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In 1981, Best and Hoekstra reported four patients with BWSp in a single family which suggested autosomal dominant inheritance, but standard clinical testing for BWSp was not available during this time. Meticulous phenotyping of this family has occurred over the past 40\u2009years of follow\u2010up with additional family members being identified and samples collected for genetic testing. Genetic testing revealed a pathogenic mutation in <jats:italic>CDKN1C<\/jats:italic>, consistent with the most common cause of familial BWSp. <jats:italic>CDKN1C<\/jats:italic> mutations account for just 5% of sporadic cases of BWSp. Here, we report the variable presentation of BWSp across the individuals affected by the <jats:italic>CDKN1C<\/jats:italic> mutation and other extended family members spanning multiple generations, all examined by the same physician. Additional phenotypes thought to be atypical in patients with BWSp were reported which included cardiac abnormalities. The incidence of tumors was documented in extended family members and included rhabdomyosarcoma, astrocytoma, and thyroid carcinoma, which have previously been reported in patients with BWSp. These observations suggest that in addition to the inheritance of the <jats:italic>CDKN1C<\/jats:italic> variant, there are modifying factors in this family driving the phenotypic spectrum observed. Alternative theories are suggested to explain the etiology of clinical variability including diffused mosaicism, anticipation, and the presence of additional variants tracking in the family. This study highlights the necessity of long\u2010term follow\u2010up in patients with BWSp and consideration of individual familial characteristics in the context of phenotype and\/or (epi)genotype associations.<\/jats:p>","DOI":"10.1002\/ajmg.a.63026","type":"journal-article","created":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:54:46Z","timestamp":1667408086000},"page":"348-356","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Familial <scp>Beckwith\u2010Wiedemann<\/scp> syndrome in a multigenerational family: Forty years of careful phenotyping"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7813-0724","authenticated-orcid":false,"given":"Lyle G.","family":"Best","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Medicine and Health Sciences University of North Dakota  Grand Forks North Dakota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8902-8453","authenticated-orcid":false,"given":"Kelly A.","family":"Duffy","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6661-3924","authenticated-orcid":false,"given":"Andrew M.","family":"George","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arupa","family":"Ganguly","sequence":"additional","affiliation":[{"name":"Department of Genetics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1500-9713","authenticated-orcid":false,"given":"Jennifer M.","family":"Kalish","sequence":"additional","affiliation":[{"name":"Division of Human Genetics Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"},{"name":"Department of Genetics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Pediatrics, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Center for Childhood Cancer Research Children's Hospital of Philadelphia  Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,11,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1004(200006)15:6<497::AID-HUMU2>3.0.CO;2-F"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2019-106498"},{"volume-title":"Extreme cytomegaly of the adrenal fetal cortex, omphalocele, hyperplasia of kidenys and pancreas, and Leydig\u2010cell hyperplasia: Another syndrome","year":"1963","author":"Beckwith J. 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