AUTHOR=Zhang Ting , Huang Sulan , Huang Fan 
  
TITLE=Novel GLA variant (c.752A>C; p.Glu251Ala) identified in a patient with Fabry cardiomyopathy and familial segregation
  
JOURNAL=Frontiers in Molecular Biosciences
  
VOLUME=Volume 13 - 2026
  
YEAR=2026
  
URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2026.1828669
  
DOI=10.3389/fmolb.2026.1828669
  
ISSN=2296-889X
  
ABSTRACT=BackgroundFabry disease (Anderson–Fabry disease,FD) is an X-linked lysosomal storage disorder caused by variants in GLA, resulting in α-galactosidase A (α-Gal A) deficiency and accumulation of globotriaosylsphingosine (lyso-Gb3), with frequent cardiac involvement.Case SummaryA 53-year-old man presented with exertional chest tightness and dyspnea. Electrocardiography and echocardiography demonstrated marked left ventricular hypertrophy. Cardiac magnetic resonance revealed diffuse hypertrophy with extensive subendocardial late gadolinium enhancement. ^99mTc-pyrophosphate scintigraphy showed minimal myocardial uptake, arguing against transthyretin cardiac amyloidosis. Biochemical testing showed markedly reduced α-Gal A activity and elevated lyso-Gb3 levels. Whole-exome sequencing identified a previously unreported GLA variant (NM_000169.3:c.752A>C; p.Glu251Ala), which was confirmed by Sanger sequencing and detected in multiple family members. The variant is currently classified as a variant of uncertain significance (VUS). Familial analysis demonstrated a segregation pattern consistent with X-linked inheritance.ConclusionWe report a novel GLA variant associated with biochemical abnormalities and familial segregation consistent with FD. These findings support a potential role of this variant in Fabry cardiomyopathy and expand the mutational spectrum of GLA, although its pathogenicity requires further validation.