{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T10:09:30Z","timestamp":1784714970331,"version":"3.55.0"},"reference-count":42,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T00:00:00Z","timestamp":1680825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>SHOX deficiency is a common genetic cause of short stature of variable degree. SHOX haploinsufficiency causes Leri\u2013Weill dyschondrosteosis (LWD) as well as nonspecific short stature. SHOX haploinsufficiency is known to result from heterozygous loss-of-function variants with pseudo-autosomal dominant inheritance, while biallelic SHOX loss-of-function variants cause the more severe skeletal dysplasia, Langer mesomelic dyschondrosteosis (LMD). Here we report for the first time the pseudo-autosomal recessive inheritance of LWD in two siblings caused by a novel homozygous non-canonical, leaky splice-site variant in intron 3 of SHOX: c.544+5G&gt;C. Transcript analyses in patient-derived fibroblasts showed homozygous patients to produce approximately equal amounts of normally spliced mRNA and mRNA with the abnormal retention of intron 3 and containing a premature stop codon (p.Val183Glyfs*31). The aberrant transcript was shown to undergo nonsense-mediated mRNA decay, and thus resulting in SHOX haploinsufficiency in the homozygous patient. Six healthy relatives who are of normal height are heterozygous for this variant and fibroblasts from a heterozygote for the c.544+5G&gt;C variant produced wild-type transcript amounts comparable to healthy control. The unique situation reported here highlights the fact that the dosage of SHOX determines the clinical phenotype rather than the Mendelian inheritance pattern of SHOX variants. This study extends the molecular and inheritance spectrum of SHOX deficiency disorder and highlights the importance of functional testing of SHOX variants of unknown significance in order to allow appropriate counseling and precision medicine for each family individual.<\/jats:p>","DOI":"10.3390\/genes14040877","type":"journal-article","created":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T04:08:03Z","timestamp":1680840483000},"page":"877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Leri\u2013Weill Dyschondrosteosis Caused by a Leaky Homozygous SHOX Splice-Site Variant"],"prefix":"10.3390","volume":"14","author":[{"given":"Julia","family":"Vodopiutz","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria"},{"name":"Vienna Bone and Growth Center, 1130 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa-Maria","family":"Steurer","sequence":"additional","affiliation":[{"name":"Vienna Bone and Growth Center, 1130 Vienna, Austria"},{"name":"Department of Pediatrics and Adolescent Medicine, Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florentina","family":"Haufler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9466-6441","authenticated-orcid":false,"given":"Franco","family":"Laccone","sequence":"additional","affiliation":[{"name":"Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Garczarczyk-Asim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Hilkenmeier","sequence":"additional","affiliation":[{"name":"Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Steinbauer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7155-0315","authenticated-orcid":false,"given":"Andreas R.","family":"Janecke","sequence":"additional","affiliation":[{"name":"Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria"},{"name":"Division of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/ng0597-54","article-title":"Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome","volume":"16","author":"Rao","year":"1997","journal-title":"Nat. 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