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Detection of novel Fabry disease-associated pathogenic variants in Japanese patients by newborn and high-risk screening.

ABSTRACT: BACKGROUND:In Japan, newborn and high-risk screening for Fabry disease (FD), an inherited X-linked disorder caused by GLA mutations, using dried blood spots was initiated in 2006. In newborn screening, 599,711 newborns were screened by December 2018, and 57 newborns from 54 families with 26 FD-associated variants were detected. In high-risk screening, 18,235 individuals who had symptoms and/or a family history of FD were screened by March 2019, and 236 individuals from 143 families with 101 FD-associated variants were detected. Totally 3, 116 variants were detected; 41 of these were not registered in Fabry-database.org or ClinVar and 33 were definitely novel. Herein, we report the clinical outcomes and discuss the pathogenicity of the 41 variants. METHODS:We traced nine newborns and 46 individuals with the 33 novel variants, and nine newborns and 10 individuals with eight other variants not registered in the FD database, and analyzed the information on symptoms, treatments, and outcomes. RESULTS:Thirty-eight of the 46 individuals with the 33 novel variants showed symptoms and received enzyme-replacement therapy and/or chaperone treatment. CONCLUSION:Delayed diagnosis should be avoided in patients with FD. Our results will help clinicians diagnose FD and determine the appropriate treatment for patients with these variants.

SUBMITTER: Sawada T

PROVIDER: S-EPMC7667298 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Detection of novel Fabry disease-associated pathogenic variants in Japanese patients by newborn and high-risk screening.

Sawada Takaaki T Kido Jun J Sugawara Keishin K Matsumoto Shirou S Takada Fumio F Tsuboi Kazuya K Ohtake Akira A Endo Fumio F Nakamura Kimitoshi K

Molecular genetics & genomic medicine 20201005 11

<h4>Background</h4>In Japan, newborn and high-risk screening for Fabry disease (FD), an inherited X-linked disorder caused by GLA mutations, using dried blood spots was initiated in 2006. In newborn screening, 599,711 newborns were screened by December 2018, and 57 newborns from 54 families with 26 FD-associated variants were detected. In high-risk screening, 18,235 individuals who had symptoms and/or a family history of FD were screened by March 2019, and 236 individuals from 143 families with ...[more]

PMID: 33016649

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Project description:The classic phenotype of Fabry disease, X-linked alpha -galactosidase A (alpha -Gal A) deficiency, has an estimated incidence of approximately 1 in 50,000 males. The recent recognition of later-onset variants suggested that this treatable lysosomal disease is more frequent. To determine the disease incidence, we undertook newborn screening by assaying the alpha-Gal A activity in blood spots from 37,104 consecutive Italian male neonates. Enzyme-deficient infants were retested, and "doubly screened-positive" infants and their relatives were diagnostically confirmed by enzyme and mutation analyses. Twelve (0.03%) neonates had deficient alpha-Gal A activities and specific mutations, including four novel missense mutations (M51I, E66G, A73V, and R118C), three missense mutations (F113L, A143T, and N215S) identified previously in later-onset patients, and one splicing defect (IVS5(+1G-->T)) reported in a patient with the classic phenotype. Molecular modeling and in vitro overexpression of the missense mutations demonstrated structures and residual activities, which were rescued/enhanced by an alpha-Gal A-specific pharmacologic chaperone, consistent with mutations that cause the later-onset phenotype. Family studies revealed undiagnosed Fabry disease in affected individuals. In this population, the incidence of alpha-Gal A deficiency was 1 in approximately 3,100, with an 11 : 1 ratio of patients with the later-onset : classic phenotypes. If only known disease-causing mutations were included, the incidence would be 1 in approximately 4,600, with a 7 : 1 ratio of patients with the later-onset : classic phenotypes. These results suggest that the later-onset phenotype of Fabry disease is underdiagnosed among males with cardiac, cerebrovascular, and/or renal disease. Recognition of these patients would permit family screening and earlier therapeutic intervention. However, the higher incidence of the later-onset phenotype in patients raises ethical issues related to when screening should be performed--in the neonatal period or at early maturity, perhaps in conjunction with screening for other treatable adult-onset disorders.

Dataset Information

Detection of novel Fabry disease-associated pathogenic variants in Japanese patients by newborn and high-risk screening.

Publications

Detection of novel Fabry disease-associated pathogenic variants in Japanese patients by newborn and high-risk screening.

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