Methylome Profiling in Fabry Disease in Clinical Practice: A Proof of Concept

Anderson-Fabry disease (FD) is an X-linked disease caused by a functional deficit of the alpha-galactosidase A enzyme. FD diagnosis relies on the clinical manifestations and research of GLA gene mutations. However, because of the lack of a clear genotype/phenotype correlation, FD diagnosis can be challenging. Recently, several studies have highlighted the importance of investigating DNA methylation patterns for confirming the correct diagnosis of different rare Mendelian diseases, but to date, no such studies have been reported for FD. Thus, in the present investigation, we analyzed for the first time the genome-wide methylation profile of a well-characterized cohort of patients with Fabry disease. We profiled the methylation status of about 850,000 CpG sites in 5 FD patients, all carrying the same mutation in the GLA gene (exon 6 c.901C>G) and presenting comparable low levels of alpha-Gal A activity. We found that, although the whole methylome profile did not discriminate the FD group from the unaffected one, several genes were significantly differentially methylated in Fabry patients. Thus, we provide here a proof of concept, to be tested in patients with different mutations and in a larger cohort, that the methylation state of specific genes can potentially identify Fabry patients and possibly predict organ involvement and disease evolution.

Automated summary

This study analyzed the genome-wide methylation profile of patients with Fabry disease for the first time. Although the whole methylome profile did not differentiate between FD patients and unaffected individuals, several genes showed significant differential methylation in Fabry patients. This finding may contribute to the identification of Fabry patients and the prediction of disease progression.