{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T19:59:56Z","timestamp":1776801596687,"version":"3.51.2"},"reference-count":34,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["EY015518"],"award-info":[{"award-number":["EY015518"]}]},{"name":"National Institutes of Health","award":["EY034398"],"award-info":[{"award-number":["EY034398"]}]},{"name":"National Institutes of Health","award":["EY033742"],"award-info":[{"award-number":["EY033742"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Disruption of HCCS results in microphthalmia with linear skin lesions (MLS) characterized by microphthalmia\/anophthalmia, corneal opacity, aplastic skin lesions, variable central nervous system and cardiac anomalies, intellectual disability, and poor growth in heterozygous females. Structural variants consisting of chromosomal rearrangements or deletions are the most common variant type, but a small number of intragenic variants have been reported. Methods: Exome sequencing identified variants affecting HCCS. Results: Three novel intragenic variants and two genomic deletions of HCCS were found in individuals with primarily ocular features of MLS. X-inactivation was highly skewed in affected individuals with all three intragenic variants. Corneal opacity was the most penetrant feature (100%). In addition, a duplication of uncertain significance including both HCCS and AMELX was identified in a male with corneal anomalies, glaucoma, an atrial septal defect, and enamel hypoplasia along with a family history of developmental ocular disorders consistent with X-linked inheritance. Conclusion: Although variable expressivity is a known feature of MLS, our findings provide additional support for including HCCS in testing for individuals with isolated ocular anomalies and provide further evidence for its association with congenital aphakia, aniridia\/other iris defects, and corneal staphyloma\/ectasia.<\/jats:p>","DOI":"10.3390\/genes15121636","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T04:33:29Z","timestamp":1734928409000},"page":"1636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Novel Intragenic and Genomic Variants Highlight the Phenotypic Variability in HCCS-Related Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5098-6336","authenticated-orcid":false,"given":"Linda M.","family":"Reis","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1801-8554","authenticated-orcid":false,"given":"Donald","family":"Basel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"Bitoun","sequence":"additional","affiliation":[{"name":"G\u00e9n\u00e9tique M\u00e9dicale, SIDVA91\/Alt\u00e9rit\u00e9, 1 Impasse de la Cour de France, 91260 Juvisy-sur-Orge, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David S.","family":"Walton","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 8 Hawthorne Place, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Human Anatomy, University of California, Davis, CA 95616, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0531-3586","authenticated-orcid":false,"given":"Elena V.","family":"Semina","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"},{"name":"Department of Pediatrics and Children\u2019s Research Institute, Medical College of Wisconsin and Children\u2019s Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"},{"name":"Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1136\/jmg.27.1.59","article-title":"Two 46,XX,t(X;Y) females with linear skin defects and congenital microphthalmia: A new syndrome at Xp22.3","volume":"27","author":"Mueller","year":"1990","journal-title":"J. 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