{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T23:57:51Z","timestamp":1778111871700,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pgen.1008802","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:00:00Z","timestamp":1607904000000}}],"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T00:00:00Z","timestamp":1606089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R00HL130523"],"award-info":[{"award-number":["R00HL130523"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Stanford CVI-MCHRI Seed Grant"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population.<\/jats:p>\n                  <jats:p>\n                    Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (\n                    <jats:italic>JAG1<\/jats:italic>\n                    ,\n                    <jats:italic>NOTCH2 FBN1<\/jats:italic>\n                    ,\n                    <jats:italic>PTPN1 and RAS-opathy genes<\/jats:italic>\n                    ,\n                    <jats:italic>and genes in the 22q11<\/jats:italic>\n                    .\n                    <jats:italic>2 locus<\/jats:italic>\n                    ) and performed a gene burden test.\n                  <\/jats:p>\n                  <jats:p>\n                    Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in\n                    <jats:italic>JAG1<\/jats:italic>\n                    ,\n                    <jats:italic>FBN1<\/jats:italic>\n                    ,\n                    <jats:italic>PTPN11<\/jats:italic>\n                    and\n                    <jats:italic>SOS2<\/jats:italic>\n                    with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in\n                    <jats:italic>PTPN11<\/jats:italic>\n                    was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in\n                    <jats:italic>FBN1<\/jats:italic>\n                    was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome.\n                  <\/jats:p>\n                  <jats:p>Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.<\/jats:p>","DOI":"10.1371\/journal.pgen.1008802","type":"journal-article","created":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T14:41:50Z","timestamp":1606142510000},"page":"e1008802","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9559-4339","authenticated-orcid":true,"given":"Catherine","family":"Tcheandjieu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9069-6475","authenticated-orcid":true,"given":"Matthew","family":"Aguirre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Gustafsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5106-9751","authenticated-orcid":true,"given":"Priyanka","family":"Saha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9999-273X","authenticated-orcid":true,"given":"Praneetha","family":"Potiny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9114-8737","authenticated-orcid":true,"given":"Melissa","family":"Haendel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2256-6972","authenticated-orcid":true,"given":"Erik","family":"Ingelsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1457-9925","authenticated-orcid":true,"given":"Manuel A.","family":"Rivas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2505-617X","authenticated-orcid":true,"given":"James R.","family":"Priest","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2020,11,23]]},"reference":[{"key":"pgen.1008802.ref001","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1056\/NEJMsa1507092","article-title":"Genetic Misdiagnoses and the Potential for Health Disparities","volume":"375","author":"AK Manrai","year":"2016","journal-title":"N Engl J Med"},{"key":"pgen.1008802.ref002","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/gim.2017.26","article-title":"Using high-resolution variant frequencies to empower clinical genome interpretation","volume":"19","author":"N Whiffin","year":"2017","journal-title":"Genet 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Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project","volume":"13","author":"LJ Carithers","year":"2015","journal-title":"Biopreserv Biobank"},{"key":"pgen.1008802.ref016","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.ymgme.2016.06.009","article-title":"Expression of FBN1 during adipogenesis: Relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions","volume":"119","author":"MR Davis","year":"2016","journal-title":"Mol Genet Metab"},{"key":"pgen.1008802.ref017","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1097\/HJH.0000000000001512","article-title":"Aortic dilatation in Marfan syndrome","volume":"36","author":"P Salvi","year":"2018","journal-title":"J Hypertens"},{"key":"pgen.1008802.ref018","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1038\/s41431-018-0164-9","article-title":"Association of modifiers and other genetic factors explain Marfan syndrome clinical 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Wang J, editor","volume":"11","author":"TG Richardson","year":"2016"}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1008802","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:00:00Z","timestamp":1607904000000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1008802","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T13:50:53Z","timestamp":1607953853000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1008802"}},"subtitle":[],"editor":[{"given":"Santhosh","family":"Girirajan","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2020,11,23]]},"references-count":40,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1008802","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/19010736","asserted-by":"object"}]},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,23]]}}}