Successful experience with high-risk and family screening for Fabry disease in Ninghai County, Zhejiang Province, Eastern China: genotype‒phenotype analysis of the GLA IVS4 + 919G > A variant

Fabry disease is a rare and non-specific disease that is difficult and expensive to diagnose. This study aimed to investigate the clinical phenotypes and genetic characteristics of patients with Fabry disease characterised by the GLA IVS4 + 919G > A variant in China through a proposed pilot program integrating high-risk and family screening. The 31-months-long pilot program assessed high-risk screening for Fabry disease in 388 patients by integrating previous screening methods that measure their dry blood spot (DBS) α-galactosidase A (α-GAL) activity, globotriaosylsphingosine (Lyso-GL-3), and GLA gene sequence at Ninghai First Hospital. Patients whose dried blood spot (DBS) α-GAL enzyme activity was low (< 2.40 µmol·L− 1·h− 1) or whose Lyso-GL-3 level was high (> 1.10 ng/mL) underwent GLA genetic testing for diagnostic confirmation. Gender-specific family screening and evaluation was carried out on the proband, and the clinical and genetic characteristics of Fabry disease characterised by the GLA IVS4 + 919G > A variant were summarised. A yield of Fabry disease diagnosis of 1.80% (7/388) was achieved, which is much larger than have been previously reported. These diagnoses include a 9.8-year-old girl, who was screened because of a high-risk profile of severe pain in the extremities, as well as 6 males, who were diagnosed with Fabry disease and who were screened because of unexplained left ventricular hypertrophy. All 7 diagnosed patients were carriers of the GLA IVS4 + 919G > A variant. Family screening of 7 probands revealed that 18 family members carried pathogenic variants, resulting in a diagnosis rate of 6.44% (25/388); 13 were clinically affected, 2 were asymptomatic carriers, and 3 declined further clinical assessment. The 25 patients had multiple affected organs and systems included the heart (60.00%), peripheral nerves (16.00%), kidney (36.00%), eye (20.00%), brain (12.00%), and gastrointestinal tract (24.00%). Screening high-risk populations and family screening is critical for early diagnosis and timely intervention in patients with Fabry disease. The GLA IVS4 + 919G > A variant is associated with diverse phenotypes of Fabry disease and is highly prevalent in late-onset cases in Ninghai County, Zhejiang Province, Eastern China.