{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:23:30Z","timestamp":1791271410802,"version":"4.1.0"},"reference-count":43,"publisher":"National Academy of Sciences","issue":"1","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2000,1,4]]},"abstract":"<jats:p>\n                    Reduced penetrance in genetic disorders may be either dependent or independent of the genetic background of gene carriers. Hirschsprung disease (HSCR) demonstrates a complex pattern of inheritance with \u224850% of familial cases being heterozygous for mutations in the receptor tyrosine kinase\n                    <jats:italic>RET<\/jats:italic>\n                    . Even when identified, the penetrance of\n                    <jats:italic>RET<\/jats:italic>\n                    mutations is only 50\u201370%, gender-dependent, and varies with the extent of aganglionosis. We searched for additional susceptibility genes which, in conjunction with\n                    <jats:italic>RET<\/jats:italic>\n                    , lead to phenotypic expression by studying 12 multiplex HSCR families. Haplotype analysis and extensive mutation screening demonstrated three types of families: six families harboring severe\n                    <jats:italic>RET<\/jats:italic>\n                    mutations (group I); and the six remaining families, five of which are\n                    <jats:italic>RET<\/jats:italic>\n                    -linked families with no sequence alterations and one\n                    <jats:italic>RET<\/jats:italic>\n                    -unlinked family (group II). Although the presence of\n                    <jats:italic>RET<\/jats:italic>\n                    mutations in group I families is sufficient to explain HSCR inheritance, a genome scan reveals a new susceptibility locus on 9q31 exclusively in group II families. As such, the gene at 9q31 is a modifier of HSCR penetrance. These observations imply that identification of new susceptibility factors in a complex disease may depend on classification of families by mutational type at known susceptibility genes.\n                  <\/jats:p>","DOI":"10.1073\/pnas.97.1.268","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:38:21Z","timestamp":1027679901000},"page":"268-273","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":175,"title":["A human model for multigenic inheritance: Phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus"],"prefix":"10.1073","volume":"97","author":[{"given":"Stacey","family":"Bolk","sequence":"first","affiliation":[{"name":"Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland OH 44106; Department of Genetics and Unite Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U-393, Hopital des Enfants Malades, 75743 Paris, France; Department of Medical Genetics, University of Groningen, Groningen, The Netherlands; and Department of Surgical Research, New Children's Hospital, Westmead, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Pelet","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland OH 44106; Department of Genetics and Unite Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U-393, Hopital des Enfants Malades, 75743 Paris, France; Department of Medical Genetics, University of Groningen, Groningen, The Netherlands; and Department of Surgical Research, New Children's Hospital, Westmead, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M. W.","family":"Hofstra","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland OH 44106; Department of Genetics and Unite Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U-393, Hopital des Enfants Malades, 75743 Paris, France; Department of Medical Genetics, University of Groningen, Groningen, The Netherlands; and Department of Surgical Research, New Children's Hospital, Westmead, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misha","family":"Angrist","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland OH 44106; Department of Genetics and Unite Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U-393, Hopital des Enfants Malades, 75743 Paris, France; Department of Medical Genetics, University of Groningen, Groningen, The Netherlands; and Department of Surgical Research, New Children's Hospital, Westmead, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remi","family":"Salomon","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland OH 44106; Department of Genetics and Unite Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U-393, Hopital des Enfants Malades, 75743 Paris, France; Department of Medical Genetics, University of Groningen, Groningen, The Netherlands; and Department of Surgical Research, New Children's Hospital, Westmead, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Croaker","sequence":"additional","affiliation":[{"name":"Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland OH 44106; Department of Genetics and Unite Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U-393, Hopital des Enfants Malades, 75743 Paris, France; Department of Medical Genetics, University of Groningen, Groningen, The Netherlands; and Department of Surgical Research, New Children's Hospital, Westmead, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles H. 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