Reader Response: D313Y Variant in Fabry Disease: A Systematic Review and Meta-analysis

The publication by Palaiodimou et al.¹ seems to have significant flaws in its data ascertainment and statistical evaluation:

1. The estimate of p.D313Y frequency in the subgroup of patients is incorrectly calculated as 0.049 (0.02 is correct given the numbers provided in Figure 2).

2. Two observational studies (ref. 37-1+39) contribute >60% of the positive cases. No matched controls were assessed and predominantly no other genetic causes evaluated.

3. Several publications evaluated for this review show substantial methodological flaws that create a high risk of false positives among the included cases.

4. The frequency of p.D313Y in the genome Aggregation database (version V2.1.1 and V3.1.2) is 0.003, which is >10× higher than the reported 0.00027 in this meta-analysis.

5. The largest control cohort (ref. 41) misses p.D313Y carriers (especially female individuals) because the screening method used did not include healthy p.D313Y carriers with normal GLA enzyme activity. This enhances the risk of false negatives, as recently documented.²

From a genetics perspective, the GLA variant p.D313Y should be classified as “benign” according to American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria, as most genetic laboratories worldwide have already done for many years.³ We strongly suggest a critical reevaluation of the presented data and correction of the inaccurate analysis and result interpretation.