{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:11:14Z","timestamp":1789132274703,"version":"build-2803163510"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":253,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIDCR","award":["K01DE027995"],"award-info":[{"award-number":["K01DE027995"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Nonsyndromic cleft lip (nsCL) exhibits a non-random laterality pattern, with left-sided clefts occurring twice as frequently as right-sided clefts. The molecular mechanisms underlying this laterality bias remain poorly understood. We performed whole-genome sequencing and methylation profiling on a family comprising monozygotic twins with mirror-image nsCL, their affected mother, and unaffected father and brother. We conducted three independent replications via publicly available whole genome data; genome-wide methylation analysis in 38 individuals with unilateral cleft; and validation of methylation results in the top 3 candidate genes in 385 unrelated individuals with unilateral nonsyndromic cleft lip with or without cleft palate (nsCL\/P) (DNA from blood or saliva). We identified a variant in FGF20 (p.Ile79Val) shared by the twins and their mother. We observed laterality and severity-associated methylation differences in three main genes. ARID5B showed higher methylation in left clefts (saliva, P\u2009=\u2009.001; blood, P\u2009=\u2009.032). ZFP57 demonstrated a strong cleft-extent effect, with cleft lip and palate (CLP) showing markedly higher methylation than cleft lip only (CL) (LCLP vs. RCL padj\u2009=\u20090.0004; LCLP vs. LCL padj\u2009=\u20090.019). HOOK2 displayed a cross-tissue cleft-extent effect in the opposite direction\u2014CLP subtypes were hypomethylated relative to CL-only subtypes in blood (P\u2009&amp;lt;\u2009.0001) and saliva (P\u2009=\u2009.0008). This study provides evidence that DNA methylation patterns play a role in both the laterality and severity of cleft lip. ARID5B provides a consistent laterality signal across tissues, while ZFP57 and HOOK2 track palatal involvement independently of side. Together, these findings suggest that epigenetic variation acts downstream of genetic predisposition to shape cleft phenotypes.<\/jats:p>","DOI":"10.1093\/hmg\/ddag088","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:11:08Z","timestamp":1788520268000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic and epigenetic contributors to cleft laterality: evidence from monozygotic mirror twins and replication cohorts"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2239-8120","authenticated-orcid":false,"given":"Aline L","family":"Petrin","sequence":"first","affiliation":[{"name":"Department of Orthodontics, College of Dentistry and Dental Clinics, University of Iowa , 801 Newton Rd, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waheed","family":"Awotoye","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, College of Dentistry and Dental Clinics, University of Iowa , 801 Newton Rd, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina E","family":"Spencer","sequence":"additional","affiliation":[{"name":"College of Dentistry and Dental Clinics, University of Iowa , 801 Newton Rd, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ligiane A","family":"Machado-Paula","sequence":"additional","affiliation":[{"name":"Iowa Institute of Human Genetics, Carver College of Medicine, University of Iowa , 431 Newton Road, 117 EMRB, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Hovey","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Tufts University School of Dental Medicine , 1 Kneeland St, Boston, MA 02111 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Keen","sequence":"additional","affiliation":[{"name":"Iowa Institute of Human Genetics, Carver College of Medicine, University of Iowa , 431 Newton Road, 117 EMRB, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Chimenti","sequence":"additional","affiliation":[{"name":"Iowa Institute of Human Genetics, Carver College of Medicine, University of Iowa , 431 Newton Road, 117 EMRB, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0650-1119","authenticated-orcid":false,"given":"Patrick","family":"Breheny","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, College of Public Health, University of Iowa , 145 N Riverside Dr, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Qian","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Computational Biology, College of Dentistry and Dental Clinics, University of Iowa , 801 Newton Rd, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shareef","family":"Dabdoub","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Computational Biology, College of Dentistry and Dental Clinics, University of Iowa , 801 Newton Rd, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James C","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Computational Biology, College of Dentistry and Dental Clinics, University of Iowa , 801 Newton Rd, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azeez","family":"Butali","sequence":"additional","affiliation":[{"name":"Department of Oral Pathology, Radiology, & Medicine, College of Dentistry and Dental Clinics, University of Iowa , 801 Newton Rd, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey C","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Carver College of Medicine, University of Iowa , 200 Hawkins Drive, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shankar Rengasamy","family":"Venugopalan","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, Tufts University School of Dental Medicine , 1 Kneeland St, Boston, MA 02111 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina M","family":"Moreno-Uribe","sequence":"additional","affiliation":[{"name":"Department of Orthodontics, College of Dentistry and Dental Clinics, University of Iowa , 801 Newton Rd, Iowa City, IA 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"2026091108544603400_ref1","doi-asserted-by":"publisher","first-page":"1773","DOI":"10.1016\/S0140-6736(09)60695-4","article-title":"Cleft lip and palate","volume":"374","author":"Mossey","year":"2009","journal-title":"Lancet"},{"key":"2026091108544603400_ref2","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/nrg2933","article-title":"Cleft lip and palate: understanding genetic and environmental influences","volume":"12","author":"Dixon","year":"2011","journal-title":"Nat Rev 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