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

Background This study aimed to conduct high-risk and family screening for patients and to investigate the clinical phenotypes and genetic characteristics of patients with Fabry disease caused by the GLA IVS4 + 919G > A variant in China. Methods In a 31-month study, a pilot program was designed to assess high-risk screening for Fabry disease in 388 patients by measuring their dry blood spot (DBS) α-galactosidase A (α-GAL) activity, globotriaosylsphingosine (Lyso-GL-3), and GLA gene sequence from October 2021 to May 2024 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. Evaluation and family screening were carried out on the proband, and the clinical and genetic characteristics of Fabry disease caused by the GLA IVS4 + 919G > A variant were summarised. Results Before the pilot program was established, no patients were diagnosed with Fabry disease in the hospital. However, 31 months following the program’s implementation, 388 patients (233 males and 155 females) were recruited to meet the inclusion criteria for high-risk screening for Fabry disease, with a yield of diagnosis of 1.80% (7/388). A 9.8-year-old girl was screened because of a high-risk profile of severe pain in the extremities, and the other 6 males, who were diagnosed with Fabry disease, 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. Among the 25 patients, 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%). Conclusions 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.