"On-Site Family Screening" in Fabry Disease: An Innovative Model for Identifying At-Risk Relatives

Background: Fabry disease remains underdiagnosed despite the availability of effective therapies. Although cascade screening is recommended for identifying at-risk relatives, its implementation is often limited by practical and accessibility barriers, resulting in missed or delayed diagnoses. On-Site Family Screening (OSFS) was developed to overcome barriers to conventional cascade screening and improve the identification of previously undiagnosed relatives with Fabry disease. Therefore, this study aimed to implement and evaluate the diagnostic impact of an On-Site Family Screening approach for identifying previously undiagnosed individuals with Fabry disease within an extended family. Methods: Following the identification of the index case, at-risk relatives were systematically evaluated through on-site visits at their place of residence. Pedigree analysis was used to identify individuals at risk. Written informed consent was obtained from all participants prior to genetic testing, and molecular analysis of the GLA gene was performed. Of all at-risk relatives identified through pedigree analysis, ten at-risk individuals declined participation for personal reasons and were excluded from the analysis. Results: A total of 56 individuals were screened. Seventeen previously undiagnosed individuals with Fabry disease were identified, including 10 males and 7 females, corresponding to a diagnostic yield of 30.4%. The mean age at diagnosis was 22.94 years, with an age range from 45 days to 55 years. Notably, two affected male infants aged 45 and 60 days were detected before the development of overt disease manifestations. All affected individuals carried the same pathogenic GLA variant, consistent with familial X-linked inheritance. Conclusions: In this single extended pedigree, on-site family screening was feasible and facilitated the identification of previously undiagnosed relatives, including individuals at very young and presymptomatic stages. This approach may provide a practical strategy for reaching at-risk individuals who might otherwise remain unscreened. However, as no conventional cascade-screening comparator was included, the incremental benefit of the on-site component cannot be established and requires evaluation in comparative studies.