{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T13:48:15Z","timestamp":1787060895863,"version":"build-2736575974"},"reference-count":29,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T00:00:00Z","timestamp":1580947200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband\u2010only sequencing, mainly due to the rapid identification of de novo disease\u2010causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X\u2010inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    ,\n                    <jats:italic>PHF6<\/jats:italic>\n                    , and\n                    <jats:italic>SOX10<\/jats:italic>\n                    ) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X\u2010inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.61511","type":"journal-article","created":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T09:15:31Z","timestamp":1580980531000},"page":"689-696","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Grandparental genotyping enhances exome variant interpretation"],"prefix":"10.1002","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8318-3599","authenticated-orcid":false,"given":"Hagit","family":"Daum","sequence":"first","affiliation":[{"name":"Department of Genetic and Metabolic Diseases Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagar","family":"Mor\u2010Shaked","sequence":"additional","affiliation":[{"name":"Department of Genetic and Metabolic Diseases Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0076-9568","authenticated-orcid":false,"given":"Asaf","family":"Ta\u2010Shma","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avraham","family":"Shaag","sequence":"additional","affiliation":[{"name":"Department of Genetic and Metabolic Diseases Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"},{"name":"Monique and Jacques Roboh Department of Genetic Research Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shira","family":"Silverstein","sequence":"additional","affiliation":[{"name":"Department of Genetic and Metabolic Diseases Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mordechai","family":"Shohat","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit \u2010 Sheba Cancer Research Center Sheba Medical Center  Tel\u2010Hashomer Israel"},{"name":"The Genetic Institute of Maccabi Health Medicinal Organization  Rehovot Israel"},{"name":"The Sackler School of Medicine Tel Aviv University  Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5041-7272","authenticated-orcid":false,"given":"Orly","family":"Elpeleg","sequence":"additional","affiliation":[{"name":"Department of Genetic and Metabolic Diseases Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"},{"name":"Monique and Jacques Roboh Department of Genetic Research Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vardiella","family":"Meiner","sequence":"additional","affiliation":[{"name":"Department of Genetic and Metabolic Diseases Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3595-7075","authenticated-orcid":false,"given":"Tamar","family":"Harel","sequence":"additional","affiliation":[{"name":"Department of Genetic and Metabolic Diseases Hadassah\u2010Hebrew University Medical Center  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,6]]},"reference":[{"issue":"6","key":"e_1_2_9_2_1","first-page":"1229","article-title":"Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen\u2010receptor gene correlates with X chromosome inactivation","volume":"51","author":"Allen R. 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