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The primary objective was to explore novel <jats:italic>ALPL<\/jats:italic> variants by whole genome sequencing (WGS) in patients with HPP who previously tested negative by standard methods for <jats:italic>ALPL<\/jats:italic> variants. The secondary objective was to search for genes beyond <jats:italic>ALPL<\/jats:italic> that may reduce ALP activity or contribute to HPP symptoms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and results<\/jats:title>\n            <jats:p>WGS was performed in 16 patients clinically diagnosed with HPP who had ALP activity below the normal range and tested negative for <jats:italic>ALPL<\/jats:italic> variants. Genetic variants in <jats:italic>ALPL<\/jats:italic> and genes possibly associated with low ALP activity or phenotypic overlap with HPP were assessed. All 16 patients had ALP activity below the normal range. WGS did not identify any novel disease-causing <jats:italic>ALPL<\/jats:italic> variants. Positive findings for other gene variants were identified in 4 patients: 1 patient presented with variants in <jats:italic>COL1A1<\/jats:italic>, <jats:italic>NLRP12<\/jats:italic>, and <jats:italic>SCN9A<\/jats:italic>, coding for collagen, type, I alpha-1 chain, nod-like receptor pyrin domain containing 12, and sodium voltage-gated channel alpha subunit 9, respectively; 1 presented with a heterozygous, likely pathogenic variant in <jats:italic>P3H1<\/jats:italic> coding for prolyl 3 hydroxylase 1; 1 presented with a heterozygous pathogenic variant in <jats:italic>SGCE<\/jats:italic>, coding for sarcoglycan epsilon; and 1 presented with a heterozygous variant of uncertain significance in <jats:italic>VDR<\/jats:italic>, encoding vitamin D receptor.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Genomic analysis did not identify novel <jats:italic>ALPL<\/jats:italic> variants or a pattern of disease-causing variants in genes other than <jats:italic>ALPL<\/jats:italic> to explain the HPP phenotype in these patients.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Registration<\/jats:title>\n            <jats:p>Clinicaltrials.gov identifier: NCT04925804.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s11033-024-09906-7","type":"journal-article","created":{"date-parts":[[2024,9,14]],"date-time":"2024-09-14T08:02:47Z","timestamp":1726300967000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Whole genome sequencing in adults with clinical hallmarks of hypophosphatasia negative for ALPL variants"],"prefix":"10.1007","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1154-3388","authenticated-orcid":false,"given":"Lothar","family":"Seefried","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8017-0170","authenticated-orcid":false,"given":"Anna","family":"Petryk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0104-1563","authenticated-orcid":false,"given":"Guillermo","family":"del Angel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Reder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9414-4555","authenticated-orcid":false,"given":"Peter","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,14]]},"reference":[{"key":"9906_CR1","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1007\/s00198-023-06844-1","volume":"35","author":"A Khan","year":"2024","unstructured":"Khan A, Brandi ML, Rush ET, Ali DS, Al-Alwani H, Almonaei K, Alsarraf F, Bacrot S, Dahir K, Dandurand K, Deal C, Ferrari SL, Giusti F, Guyatt G, Hatcher E, Ing SW, Javaid MK, Khan S, Kocijan R, Linglart A, M\u2019Hiri I, Marini F, Nunes ME, Rockman-Greenberg C, Roux C, Seefried L, Simmons JH, Starling SR, Ward LM, Yao L, Brignardello-Petersen R, Lewiecki EM (2024) Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. 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The study was conducted in compliance with guidelines for Good Clinical Practice and the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from patients prior to initiation of study procedures.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Lothar Seefried is a consultant for and has received research funding and honoraria from Alexion, AstraZeneca Rare Disease. Anna Petryk and Guillermo del Angel are employees of and may own stock\/options in Alexion, AstraZeneca Rare Disease. Felix Reder is an employee of and may own stock\/options in Centogene GmbH, which received funding from Alexion, AstraZeneca Rare Disease for the conduct of the study. Peter Bauer is a board member of and may own stock\/options in Centogene GmbH.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"984"}}