCPH1 c.2222G>A p.(Arg741Gln) and MCPH1 c.2234A>C p.(His745Pro) were identified in two probands; one of the probands had an affected sibling who is a heterozygous carrier of MCPH1 c.2234A>C p.(His745Pro). Computational analysis suggests that these variants are potentially pathogenic, as they occur in mutational hotspots within MCPH1 and a domain susceptible to missense loss-of-function mutations. The evolutionary analyses revealed that the MCPH1 protein evolved in 150 taxa, while about 28 condensed into a phylogeny cluster that indicated similar substitution rates, divergent lengths, and positive selection, particularly in the two closest taxa to humans (chimpanzee and gorilla), suggesting that MCPH1 is a stable gene. The protein modelling and surface hydrophobicity analyses indicate a change in atomic charges at the helix-loop that mediates dimerization and DNA binding, such that the wildtype equilibrates at 0.072 nm. In contrast, the mutant equilibrates at 0.042 nm in-silico. The study further reveals an association between the MCPH1 gene and NSHI. The aberrations in the MCPH1 gene are emerging with multiple conditions, understanding its genetic variations in different populations will be very important in genomic medicine.
SN  - 2577-5790
UR  - https://doi.org/10.21926/obm.genet.2502299
DO  - 10.21926/obm.genet.2502299
ID  - Oluwole2025
ER  -