Genetic Management Algorithm in High-Risk Fabry Disease Cases; Especially in Female Indexes with Mutations

Fabry Disease (FD, OMIM#301500) is a progressive, life-threatening, multisystemic, rare lysosomal storage disease. Today, approximately 1000 mutations are recorded in the Human Gene Mutation Database (www.hgmd.org) for GLA. Among the identified mutations, genetic variants of unknown significance (GVUS) and novel mutations cause problems in terms of diagnosis and treatment approach.

In our study, 510 high-risk patients were enrolled. 229 out of 510 were Male (45%) (Mean age was 40.8 ±15.0) and 281 of were Female (55%) (Mean age was 39, 7±15.5). The definite diagnosis of the FD was confirmed by GLA gene sequence analysis. GLA mutation was found in 15 cases (3.4%). Family members of the relevant indexes were included in the screening programs according to the X-linked inheritance pattern. And then we conducted family screening on 74 family members of 15 index cases. Of those 74 cases, 39 had mutations (53%). In males, α-GalA activity and in both gender Lyso-Gb3 levels were measured and multisystem evaluation was performed in all cases with the mutation.

We found six different familial mutation types; two of them pathogenic; p.D170N (1), p.P205S (13), one of them GVUS; p.Q330R (1), three of them likely benign; p.D313Y (12), p.S126G (25), c.-30G>A (2) mutations were detected.

The purpose of this retrospective study is to approach Fabry disease on a genetic basis and to improve its management and to draw attention to the importance of early diagnosis. We also aimed to evaluate the appropriate algorithms to determine whether the mutation is the FD-causing mutation or not.