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High-resolution array-based comparative genomic hybridization has increased the ability to detect copy number variants (CNVs) that can be causative for complex diseases such as cleft lip and\/or palate. Utilizing this technique on 97 nonsyndromic cleft lip and palate cases and 43 cases with cleft palate only, we identified a heterozygous deletion of Isthmin 1 in one affected case, as well as a deletion in a second case that removes putative 3\u2032 regulatory information. Isthmin 1 is a strong candidate for clefting, as it is expressed in orofacial structures derived from the first branchial arch and is also in the same \u201csynexpression group\u201d as fibroblast growth factor 8 and sprouty RTK signaling antagonist 1a and 2, all of which have been associated with clefting. CNVs affecting Isthmin 1 are exceedingly rare in control populations, and Isthmin 1 scores as a likely haploinsufficiency locus. Confirming its role in craniofacial development, knockdown or clustered randomly interspaced short palindromic repeats\/Cas9-generated mutation of isthmin 1 in Xenopus laevis resulted in mild to severe craniofacial dysmorphologies, with several individuals presenting with median clefts. Moreover, knockdown of isthmin 1 produced decreased expression of LIM homeobox 8, itself a gene associated with clefting, in regions of the face that pattern the maxilla. Our study demonstrates a successful pipeline from CNV identification of a candidate gene to functional validation in a vertebrate model system, and reveals Isthmin 1 as both a new human clefting locus as well as a key craniofacial patterning gene.<\/jats:p>","DOI":"10.1534\/genetics.117.300535","type":"journal-article","created":{"date-parts":[[2017,11,21]],"date-time":"2017-11-21T22:15:52Z","timestamp":1511302552000},"page":"283-296","source":"Crossref","is-referenced-by-count":26,"title":["Identification of <i>Isthmin 1<\/i> as a Novel Clefting and Craniofacial Patterning Gene in Humans"],"prefix":"10.1093","volume":"208","author":[{"given":"Lisa A","family":"Lansdon","sequence":"first","affiliation":[{"name":"Department of Pediatrics"},{"name":"Department of Biology"},{"name":"Interdisciplinary Graduate Program in Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin W","family":"Darbro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"},{"name":"Interdisciplinary Graduate Program in Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline L","family":"Petrin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"},{"name":"College of Dentistry, University of Iowa, Iowa 52242 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissa M","family":"Hulstrand","sequence":"additional","affiliation":[{"name":"Department of Biology, Northland College, Ashland, Wisconsin 54806"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M","family":"Standley","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel B","family":"Brouillette","sequence":"additional","affiliation":[{"name":"Department of Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abby","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Adela","family":"Mansilla","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A","family":"Cornell","sequence":"additional","affiliation":[{"name":"Interdisciplinary Graduate Program in Genetics"},{"name":"Department of Anatomy and Cell Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey C","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"},{"name":"Department of Biology"},{"name":"Department of Anatomy and Cell Biology, and"},{"name":"Interdisciplinary Graduate Program in Genetics"},{"name":"College of Dentistry, University of Iowa, Iowa 52242 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas W","family":"Houston","sequence":"additional","affiliation":[{"name":"Department of Biology"},{"name":"Interdisciplinary Graduate Program in Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Robert","family":"Manak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"},{"name":"Department of Biology"},{"name":"Interdisciplinary Graduate Program in Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,1,1]]},"reference":[{"key":"2022011308590848100_bib1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes.","volume":"491","author":"1000 Genomes Project Consortium","year":"2012","journal-title":"Nature"},{"key":"2022011308590848100_bib2","doi-asserted-by":"crossref","first-page":"4613","DOI":"10.1242\/dev.129.19.4613","article-title":"Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse.","volume":"129","author":"Abu-Issa","year":"2002","journal-title":"Development"},{"key":"2022011308590848100_bib3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1242\/jcs.035246","article-title":"Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice.","volume":"122","author":"Aluwihare","year":"2009","journal-title":"J. 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