Inherited genetic background, specifically variants in the EGLN1/SPRTN region, contributes to variation in cardiac remodeling severity among male carriers of the same pathogenic GLA IVS4+919G>A variant.
Key Findings
Results
Mean left ventricular mass index increased substantially with age among male IVS4+919G>A carriers, but with marked variability within each age stratum.
Mean LVMI increased from 34.6 ± 11.3 g/m2.7 at ages 20–39 years to 75.1 ± 34.0 g/m2.7 at ages ≥60 years.
The study included 167 unrelated male carriers of the GLA IVS4+919G>A founder variant.
Substantial variability persisted within each age stratum despite the same underlying pathogenic variant.
LVH was defined as LVMI ≥ 51 g/m2.7 and septal hypertrophy as IVSd ≥ 1.2 cm.
Results
Two variants, rs1435166 and rs2572260, located in the EGLN1/SPRTN region, reached genome-wide significance for association with left ventricular hypertrophy.
Both rs1435166 and rs2572260 showed identical association p-values of 4.14 × 10⁻⁸ for LVH.
The two variants were in complete linkage disequilibrium across all 81 participants (dosage r² = 1.00; D' = 1.00), indicating a single regional association signal.
The genome-wide association analysis for LVH included 81 men aged ≥50 years.
The association remained evident in exact testing, Firth logistic regression, and age-adjusted continuous-LVMI analysis.
Genotyping was performed with the Axiom Genome-Wide TPM 2.0 Array.
Results
Each rs1435166 T allele was associated with a 12.8 g/m2.7 lower LVMI in an age-adjusted continuous analysis.
The age-adjusted continuous-LVMI analysis yielded concordant results with the binary LVH analysis.
The effect size was 12.8 g/m2.7 lower LVMI per T allele of rs1435166.
This finding supports a quantitative, allele-dose relationship between the EGLN1/SPRTN region variant and cardiac remodeling severity.
Results
Two intergenic variants met an exploratory significance threshold for septal hypertrophy, but no variant reached genome-wide significance for plasma lyso-Gb3 levels.
Septal hypertrophy was defined as interventricular septal thickness at end-diastole (IVSd) ≥ 1.2 cm.
The genome-wide association analysis for septal hypertrophy also included 81 men aged ≥50 years.
Lyso-Gb3 analyses included 149 men with available plasma globotriaosylsphingosine measurements.
The two septal hypertrophy variants were described as intergenic and reached only an exploratory threshold, not genome-wide significance.
Background
The GLA IVS4+919G>A variant causes a late-onset, cardiac-predominant form of Fabry disease, yet cardiac remodeling severity varies markedly among affected men carrying the same variant.
The IVS4+919G>A allele is described as a founder variant associated with late-onset, cardiac-predominant Fabry disease.
167 unrelated male carriers were studied, providing evidence of inter-individual variability despite a shared genetic cause.
The study was designed specifically to identify genetic modifiers of this variability.
The authors conclude that inherited genetic background contributes to variation in cardiac remodeling severity among carriers of the same pathogenic GLA variant.
Conclusions
The authors note that independent replication, regional fine-mapping, and functional validation of the EGLN1/SPRTN region findings are required.
The study sample was limited to 81 men aged ≥50 years for the LVH genome-wide association analysis.
The authors explicitly state: 'Independent replication, regional fine-mapping, and functional validation are required.'
The findings are framed as supporting a hypothesis rather than establishing a definitive causal relationship.
What This Means
Fabry disease is a rare inherited condition caused by mutations in the GLA gene that leads to the buildup of fatty substances in cells, often causing serious heart problems. One specific mutation, called IVS4+919G>A, is particularly common in certain populations and mainly affects the heart in middle age and beyond. However, doctors have long noticed that some people with this exact same mutation develop severe heart thickening (called left ventricular hypertrophy) while others are much less affected, even at similar ages. This study investigated whether differences in other parts of the genome — genetic modifiers — might help explain this variability.
Researchers studied 167 unrelated men who all carried the same GLA mutation and scanned their genomes for variants associated with heart wall thickness. They found that two genetic variants in a region near genes called EGLN1 and SPRTN were strongly associated with whether a person developed significant heart thickening, reaching the stringent statistical threshold used in genome-wide studies. Men carrying certain versions of these variants had, on average, about 12.8 units lower left ventricular mass index — a meaningful difference in heart muscle burden. The two variants were perfectly correlated with each other, suggesting they tag the same underlying genetic signal in this region.
This research suggests that a person's broader genetic background — beyond just the Fabry disease mutation itself — may influence how severely the heart is affected. This could help explain why some carriers develop life-threatening cardiac complications while others do not. However, the study was relatively small and the findings need to be confirmed in independent groups of patients. If replicated, identifying these genetic modifiers could eventually help clinicians predict which Fabry disease patients are at highest risk for cardiac complications and might benefit most from early or more intensive treatment.
Sung K, Hsu C, Lu Y, Hung C, Niu D. (2026). Genetic Modifiers of Cardiac Remodeling Severity in IVS4+919G>A-Associated Fabry Cardiomyopathy.. International journal of molecular sciences. https://doi.org/10.3390/ijms27167447