{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:47:33Z","timestamp":1790801253494,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,10,28]],"date-time":"2023-10-28T00:00:00Z","timestamp":1698451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Fabry disease (FD) is a rare hereditary multisystem disease caused by variants of the GLA gene. Determination of GLA gene variants and identification of genotype\u2013phenotype correlations allow us to explain the features of FD associated with predominant damage of one or another system, both in the classical and atypical forms of FD, as well as in cases with late manifestation and involvement of one of the systems. Methods: The study included 293 Russian patients with pathogenic variants of the GLA gene, which were identified as a result of various selective screening programs. Screening was carried out for 48,428 high-risk patients using a two-step diagnostic algorithm, including the determination of the concentration of the biomarker lyso-Gb3 as a first-tier test. Screening of atypical FD among patients with HCM was carried out via high-throughput sequencing in another 2427 patients. Results: 102 (0.20%) cases of FD were identified among unrelated patients as a result of the study of 50,855 patients. Molecular genetic testing allowed us to reveal the spectrum and frequencies of 104 different pathogenic variants of the GLA gene in 293 examined patients from 133 families. The spectrum and frequencies of clinical manifestations in patients with FD, including 20 pediatric patients, were described. Correlations between the concentration of the lyso-Gb3 biomarker and the type of pathogenic variants of the GLA gene have been established. Variants identified in patients with early stroke were described, and the association of certain variants with the development of stroke was established. Conclusions: The results of a large-scale selective FD screening, as well as clinical and molecular genetic features, in a cohort of 293 Russian patients with FD are described.<\/jats:p>","DOI":"10.3390\/genes14112016","type":"journal-article","created":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T09:27:28Z","timestamp":1698658048000},"page":"2016","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genotype\u2013Phenotype Correlations in 293 Russian Patients with Causal Fabry Disease Variants"],"prefix":"10.3390","volume":"14","author":[{"given":"Kirill","family":"Savostyanov","sequence":"first","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Pushkov","sequence":"additional","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1423-0379","authenticated-orcid":false,"given":"Ilya","family":"Zhanin","sequence":"additional","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya","family":"Mazanova","sequence":"additional","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Pakhomov","sequence":"additional","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Trufanova","sequence":"additional","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Alexeeva","sequence":"additional","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2638-3727","authenticated-orcid":false,"given":"Dmitry","family":"Sladkov","sequence":"additional","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludmila","family":"Kuzenkova","sequence":"additional","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliy","family":"Asanov","sequence":"additional","affiliation":[{"name":"Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey","family":"Fisenko","sequence":"additional","affiliation":[{"name":"FSAI National Medical Research Center for Children\u2019s Health of the Russian Federation Ministry of Health, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1001\/archneur.63.3.453","article-title":"Later-Onset Fabry Disease: An adult variant presenting with the cramp-fasciculation syndrome","volume":"63","author":"Nance","year":"2006","journal-title":"Arch. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1001\/jama.281.3.249","article-title":"Prevalence of Lysosomal Storage Disorders","volume":"281","author":"Meikle","year":"1999","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1097\/01.ASN.0000124671.61963.1E","article-title":"Results of a Nationwide Screening for Anderson-Fabry Disease among Dialysis Patients","volume":"15","author":"Kotanko","year":"2004","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1161\/01.CIR.0000012626.81324.38","article-title":"Prevalence of Anderson-Fabry Disease in Male Patients with Late Onset Hypertrophic Cardiomyopathy","volume":"105","author":"Sachdev","year":"2002","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1016\/S0140-6736(05)67635-0","article-title":"Prevalence of Fabry disease in patients with cryptogenic stroke: A prospective study","volume":"366","author":"Rolfs","year":"2005","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/8904_2015_435","article-title":"The Frequencies of Different Inborn Errors of Metabolism in Adult Metabolic Centres: Report from the SSIEM Adult Metabolic Physicians Group","volume":"27","author":"Sirrs","year":"2016","journal-title":"JIMD Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lukas, J., Giese, A.K., Markoff, A., Grittner, U., Kolodny, E., Mascher, H., Lackner, K.J., Meyer, W., Wree, P., and Saviouk, V. (2013). Functional Characterisation of Alpha-Galactosidase A Mutations as a Basis for a New Classification System in Fabry Disease. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003632"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4859","DOI":"10.1073\/pnas.83.13.4859","article-title":"Human alpha-galactosidase A: Nucleotide sequence of a cDNA clone encoding the mature enzyme","volume":"83","author":"Bishop","year":"1986","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ymgme.2014.11.005","article-title":"Absence of \u03b1-galactosidase cross-correction in Fabry heterozygote cultured skin fibroblasts","volume":"114","author":"Fuller","year":"2015","journal-title":"Mol. Genet. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/cge.12613","article-title":"X-chromosome inactivation in female patients with Fabry disease","volume":"89","author":"Echevarria","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_11","first-page":"34","article-title":"Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life","volume":"9","author":"Wang","year":"2007","journal-title":"Anesthesia Analg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.pharmthera.2009.01.003","article-title":"Fabry disease","volume":"122","author":"Schiffmann","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"425","DOI":"10.7326\/0003-4819-146-6-200703200-00007","article-title":"Narrative review: Fabry disease","volume":"146","author":"Clarke","year":"2007","journal-title":"Ann. Intern. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0014-5793(02)02491-2","article-title":"Synthesis of novel internal standards for the quantitative determination of plasma ceramide trihexoside in Fabry disease by tandem mass spectrometry","volume":"515","author":"Mills","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1073\/pnas.0712309105","article-title":"Elevated globotriaosylsphingosine is a hallmark of Fabry disease","volume":"105","author":"Aerts","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/jmedgenet-2014-102872","article-title":"Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease","volume":"52","author":"Smid","year":"2015","journal-title":"J. Med. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1750-1172-4-21","article-title":"Fabry disease: Recent advances in pathology, diagnosis, treatment and monitoring","volume":"4","author":"Hoffmann","year":"2009","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1136\/jmg.2008.065904","article-title":"Natural course of Fabry disease: Changing pattern of causes of death in FOS\u2014Fabry Outcome Survey","volume":"46","author":"Mehta","year":"2009","journal-title":"J. Med. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1046\/j.1523-1755.2003.00160.x","article-title":"Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a \u201crenal variant\u201d phenotype1","volume":"64","author":"Nakao","year":"2003","journal-title":"Kidney Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1002\/humu.10212","article-title":"Human Gene Mutation Database (HGMD\u00ae): 2003 update","volume":"21","author":"Stenson","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/1750-1172-8-47","article-title":"Long term enzyme replacement therapy for Fabry disease: Effectiveness on kidney, heart and brain","volume":"8","author":"Rombach","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13023-015-0253-6","article-title":"Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: The European Fabry Working Group consensus document","volume":"10","author":"Biegstraaten","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1159\/000495886","article-title":"The Prevalence and Clinical Features of Fabry Disease in Hemodialysis Patients: Russian Nationwide Fabry Dialysis Screening Program","volume":"141","author":"Moiseev","year":"2019","journal-title":"Nephron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1186\/s13023-022-02319-4","article-title":"The prevalence of Fabry disease among 1009 unrelated patients with hypertrophic cardiomyopathy: A Russian nationwide screening program using NGS technology","volume":"17","author":"Savostyanov","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1007\/s00431-017-2992-y","article-title":"Fabry disease in children: A federal screening programme in Russia","volume":"176","author":"Baranov","year":"2017","journal-title":"Eur. J. Pediatr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1002\/humu.22910","article-title":"Functional and Clinical Consequences of Novel \u03b1-Galactosidase A Mutations in Fabry Disease","volume":"37","author":"Lukas","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lenders, M., Duning, T., Schelleckes, M., Schmitz, B., Stander, S., Rolfs, A., Brand, S.-M., and Brand, E. (2013). Multifocal White Matter Lesions Associated with the D313Y Mutation of the \u03b1-Galactosidase A Gene. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055565"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S101","DOI":"10.1016\/j.ymgme.2016.11.254","article-title":"14 novel mutations of GLA gene as a result of selective Fabry disease screening in Russian Federation","volume":"120","author":"Savostyanov","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1161\/CIRCGENETICS.109.862920","article-title":"High Incidence of the Cardiac Variant of Fabry Disease Revealed by Newborn Screening in the Taiwan Chinese Population","volume":"2","author":"Lin","year":"2009","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_30","first-page":"1","article-title":"A systematic review on screening for Fabry disease: Prevalence of individuals with genetic variants of unknown significance","volume":"51","author":"Smid","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/j.1651-2227.2006.tb02186.x","article-title":"Clinical manifestations of Fabry disease in children: Data from the Fabry Outcome Survey","volume":"95","author":"Ramaswami","year":"2006","journal-title":"Acta Paediatr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"341","DOI":"10.15690\/vsp.v14i3.1369","article-title":"Fabry Disease: Symptoms in Children and Teenagers","volume":"14","author":"Kuzenkova","year":"2015","journal-title":"Curr. Pediatr."},{"key":"ref_33","first-page":"37","article-title":"Paediatric Fabry disease","volume":"5","author":"Ellaway","year":"2016","journal-title":"Transl. Pediatr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.ymgmr.2014.09.002","article-title":"Fabry disease: Evidence for a regional founder effect of the GLA gene mutation 30delG in Brazilian patients","volume":"1","author":"Netto","year":"2014","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1093\/hmg\/2.7.1051","article-title":"Mutation analysis in patients with the typical form of Anderson\u2014Fabry disease","volume":"2","author":"Davies","year":"1993","journal-title":"Hum. Mol. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1093\/hmg\/3.6.1019","article-title":"A nonsense mutation (R220X) in the \u03b1-galactosidase A gene detected in a female carrier of Fabry disease","volume":"3","author":"Meaney","year":"1994","journal-title":"Hum. Mol. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1161\/CIRCEP.114.002569","article-title":"Pathology and Function of Conduction Tissue in Fabry Disease Cardiomyopathy","volume":"8","author":"Frustaci","year":"2015","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Citro, V., Pe\u00f1a-Garc\u00eda, J., Den-Haan, H., P\u00e9rez-S\u00e1nchez, H., Del Prete, R., Liguori, L., Cimmaruta, C., Lukas, J., Cubellis, M.V., and Andreotti, G. (2016). Identification of an Allosteric Binding Site on Human Lysosomal Alpha-Galactosidase Opens the Way to New Pharmacological Chaperones for Fabry Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165463"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1651-2227.2005.tb02119.x","article-title":"Genotype and phenotype in Fabry disease: Analysis of the Fabry Outcome Survey","volume":"94","author":"Schaefer","year":"2005","journal-title":"Acta Paediatr."},{"key":"ref_40","first-page":"227","article-title":"Fabry disease: Twenty-two novel mutations in the \u03b1-galactosidase A gene and genotype\/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes","volume":"48","author":"Tong","year":"2000","journal-title":"J. Investig. Med. Off. Publ. Am. Fed. Clin. Res."},{"key":"ref_41","first-page":"S130","article-title":"Lyso-GB3 is as a primary biomarker for Fabry disease screening among high-risk contingents","volume":"126","author":"Savostyanov","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lavalle, L., Thomas, A.S., Beaton, B., Ebrahim, H., Reed, M., Ramaswami, U., Elliott, P., Mehta, A.B., and Hughes, D.A. (2018). Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193550"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1161\/CIRCGENETICS.113.000249","article-title":"Gene Mutations Versus Clinically Relevant Phenotypes","volume":"7","author":"Niemann","year":"2014","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1007\/s10157-017-1525-3","article-title":"Plasma lyso-Gb3: A biomarker for monitoring fabry patients during enzyme replacement therapy","volume":"22","author":"Sakuraba","year":"2017","journal-title":"Clin. Exp. Nephrol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/11\/2016\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:13:18Z","timestamp":1760130798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/11\/2016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,28]]},"references-count":44,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["genes14112016"],"URL":"https:\/\/doi.org\/10.3390\/genes14112016","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,28]]}}}