Novel genotype–phenotype correlation of functionally characterized LMX1A variants linked to sensorineural hearing loss

Abstract

LMX1A, encoding the LIM homeobox transcription factor, is essential for inner ear development. Despite previous reports of three human LMX1A variants with nonsyndromic hearing loss (NSHL) in the literature, functional characterization of these variants has never been performed. Encouraged by identification of a de novo, heterozygous, missense variant (c.595A > G; p.Arg199Gly) located in the home

Genetic Load of Alternations of Transcription Factor Genes in Non-Syndromic Deafness and the Associated Clinical Phenotypes: Experience from Two Tertiary Referral Centers

“…In most cases, the pedigrees indicated an autosomal dominant inheritance pattern. In one family, a de novo heterozygous missense variant (c.595A>G:p.Arg199Gly) was previously reported [ 18 ]. Four of the six variants were in the homeodomain, and the remaining two were truncated variants in LIM2 and the C-terminus, respectively ( Figure 1 c).…”

“…LMX1A , a LIM homeobox TF, has been recently implicated in non-syndromic deafness. LMX1A plays a vital role in ear patterning, regulating the morphogenesis of inner ear structures [ 18 ]. To date, only nine LMX1A variants have been reported in the literature.…”

“…Schrauwen et al [ 43 ] described a Pakistani family with an LMX1A recessive C-terminus missense variant (c.1106T>C;p.Ile369Thr) associated with profound SNHL. In recent studies, we reported five LMX1A heterozygous variants (c.595A>G:p.Arg199Gly, c.622C>T;p.Arg208*, c.719A>G;p.Gln240Arg, c.721G>A;p.Val241Met, and c.887dup;p.Gln297Thrfs*41) in five Korean families and one LMX1A heterozygous variant (c.686C>A; p.Ala229Asp) in a Polish family [ 18 , 44 ]. Together, these results suggest that alterations in LMX1A are associated with dominantly inherited asymmetric deafness.…”

“…Together, these results suggest that alterations in LMX1A are associated with dominantly inherited asymmetric deafness. In these variants, audiological severity correlated with the extent of transcriptional activation, measured in a luciferase-reporter assay, implying a genotype–phenotype correlation [ 18 ]. Our study expands the genotypic spectrum of LMX1A in DFNA7 by identifying a novel variant (c.331del:p.Gln111Argfs*7), in addition to demonstrating audiologic asymmetry (SH421).…”

“…The resulting reads were compared with the UCSC hg19 reference genome, and non-synonymous single-nucleotide polymorphisms (SNPs) were filtered at a depth of 40; dbSNP138 was filtered out, except for the flagged SNP. Disease-causing variants were detected in this study using a comprehensive filtering process and bioinformatics analyses, as described previously [ 16 , 17 , 18 ]. The pathogenic potential of the novel variants identified herein was evaluated according to the ACMG/AMP guidelines developed for hearing loss [ 19 ].…”