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Paternally inherited inactivating mutations lead to isolated <jats:styled-content style=\"fixed-case\">AHO<\/jats:styled-content> signs characterizing pseudo\u2010pseudohypoparathyroidism (<jats:styled-content style=\"fixed-case\">PPHP<\/jats:styled-content>). Mutations are distributed throughout the Gs<jats:italic>\u03b1<\/jats:italic> coding exons of <jats:italic><jats:styled-content style=\"fixed-case\">GNAS<\/jats:styled-content><\/jats:italic> and there is a lack of genotype\u2013phenotype correlation. In this study, we sequenced exon 1\u201313 of <jats:italic><jats:styled-content style=\"fixed-case\">GNAS<\/jats:styled-content><\/jats:italic> in a large cohort of <jats:styled-content style=\"fixed-case\">PHPI<\/jats:styled-content>a\u2010 and <jats:styled-content style=\"fixed-case\">PPHP<\/jats:styled-content> patients and identified 58 different mutations in 88 patients and 27 relatives. Thirty\u2010three mutations including 15 missense mutations were newly discovered. Furthermore, we found three hot spots: a known hotspot (p.D190MfsX14), a second at codon 166 (p.R166C), and a third at the exon 5 acceptor splice site (c.435\u00a0+\u00a01G&gt;A), found in 15, 5, and 4 unrelated patients, respectively. Comparing the clinical features to the molecular genetic data, a significantly higher occurrence of subcutaneous calcifications in patients harboring truncating versus missense mutations was demonstrated. Thus, in the largest cohort of <jats:styled-content style=\"fixed-case\">PHPI<\/jats:styled-content>a patients described to date, we extend the spectrum of known <jats:italic><jats:styled-content style=\"fixed-case\">GNAS<\/jats:styled-content><\/jats:italic> mutations and hot spots and demonstrate for the first time a correlation between the genetic defects and the expression of a clinical <jats:styled-content style=\"fixed-case\">AHO<\/jats:styled-content>\u2010feature.<\/jats:p>","DOI":"10.1002\/mgg3.117","type":"journal-article","created":{"date-parts":[[2014,12,5]],"date-time":"2014-12-05T02:33:35Z","timestamp":1417746815000},"page":"111-120","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["A positive genotype\u2013phenotype correlation in a large cohort of patients with Pseudohypoparathyroidism Type Ia and Pseudo\u2010pseudohypoparathyroidism and 33 newly identified mutations in the <i><scp>GNAS<\/scp><\/i> gene"],"prefix":"10.1002","volume":"3","author":[{"given":"Susanne","family":"Thiele","sequence":"first","affiliation":[{"name":"Division of Experimental Paediatric Endocrinology and Diabetes Department of Paediatrics University of L\u00fcbeck L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Werner","sequence":"additional","affiliation":[{"name":"Division of Experimental Paediatric Endocrinology and Diabetes Department of Paediatrics University of L\u00fcbeck L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Gr\u00f6tzinger","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry Christian\u2010Albrechts\u2010University of Kiel Kiel Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Brix","sequence":"additional","affiliation":[{"name":"Division of Experimental Paediatric Endocrinology and Diabetes Department of Paediatrics University of L\u00fcbeck L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Staedt","sequence":"additional","affiliation":[{"name":"Division of Experimental Paediatric Endocrinology and Diabetes Department of Paediatrics University of L\u00fcbeck L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Struve","sequence":"additional","affiliation":[{"name":"Division of Experimental Paediatric Endocrinology and Diabetes Department of Paediatrics University of L\u00fcbeck L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Reiz","sequence":"additional","affiliation":[{"name":"Institute for Integrative and Experimental Genomics University of L\u00fcbeck L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennane","family":"Farida","sequence":"additional","affiliation":[{"name":"Service de P\u00e9diatrie 2 unit\u00e9 H\u00f4pital universitaire Abderrahim Harouchi Chu ibn Rochd Casablanca Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Hiort","sequence":"additional","affiliation":[{"name":"Division of Experimental Paediatric Endocrinology and Diabetes Department of Paediatrics University of L\u00fcbeck L\u00fcbeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,12,4]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32346"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1515\/JPEM.2006.19.S2.647"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.86.10.4630"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1515\/JPEM.2006.19.S2.635"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1004(200009)16:3<183::AID-HUMU1>3.0.CO;2-L"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(02)00006-3"},{"key":"e_1_2_7_8_1","doi-asserted-by":"crossref","first-page":"29339","DOI":"10.1016\/S0021-9258(18)43878-1","article-title":"Requirement for intramolecular domain interaction in activation of a G protein subunit by aluminium fluoride and GDP but not by GPTgammaS","volume":"269","author":"Codina J.","year":"1994","journal-title":"J. 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