{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T07:49:56Z","timestamp":1753861796096,"version":"3.41.2"},"reference-count":32,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T00:00:00Z","timestamp":1743552000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100023557","name":"Fondation Mirella et Lino Saputo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100023557","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>\n<jats:italic>NPR3<\/jats:italic>\u2010related tall stature is characterized by tall stature, elongated big toes, and additional epiphyses in hand and foot bones. The condition is caused by biallelic loss\u2010of\u2010function variants affecting natriuretic peptide receptor 3 (NPR3). Five individuals from four different families have been reported. Here we describe three siblings with <jats:italic>NPR3<\/jats:italic>\u2010related tall stature who were tall (height <jats:italic>z<\/jats:italic>\u2010scores between +2.9 and\u2009+\u20094.9) and had markedly elongated proximal and middle phalanges. Two siblings had additional epiphyses in phalangeal and metacarpal bones. All three siblings developed scoliosis, requiring spinal fusion surgery in one individual. Lumbar spine bone mineral density appeared low considering the tall stature. Sequencing of a skeletal disorders gene panel in one sibling revealed a homozygous missense variant in <jats:italic>NPR3<\/jats:italic> (NM_001204375.2; c.382C&gt;T; p.Pro128Ser). Sanger sequencing demonstrated the same homozygous variant in the other siblings. In\u00a0vitro functional testing in MC3T3\u2010E1 preosteoblastic cells showed that NPR3 carrying the p.Pro128Ser variant was expressed but was retained in the endoplasmic reticulum, leading to loss of NPR3 function. In conclusion, the novel homozygous p.Pro128Ser loss\u2010of\u2010function variant in <jats:italic>NPR3<\/jats:italic> led to the typical features of <jats:italic>NPR3<\/jats:italic>\u2010related tall stature and, in addition, was associated with scoliosis. These observations expand the genotypic and phenotypic spectrum of <jats:italic>NPR3<\/jats:italic>\u2010related tall stature.<\/jats:p>","DOI":"10.1002\/ajmg.a.64080","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T07:05:07Z","timestamp":1743750307000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tall Stature and Scoliosis Associated With a Novel Homozygous Loss\u2010of\u2010Function Missense Variant in <i>NPR3<\/i>"],"prefix":"10.1002","volume":"197","author":[{"given":"Pierre","family":"Moffatt","sequence":"first","affiliation":[{"name":"Shriners Hospital for Children \u2010 Canada  Montreal Quebec Canada"},{"name":"Faculty of Dental Medicine and Oral Health Sciences McGill University  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chantal","family":"Janelle","sequence":"additional","affiliation":[{"name":"Shriners Hospital for Children \u2010 Canada  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valancy","family":"Miranda","sequence":"additional","affiliation":[{"name":"Shriners Hospital for Children \u2010 Canada  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghalib","family":"Bardai","sequence":"additional","affiliation":[{"name":"Shriners Hospital for Children \u2010 Canada  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6261-0360","authenticated-orcid":false,"given":"Frank","family":"Rauch","sequence":"additional","affiliation":[{"name":"Shriners Hospital for Children \u2010 Canada  Montreal Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01132-x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2023.11.009"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.06.007"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-023-02867-x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1534\/g3.113.007310"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24119642"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0167916"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-2358"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"issue":"18","key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"10278","DOI":"10.1073\/pnas.96.18.10278","article-title":"Three New Allelic Mouse Mutations That Cause Skeletal Overgrowth Involve the Natriuretic Peptide Receptor C Gene (Npr3)","volume":"96","author":"Jaubert J.","year":"1999","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61923"},{"issue":"4","key":"e_1_2_9_14_1","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvac019","article-title":"Broadening the Spectrum of Loss\u2010Of\u2010Function Variants in NPR\u2010C\u2010Related Extreme Tall Stature","volume":"6","author":"Lauffer P.","year":"2022","journal-title":"Journal of the Endocrine Society"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa190"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23042148"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.13.7403"},{"issue":"1","key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1002\/ajmg.a.36218","article-title":"Overgrowth Syndrome Associated With a Gain\u2010of\u2010Function Mutation of the Natriuretic Peptide Receptor 2 (NPR2) Gene","volume":"164","author":"Miura K.","year":"2014","journal-title":"American Journal of Medical Genetics. Part A"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0042180"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708596200"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.109.1.45"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.10.013"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.112.964742"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2116470119"},{"issue":"2","key":"e_1_2_9_25_1","first-page":"119","article-title":"Peripheral Quantitative Computed Tomography of the Distal Radius in Young Subjects \u2010 New Reference Data and Interpretation of Results","volume":"5","author":"Rauch F.","year":"2005","journal-title":"Journal of Musculoskeletal & Neuronal Interactions"},{"issue":"3","key":"e_1_2_9_26_1","first-page":"217","article-title":"Peripheral Quantitative Computed Tomography of the Proximal Radius in Young Subjects\u2014New Reference Data and Interpretation of Results","volume":"8","author":"Rauch F.","year":"2008","journal-title":"Journal of Musculoskeletal & Neuronal Interactions"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23115916"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.06.020"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2022.12.005"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109380"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.160416"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05275-y"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.64080","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T06:48:40Z","timestamp":1751525320000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.64080"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,2]]},"references-count":32,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1002\/ajmg.a.64080"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.64080","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"type":"print","value":"1552-4825"},{"type":"electronic","value":"1552-4833"}],"subject":[],"published":{"date-parts":[[2025,4,2]]},"assertion":[{"value":"2024-12-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e64080"}}