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

Abstract

Anderson−Fabry disease (FD) is an X-linked disease caused by a functional deficit of the α-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 α-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.

Keywords: Fabry disease; Mendelian disease; methylome.

Figure 1

Principal Component Analysis for the Fabry Disease Group and CTRL Group. PCA plots showing the cluster of Fabry and CTRL groups in orange and in green, respectively. The plots are shown considering the DNA methylation levels at CpG sites (a), genes (b) and promoters (c).

Figure 2

Hierarchical Cluster for the Fabry Disease group and CTRL Group. Heatmaps showing the methylation profiles at selected sites/regions with the highest variance across all samples.

Figure 3

Venn diagram showing the statistically significant differentially methylated CpG sites in the FD and CTRL groups.