{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:23:20Z","timestamp":1786116200127,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Hypophosphatasia (HPP) is a rare hereditary metabolic disorder caused by nucleotide variants (NVs) in the ALPL gene, leading to a deficiency of tissue-nonspecific alkaline phosphatase (TNSALP). HPP has a variable clinical presentation (such as impaired mineralization of bones and teeth, respiratory dysfunctions, muscle weakness, muscle and bone pain, growth deficiency, nephrocalcinosis, seizures, encephalopathy, intracranial hypertension, and intellectual disability) overlapping with other disorders which often delays a correct diagnosis. In this study, we present the results of a two-center (Moscow and Saint Petersburg) selective screening program conducted in the period 2022\u20132026 in Russia, based on next-generation sequencing (NGS) of 4912 patients with suspected HPP. Each center used its own NGS gene panel. In Moscow, causal nucleotide variants in ALPL were found in 9.45% of patients, and variants in other genes from the panel were identified in 9.77% of patients. The selection criteria for the screening evolved during the study, resulting in a higher diagnostic yield. In Saint Petersburg, causal variants in ALPL were found in 3.5% of patients. The most frequent ALPL variant was c.571G&gt;A (28%), which is consistent with its founder effect in Northern Europe. In the differential diagnosis gene panel, pathogenic or likely pathogenic variants were most commonly found in the COL1A2, COL1A1, and CASR genes, highlighting the phenotypic overlap of HPP with osteogenesis imperfecta and related disorders, and underscoring the value of targeted NGS for resolving diagnostic uncertainty in HPP. Overall, this study provides the most comprehensive data on the genetics of HPP in the Russian population to date.<\/jats:p>","DOI":"10.3390\/ijms27157008","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T12:32:43Z","timestamp":1785846763000},"page":"7008","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypophosphatasia: Results of a Country-Wide Selective Screening Program Using NGS Technology as a First-Tier Test"],"prefix":"10.3390","volume":"27","author":[{"given":"Aleksander A.","family":"Pushkov","sequence":"first","affiliation":[{"name":"National Medical Research Center of Children\u2019s Health, Ministry of Health of the Russian Federation, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1423-0379","authenticated-orcid":false,"given":"Ilya S.","family":"Zhanin","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Children\u2019s Health, Ministry of Health of the Russian Federation, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9354-6824","authenticated-orcid":false,"given":"Daria A.","family":"Chudakova","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Children\u2019s Health, Ministry of Health of the Russian Federation, 119991 Moscow, Russia"},{"name":"Center for Precision Genetic Technologies for Medicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1193-0519","authenticated-orcid":false,"given":"Anastasia A.","family":"Rusakova","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Children\u2019s Health, Ministry of Health of the Russian Federation, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry S.","family":"Demianov","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Children\u2019s Health, Ministry of Health of the Russian Federation, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander V.","family":"Pakhomov","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Children\u2019s Health, Ministry of Health of the Russian Federation, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeriya B.","family":"Koroleva","sequence":"additional","affiliation":[{"name":"Center for Genomic Technologies \u00abCerbalab\u00bb, 199106 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliya S.","family":"Koshevaya","sequence":"additional","affiliation":[{"name":"Center for Genomic Technologies \u00abCerbalab\u00bb, 199106 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia S.","family":"Burlachenko","sequence":"additional","affiliation":[{"name":"Center for Genomic Technologies \u00abCerbalab\u00bb, 199106 Saint-Petersburg, Russia"},{"name":"Federal State Budgetary Institution \u00abFederal Scientific and Clinical Center for Infectious Diseases of the Federal Medical and Biological Agency\u00bb, 197022 Saint-Petersburg, Russia"},{"name":"State Budgetary Healthcare Institution of the City of Moscow \u00abMoscow Scientific and Practical Center of Laboratory Research of the Moscow Healthcare Department\u00bb, 115580 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yury A.","family":"Eismont","sequence":"additional","affiliation":[{"name":"Center for Genomic Technologies \u00abCerbalab\u00bb, 199106 Saint-Petersburg, Russia"},{"name":"Federal State Budgetary Institution \u00abFederal Scientific and Clinical Center for Infectious Diseases of the Federal Medical and Biological Agency\u00bb, 197022 Saint-Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0091-2224","authenticated-orcid":false,"given":"Oleg S.","family":"Glotov","sequence":"additional","affiliation":[{"name":"Center for Genomic Technologies \u00abCerbalab\u00bb, 199106 Saint-Petersburg, Russia"},{"name":"Federal State Budgetary Institution \u00abFederal Scientific and Clinical Center for Infectious Diseases of the Federal Medical and Biological Agency\u00bb, 197022 Saint-Petersburg, Russia"},{"name":"State Budgetary Healthcare Institution of the City of Moscow \u00abMoscow Scientific and Practical Center of Laboratory Research of the Moscow Healthcare Department\u00bb, 115580 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey P.","family":"Fisenko","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Children\u2019s Health, Ministry of Health of the Russian Federation, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4885-4171","authenticated-orcid":false,"given":"Kirill V.","family":"Savostyanov","sequence":"additional","affiliation":[{"name":"National Medical Research Center of Children\u2019s Health, Ministry of Health of the Russian Federation, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13","DOI":"10.33176\/AACB-19-00031","article-title":"Hypophosphatasia: Biological and Clinical Aspects, Avenues for Therapy","volume":"41","author":"Salles","year":"2020","journal-title":"Clin. 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