{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:51:03Z","timestamp":1790779863960,"version":"4.1.0"},"reference-count":21,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T00:00:00Z","timestamp":1572998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["HG200388"],"award-info":[{"award-number":["HG200388"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt C"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Phenotype\u2010based diagnostic criteria were developed for Proteus syndrome in 1999 and updated in 2006. Subsequently, the causative mosaic gene alteration was discovered, the c.49G&gt;A p.E17K variant in <jats:italic>AKT1<\/jats:italic>. As well, a number of overlapping overgrowth disorders attributable to mosaic <jats:italic>PIK3CA<\/jats:italic> variants have now been characterized, leading to the designation of <jats:italic>PIK3CA<\/jats:italic>\u2010related overgrowth spectrum (PROS). Finally, ongoing work to better characterize Proteus syndrome has led to identification of additional features of that disorder that could be useful in diagnostic criteria. We have taken the opportunity of these discoveries to re\u2010evaluate the Proteus syndrome diagnostic criteria. Here we propose a new set of diagnostic criteria that establishes a weighted, point\u2010based system for the phenotypic attributes and then integrates that with the potential molecular test results to result in one of two designations: <jats:italic>AKT1<\/jats:italic>\u2010related Proteus syndrome or <jats:italic>AKT1<\/jats:italic>\u2010related overgrowth spectrum. A patient whose only manifestation is an <jats:italic>AKT1<\/jats:italic> c.49G&gt;A\u2010positive tumor would receive neither of these designations. Here we review the rational basis of diagnostic criteria and argue that a unitary diagnostic entity is a distinct gene\u2010phenotype dyad and that this should be the model for all mendelian disorders. The gene\u2010alone or phenotype\u2010alone approach is inadequate to rigorously delineate a unitary diagnostic entity.<\/jats:p>","DOI":"10.1002\/ajmg.c.31744","type":"journal-article","created":{"date-parts":[[2019,11,6]],"date-time":"2019-11-06T12:12:20Z","timestamp":1573042340000},"page":"565-570","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["A dyadic genotype\u2013phenotype approach to diagnostic criteria for Proteus syndrome"],"prefix":"10.1002","volume":"181","author":[{"given":"Julie C.","family":"Sapp","sequence":"first","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Buser","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"Burton\u2010Akright","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8250-164X","authenticated-orcid":false,"given":"Kim M.","family":"Keppler\u2010Noreuil","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health  Bethesda Maryland"},{"name":"Division of Genetics Children's National Medical Center  Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0197-3811","authenticated-orcid":false,"given":"Leslie G.","family":"Biesecker","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute National Institutes of Health  Bethesda Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,11,6]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471695998.mgs037"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201638"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19990611)84:5<389::AID-AJMG1>3.0.CO;2-O"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19981002)79:4<311::AID-AJMG14>3.0.CO;2-U"},{"key":"e_1_2_7_6_1","volume-title":"GeneReviews","author":"Biesecker L. 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