A Novel LMX1A Frameshift Variant Underlies Familial Phenotypic Heterogeneity in DFNA7

Pathogenic variants in the LIM-homeodomain transcription factor LMX1A represent a rare yet critical etiology for autosomal dominant nonsyndromic hearing loss 7 (DFNA7) and less frequently, its autosomal recessive counterpart (ARNSHL). Here, we describe a novel heterozygous frameshift variant, LMX1A c.405delT (p.Phe135LeufsTer3), identified in a three-generation Chinese family, cosegregating with progressive and asymmetric sensorineural hearing loss (ASNHL). Clinical manifestations exhibited significant intrafamilial phenotypic variability, with hearing loss (HL) severity ranging from mild to profound, and onset varying from infancy to mid-adulthood. High-resolution imaging revealed bilateral cochlear aperture stenosis (CAS) in the severely affected proband. Whole-exome sequencing (WES) and cosegregation analysis confirmed this novel variant. Structural modeling predicted the truncation of both the DNA-binding homeodomain and the C-terminus. Subsequent reporter assays demonstrated a significant loss of transcriptional activity. Furthermore, plasmid titration experiments and Actinomycin D chase assays functionally corroborated the haploinsufficiency mechanism and excluded the dominant-negative effect. Integrative multiomics profiling (RNA-seq and DIA-based proteomics) of in vitro HEI-OC1 model revealed molecular perturbations following Lmx1a deficiency, primarily involved in synaptic signaling and immune-inflammatory cascades. This study broadens the LMX1A mutational landscape, refines the clinical phenotypic spectrum of DFNA7 and establishes insufficient LMX1A dosage as the primary disease driver.