{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T11:20:06Z","timestamp":1764588006462,"version":"3.40.5"},"reference-count":24,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2019,6,22]],"date-time":"2019-06-22T00:00:00Z","timestamp":1561161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"JCR Pharmaceuticals"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\n<jats:italic>SHOX<\/jats:italic> haploinsufficiency leading to Leri\u2010Weill dyschondrosteosis (LWD) and idiopathic short stature typically results from intragenic mutations or copy\u2010number variations (CNVs) involving <jats:italic>SHOX<\/jats:italic> and\/or its putative enhancer regions that are distributed in the genomic interval between 400\u2009kb and 840\u2009kb from Xpter\/Ypter. Here, we report two sisters with LWD, who carried a deletion in the far\u2010downstream region of <jats:italic>SHOX<\/jats:italic>. The 0.62\u2009Mb deletion contained 50 single nucleotide polymorphisms (SNPs) and short insertions and deletions (indels), whose genotypes were linked to <jats:italic>SHOX<\/jats:italic> expression levels in the Genotype\u2010Tissue Expression portal. Notably, most of these SNPs\/indels accumulated within a ~20\u2009kb interval that was positioned ~900\u2009kb away from Xpter\/Ypter. These SNPs\/indels showed similar minor allele frequencies, indicating that they reside within a haplotype block. The ~20\u2009kb interval was not evolutionarily conserved; however, it was associated with the previously determined peak of chromosome conformation capture profiling (4C)\u2010seq. Importantly, the deletion in the present cases partially overlapped with CNVs of three previous cases with skeletal deformity and\/or short stature. The results indicate that far\u2010downstream CNVs constitute rare genetic causes of <jats:italic>SHOX<\/jats:italic> haploinsufficiency. These CNVs possibly impair <jats:italic>SHOX<\/jats:italic> expression through copy\u2010number changes of a human\u2010specific cis\u2010regulatory haplotype block. This notion awaits further validation.<\/jats:p>","DOI":"10.1002\/ajmg.a.61275","type":"journal-article","created":{"date-parts":[[2019,6,22]],"date-time":"2019-06-22T12:20:18Z","timestamp":1561206018000},"page":"1778-1782","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<i>SHOX<\/i> far\u2010downstream copy\u2010number variations involving cis\u2010regulatory nucleotide variants in two sisters with Leri\u2010Weill dyschondrosteosis"],"prefix":"10.1002","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7620-6721","authenticated-orcid":false,"given":"Kenichiro","family":"Ogushi","sequence":"first","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"},{"name":"Department of Pediatrics St. Marianna University School of Medicine  Kawasaki Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Muroya","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism Kanagawa Children's Medical Center  Yokohama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirohito","family":"Shima","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoko","family":"Jinno","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mami","family":"Miyado","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo 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