Systematic cascade screening in the Danish Fabry Disease Centre: 20 years of a national single-centre experience

The lysosomal storage disorder Fabry disease is caused by deficient or absent activity of the GLA gene enzyme alpha-galactosidase A. In the present study we present the molecular and biochemical data of the Danish Fabry cohort and report 20 years' (2001-2020) experience in cascade genetic screening at the Danish National Fabry Disease Center. The Danish Fabry cohort consisted of 26 families, 18 index patients (9 males and 9 females, no available data for 8 index-patients) and 97 family members with a pathogenic GLA variant identified by cascade genetic testing (30 males and 67 females). Fourteen patients (5 males and 9 females; mean age of death 47.0 and 64.8 years respectively) died during follow-up. The completeness of the Fabry patient identification in the country has resulted in a cohort of balanced genotypes according to gender (twice number of females compared to males), indicating that the cohort was not biased by referral, and further resulted in earlier diagnosis of the disease by a lower age at diagnosis in family members compared to index-patients (mean age at diagnosis: index-patients 42.2 vs. family members 26.0 years). Six previously unreported disease-causing variants in the GLA gene were discovered. The nationwide screening and registration of Fabry disease families provide a unique possibility to establish a complete cohort of Fabry patients and to advance current knowledge of this inherited rare lysosomal storage disorder.

Automated summary

The present study provides molecular and biochemical data of the Danish Fabry cohort and reports the experience of cascade genetic screening at the Danish National Fabry Disease Center over a period of 20 years. The study findings demonstrate the identification of pathogenic GLA variants in 96 family members through cascade genetic testing and the discovery of six previously unreported disease-causing variants in the GLA gene.