{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T08:46:21Z","timestamp":1791708381599,"version":"4.3.4"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["1R01HG012657-01"],"award-info":[{"award-number":["1R01HG012657-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hypophosphatasia (HPP) is a heritable multisystem disorder caused by pathogenic variants in the tissue nonspecific alkaline phosphatase (ALP)-coding gene ALPL. The genotype\u2013phenotype correlation in heterozygous adults with HPP remains incompletely understood. In this genotype-based study, we aimed to measure the prevalence of pathogenic or likely-pathogenic ALPL variants and to test the hypothesis that HPP penetrance is low in adult carriers. A total of 37\u2009147 genomes from unselected individuals visiting a tertiary care, academic medical center were investigated. Variants classified as pathogenic or likely-pathogenic were observed with a prevalence of 0.3% (n\u2009=\u2009109) or 1\/341. Variant c.571G&amp;gt;A was most frequent (67.9%). A subset of 70 individuals had linked electronic health records (EHRs) and were termed ALPL+. All 70 ALPL+ individuals showed mild, mainly neurological, symptoms often reported in adults with HPP. However, low serum ALP, a hallmark of HPP, was found in only 65.7% (38\/70) of ALPL+ individuals, and 12.9% (9\/70) met the diagnostic criteria for HPP based on consensus guidelines, thus complete penetrance was low. Compared to controls lacking pathogenic or likely-pathogenic variants (ALPL\u2212), the ALPL+ individuals had a higher probability of progression for mobility issues (median age 73\u00a0yr ALPL+ vs 82\u00a0yr ALPL\u2212, p\u2009=\u2009.03), as well as a similar probability of progression for fatigue, arthritis, or dental problems. Unexpectedly, 3.4% (5\/148) of individuals in the ALPL- group met the diagnostic criteria for HPP, possibly due to unidentified variants or non-ALPL genetic factors. Overall, the data support our hypothesis and aids the management of carriers of pathogenic ALPL variants.<\/jats:p>","DOI":"10.1093\/jbmr\/zjaf176","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T13:11:15Z","timestamp":1763557875000},"page":"270-281","source":"Crossref","is-referenced-by-count":3,"title":["Hypophosphatasia: low penetrance of pathogenic and likely-pathogenic\n                    <i>ALPL<\/i>\n                    variants identified through an unselected biorepository"],"prefix":"10.1093","volume":"41","author":[{"given":"Kathryn M","family":"Dahir","sequence":"first","affiliation":[{"name":"Program for Metabolic Bone Disorders, Division of Endocrinology, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E","family":"Below","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Javid","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanchao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Bastarache","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center , Nashville, TN 37232 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"issue":"6","key":"2026101103511309900_ref1","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1001\/archpedi.1948.02030020840003","article-title":"Hypophosphatasia; a new developmental anomaly","volume":"75","author":"Rathbun","year":"1948","journal-title":"Am J Dis Child (1911)"},{"issue":"4","key":"2026101103511309900_ref2","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/nrendo.2016.14","article-title":"Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment","volume":"12","author":"Whyte","year":"2016","journal-title":"Nat Rev 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