Genetic epidemiological study doesn't support GLA IVS4?+?919G?>?A variant is a significant mutation in Fabry disease

Background The GLA IVS4?+?919G?>?A which is linked to late-onset Fabry disease shows high frequency in Taiwan. Methods To determine whether IVS4?+?919G?>?A is a frequent cause of heart disease, we genotyped it in normal controls and other disease cohorts (type 2 diabetes, heart failure, ventricular tachycardia, atrial fibrillation and coronary artery disease). Normal controls and diabetes patients carrying the variant were evaluated for their cardiac condition. Minigene constructs were used to study GLA splicing patterns in different cell lines. Results GLA IVS4?+?919A was found in 4/1634 males (0.245%) and 2/1634 females (0.123%) in normal controls and in 4/2133 males (0.188%) and 7/1816 females (0.385%) in the type 2 diabetes cohort. Of all the 17 IVS4?+?919A carriers in these two groups, only two males reported heart-related disease (myocardial infarction and hypertensive heart disease). Furthermore, in the heart disease cohort (n?=?649), only one male carried the variant. Minigene constructs showed that the AGS (stomach) cell line showed a distinct GLA splicing pattern. Conclusion Most subjects carrying GLA IVS4?+?919A did not show abnormal cardiac phenotypes. The near-absence of GLA IVS4?+?919A in heart disease cohort suggested that this variant is not a frequent cause of overt heart diseases in Taiwan and that the genotype-phenotype correlation and natural course of the disease need further investigation. We also showed that the GLA IVS4?+?919G?>?A nucleotide change did influence alternative splicing in a tissue-specific manner. Synopsis The GLA IVS4?+?919G?>?A variant is not a frequent cause of overt heart disease in Taiwan. ? 2017