Genotype-Phenotype Correlations in 293 Russian Patients with Causal Fabry Disease Variants

Area of Science:

• Genetics
• Rare Diseases
• Biomarkers

Background:

• Fabry disease (FD) is a rare, inherited, multisystem disorder caused by pathogenic variants in the GLA gene.
• Genotype-phenotype correlations are crucial for understanding diverse clinical presentations of FD, including classical, atypical, late-onset, and system-specific forms.

Purpose of the Study:

• To conduct large-scale screening for Fabry disease in a Russian population.
• To identify GLA gene variants and establish genotype-phenotype and genotype-biomarker correlations.
• To describe the clinical spectrum and frequencies of manifestations in a cohort of Russian FD patients.

Main Methods:

• A two-step diagnostic algorithm was employed, starting with lyso-Gb3 biomarker concentration measurement for 48,428 high-risk individuals.
• High-throughput sequencing was used to screen 2427 additional patients with hypertrophic cardiomyopathy (HCM) for atypical FD.
• Molecular genetic testing identified GLA gene variants in 293 confirmed FD cases from 133 families.

Main Results:

• Fabry disease was detected in 102 (0.20%) of 50,855 screened patients.
• A spectrum of 104 distinct pathogenic GLA gene variants was identified in 293 patients, with detailed clinical manifestations described, including 20 pediatric cases.
• Correlations were established between lyso-Gb3 biomarker levels and specific pathogenic GLA variants, and certain variants were associated with early stroke development.

Conclusions:

• Large-scale screening effectively identified Fabry disease cases in the Russian population.
• The study provides comprehensive clinical and molecular genetic data for a significant cohort of Russian FD patients.
• Established correlations enhance understanding of FD pathogenesis and can inform diagnostic and therapeutic strategies.