A Novel LMX1A Frameshift Variant Underlies Familial Phenotypic Heterogeneity in DFNA7

Hereditary hearing loss (HHL) exhibits significant genetic heterogeneity, with mutations in LMX1A related to autosomal dominant non-syndromic hearing loss (DFNA7). Here, we report a novel heterozygous frameshift variant, LMX1A c.405delT (p. Phe135LeufsTer3) in a three-generation Chinese family with progressive and asymmetric sensorineural hearing loss (ASNHL). Clinical evaluations revealed variable severity (mild-to-profound) and onset (infancy to mid-adulthood), with cochlear aperture stenosis observed in the proband. Whole exon sequencing (WES), Sanger sequencing and segregation analysis confirmed the novel mutation and its cosegregation with the phenotype. Structural modeling predicted that truncation within the conserved LIM2 domain disrupts protein function. Functional studies demonstrated reduced transcriptional activity, supporting haploinsufficiency as the pathogenic mechanism. RNA sequencing (RNA-seq) of HEI-OC1 cells revealed dysregulation of neurodevelopmental, synaptic and mitochondrial pathways, implicating neurodegeneration and metabolic dysfunction in LMX1A-related hearing loss. This study highlights the role of LMX1A in auditory homeostasis, provides insights into genotype-phenotype correlations and underscores structural cochlear anomalies as potential contributors to ASNHL.