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Here we present the pertinent clinical findings among members of an unusually large kindred ascertained over 15 years ago following the evaluation and subsequent genetic work\u2010up of a female infant with congenital anomalies. A genome\u2010wide scan and linkage analysis showed only suggestive evidence of linkage to markers on chromosome 2 among the most likely of several pedigree interpretations. We now report that a novel missense mutation in the <jats:italic>SIX3<\/jats:italic> holoprosencephaly gene is the likely cause in this family. Molecular genetic analysis and\/or clinical characterization now show that at least 15 members of this family are presumed <jats:italic>SIX3<\/jats:italic> mutation gene carriers, with clinical manifestations ranging from phenotypically normal adults (non\u2010penetrance) to alobar holoprosencephaly incompatible with postnatal life. This particular family represents a seminal example of the variable manifestations of gene mutations in holoprosencephaly and difficulties encountered in their elucidation. Published 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.a.32813","type":"journal-article","created":{"date-parts":[[2009,4,7]],"date-time":"2009-04-07T19:03:13Z","timestamp":1239130993000},"page":"919-925","source":"Crossref","is-referenced-by-count":34,"title":["A novel <i>SIX3<\/i> mutation segregates with holoprosencephaly in a large family"],"prefix":"10.1002","volume":"149A","author":[{"given":"Benjamin 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