Novel Mutations in CLPP, LARS2, CDH23, and COL4A5 Identified in Familial Cases of Prelingual Hearing Loss

Abstract

We report the underlying genetic causes of prelingual hearing loss (HL) segregating in eight large consanguineous families, ascertained from the Punjab province of Pakistan. Exome sequencing followed by segregation analysis revealed seven potentially pathogenic variants, including four novel alleles c.257G>A, c.6083A>C, c.89A>G, and c.1249A>G of CLPP, CDH23, COL4A5, and LARS2, respectively. We also identified three previously reported HL-causing variants (c.4528C>T, c.35delG, and c.1219T>C) of MYO15A, GJB2, and TMPRSS3 segregating in four families. All identified variants were either absent or had very low frequencies in the control databases. Our in silico analyses and 3-dimensional (3D) molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in MYO15A, GJB2, TMPRSS3, and CDH23 were classified as “pathogenic” or “likely pathogenic”, while the variants in CLPP and LARS2 fall in the category of “uncertain significance” based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant pathogenicity guidelines. This paper highlights the genetic diversity of hearing disorders in the Pakistani population and reports the identification of four novel mutations in four HL families.

Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches

“…This is in accordance with the observation that beta hairpin motifs are implicated in protein stability 29 , 30 . Moreover, the substitution of p.Ala508 in Escherichia coli LeuRS (analogous to human LeuRS p.Thr629) with a nonpolar methionine disrupts the structure and/or position of the leucine-specific domain and thus shifts the location of the KMSKS loop and reduces the catalytic efficiency 16 , 31 . It should be noted that the present model of human LeuRS is an improved version of those previously reported 16 , 32 since we used a variety of selected crystals.…”

Identification of novel gene variants causing autosomal recessive non-syndromic hearing loss in Iranian families

“…It is interesting to note that with increasing age, the frequency of autosomal dominant and autosomal recessive inheritance patterns increases and decreases, respectively (Venkatesh et al, 2015). On the other hand, consanguineous marriages increase the chance of having genetic disorders with autosomal recessive inheritance by about 0.25 to 20% [7], and Iran is no exception to this rule with nearly 40% consanguinity (Mehregan et al, 2019). Hereditary deafness is considered the second disability in Iran after mental retardation.…”

Genetics of Hearing Impairment

“…Perrault syndrome is genetically heterogeneous, as eight genes are known to be involved. Zafar et al report homozygous pathogenic variants in two of them, CLPP and LARS2 [7]. These variants were found, respectively, in two Pakistani consanguineous familial cases with apparently non-syndromic HI.…”

“…For genes that can cause syndromic as well as non-syndromic hearing loss when defective, it is even more important to understand the genotype-phenotype correlations. Two articles in this issue report families with non-syndromic hearing loss caused by missense variants in CDH23 [6,7]. Three (novel) missense variants in this gene underlie non-syndromic hearing loss (DFNB12).…”