Evolutionary Analyses and Identification of Rare Pathogenic Variant in The MCPH1 BRCT3 Domain Broaden Its Role in Non-syndromic Hearing Impairment

Abstract

Human mouse orthologous hearing impairment genes were investigated in African patients for causal variants. A homozygous mutation in the exon 13 BRCT3 of microcephalin1 (MCPH1) gene was reported in non-syndromic hearing impairment (NSHI). The present study screened multiplex families; ninety (n=90) patients and 106 controls from Cameroon and South Africa. The estimated mode of inheritance 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 candidate gene (MCPH1). The variants MCPH1 c.2222G>A p.(R741Q) (Alt Allele A=0.0000) and novel homozygous MCPH1 c.2234A>C p.(H745P) were absent in the 106 ethnically matched controls. The evolutionary analyses revealed that the MCPH1 protein evolved in 150 taxa while about 28 condensed in a phylogeny cluster that indicated similar substitution rates, divergent lengths, and positive selections, particularly in the two closest taxa to humans (chimpanzee and gorilla). The protein modelling and surface hydrophobicity analyses suggest a change in atomic charges at the helix-loop that mediates dimerization and DNA binding, such that the wildtype equilibrates at 0.072 nm while the mutant equilibrates at 0.042 nm in-silico. Our study suggests a further understanding of the roles of MCPH1 gene in NSHI using functional assays.

Leveraging human–mouse studies to advance the genetics of hearing impairment in Africa

“…The screening of MCPH1 for pathogenic variants is leading to the detection of variants of interest in NSHI in Africa, particularly in Cameroon. 12,78 In a more recent study on MCPH1 genetic variations in gnomAD data, one of the hypotheses tested in our study was how homogenous the allele frequencies of variations are in MCPHI based on the number of alleles counted. 79 In the majority of studies examining the genetic basis of complex diseases, it has been assumed that populations are genetically homogenous and that allele frequencies are similar across different world populations.…”