Homoizigot LMX1A Varyantının Konjenital Şiddetli-Profound Sensörinöral İşitme Kaybıyla İlişkisi: Akraba Evliliği Olan Yemen Ailesinin Klinik ve Genetik Analizi

Özet (abstract)

Background: Hereditary hearing loss is genetically and clinically heterogeneous. Although heterozygous LMX1A variants are mainly associated with autosomal dominant nonsyndromic hearing loss (DFNA7), the contribution of biallelic LMX1A variants remains poorly understood. This study aimed to investigate the clinical and genetic significance of a homozygous LMX1A variant in a consanguineous Yemeni family. Methods: The proband and available family members underwent clinical and audiological evaluation, targeted next-generation sequencing, Sanger validation, and segregation analysis. The potential molecular consequences of the identified variant were assessed using transcript structure, population databases, previous functional studies, and genotype–phenotype correlation. Results: The proband, an 18-month-old Yemeni Arab girl, presented with congenital bilateral profound sensorineural hearing loss. Genetic testing identified a homozygous nonsense variant in LMX1A, NM_177398.4:c.937C>T [p.(Arg313Ter)]. Her father (33 years), mother (31 years), and elder sister (6 years) were heterozygous carriers with pure-tone hearing thresholds within the normal range, although the father exhibited bilaterally absent distortion-product otoacoustic emissions. The observed genotype–phenotype pattern was consistent with a possible autosomal recessive contribution but did not establish a definitive recessive inheritance mechanism. The variant is predicted to result in the loss of approximately 70 C-terminal amino acids if a truncated protein is produced. Nonsense-mediated mRNA decay escape remains a possible molecular consequence, but no variant-specific functional validation was performed. Conclusions: This study provides additional clinical observations consistent with a possible recessive contribution of LMX1A variants to hearing loss and broadens the reported genotype–phenotype spectrum of LMX1A-related hearing loss. However, the available evidence does not establish a definitive causal relationship or a strictly autosomal recessive inheritance mechanism. Further independent cases, functional investigations, and longitudinal audiological follow-up are needed to clarify the clinical significance and potential molecular consequences of p.(Arg313Ter).

Yazarların özeti; kaynağından alınmıştır. Genes, 2026 · DOI ↗