{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T05:45:28Z","timestamp":1780983928864,"version":"3.54.1"},"reference-count":37,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T00:00:00Z","timestamp":1712016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T00:00:00Z","timestamp":1712016000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Sonic hedgehog signaling molecule (SHH) is a key molecule in the cilia\u2010mediated signaling pathway and a critical morphogen in embryogenesis. The association between loss\u2010of\u2010function variants of SHH and holoprosencephaly is well established. In mice experiments, reduced or increased signaling of SHH have been shown to be associated with narrowing or excessive expansion of the facial midline, respectively. Herein, we report two unrelated patients with de novo truncating variants of SHH presenting with hypertelorism rather than hypotelorism. The first patient was a 13\u2010year\u2010old girl. Her facial features included hypertelorism, strabismus, telecanthus, malocclusion, frontal bossing, and wide widow's peak. She had borderline developmental delay and agenesis of the corpus callosum. She had a nonsense variant of\n                    <jats:italic>SHH<\/jats:italic>\n                    : Chr7(GRCh38):g.155802987C\u2009&gt;\u2009T, NM_000193.4:c.1302G\u2009&gt;\u2009A, p.(Trp434*). The second patient was a 25\u2010year\u2010old girl. Her facial features included hypertelorism and wide widow's peak. She had developmental delay and agenesis of the corpus callosum. She had a frameshift variant of\n                    <jats:italic>SHH<\/jats:italic>\n                    : Chr7(GRCh38):g.155803072_155803074delCGGinsT, NM_000193.4:c.1215_1217delCCGinsA, p.(Asp405Glufs*92). The hypertelorism phenotype contrasts sharply with the prototypical hypotelorism\u2010holoprosencephaly phenotype associated with loss\u2010of\u2010function of SHH. We concluded that a subset of truncating variants of SHH could be associated with hypertelorism rather than hypotelorism.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.63614","type":"journal-article","created":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T03:29:46Z","timestamp":1712028586000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Truncating variants of the sterol recognition region of\n                    <i>SHH<\/i>\n                    cause hypertelorism phenotype rather than hypotelorism\u2010holoprosencephaly"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4039-8899","authenticated-orcid":false,"given":"Mamiko","family":"Yamada","sequence":"first","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine  Tokyo 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