Genetic and epigenetic contributors to cleft laterality: evidence from monozygotic mirror twins and replication cohorts

Aline L Petrin; Waheed Awotoye; Christina E Spencer; Ligiane A Machado-Paula; Luke Hovey; Henry Keen; Michael Chimenti; Patrick Breheny; Fang Qian; Shareef Dabdoub; James C Thomas; Azeez Butali; Jeffrey C Murray; Shankar Rengasamy Venugopalan; Lina M Moreno-Uribe

doi:10.1093/hmg/ddag088

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Genetic and epigenetic contributors to cleft laterality: evidence from monozygotic mirror twins and replication cohorts

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Genetic and epigenetic contributors to cleft laterality: evidence from monozygotic mirror twins and replication cohorts

Aline L Petrin, Waheed Awotoye, Christina E Spencer, Ligiane A Machado-Paula, Luke Hovey, Henry Keen, Michael Chimenti, Patrick Breheny, Fang Qian, Shareef Dabdoub, …

Human molecular genetics, Vol.35(19), ddag088

09/11/2026

DOI: 10.1093/hmg/ddag088

PMCID: PMC13626208

PMID: 42725914

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Abstract

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 = .001; blood, P = .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 = 0.0004; LCLP vs. LCL padj = 0.019). HOOK2 displayed a cross-tissue cleft-extent effect in the opposite direction-CLP subtypes were hypomethylated relative to CL-only subtypes in blood (P < .0001) and saliva (P = .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.

Epigenetics

complex disease

DNA methylation

whole genome sequencing

epigenomics

ggenomics

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Details

Title: Subtitle: Genetic and epigenetic contributors to cleft laterality: evidence from monozygotic mirror twins and replication cohorts
Creators: Aline L Petrin - University of Iowa
Waheed Awotoye - University of Iowa
Christina E Spencer - University of Iowa
Ligiane A Machado-Paula - University of Iowa
Luke Hovey - Tufts University
Henry Keen - University of Iowa
Michael Chimenti - University of Iowa
Patrick Breheny - University of Iowa
Fang Qian - University of Iowa
Shareef Dabdoub - University of Iowa
James C Thomas - University of Iowa
Azeez Butali - University of Iowa
Jeffrey C Murray - University of Iowa
Shankar Rengasamy Venugopalan - Tufts University
Lina M Moreno-Uribe - University of Iowa
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.35(19), ddag088
DOI: 10.1093/hmg/ddag088
PMID: 42725914
PMCID: PMC13626208
NLM abbreviation: Hum Mol Genet
ISSN: 1460-2083
eISSN: 1460-2083
Publisher: Oxford University Press
Grant note: K01DE027995 / NIH/NIDCR
Language: English
Date published: 09/11/2026
Academic Unit: Preventive and Community Dentistry; Oral Pathology, Radiology and Medicine; Biostatistics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Otolaryngology; Iowa Institute of Human Genetics; Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Dental Research; Periodontics
Record Identifier: 9985224448002771

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