A 2025 study of 2,268 children with orofacial clefts asked whether the cleft subtypes share their genetics — the answer was "partly": 27 risk regions, some shared, some specific to one subtype, three pulling in opposite directions.
Cleft lip with cleft palate is one of several orofacial cleft subtypes — the others include cleft lip alone, cleft palate alone and Pierre Robin Sequence. Most genetic studies had either lumped every cleft together or looked only at non-syndromic cleft lip with or without palate; very few had asked whether the subtypes actually share their genetics.
A 2025 study in Human Molecular Genetics ran a genome-wide association study on 2,268 cleft cases from the Cleft Collective and 7,913 population-based controls, analysing all orofacial clefts together and then seven subgroups separately, with replication in a meta-analysis of independent samples. It identified 27 regions at genome-wide significance, 8 of them novel. Three variants under the cleft-lip-with-cleft-palate subgroup are catalogued here: rs10483604 (TRIM9), rs13385292 (near CYRIA) and rs2600519 (near FMN1). None of the three is among the novel loci the paper names; they are part of the wider 27-region result.
The novel loci the abstract does name are each tied to a subtype: LHX8 and TSBP1 for combined clefts, ARHGEF18 and ARHGEF19 for cleft lip with or without palate, FBN2 for cleft lip only, SLC35B3 for cleft palate only, CASC20 for Pierre Robin Sequence, and CHRM2 for non-syndromic cleft palate only. Several sit in regions previously associated with facial morphology, or in pathways of neural crest cell migration and craniofacial development.
The study's central finding is about heterogeneity: some loci had similar effects across every subgroup, some were specific to one subtype, and three loci had opposing effects on cleft lip and Pierre Robin Sequence — raising risk of one while lowering risk of the other. It also ran the first genome-wide study of Pierre Robin Sequence, finding one significant variant and 21 suggestive ones despite only 237 cases. The authors' conclusion is methodological as much as biological: cleft studies should include every subtype and test for differences between them, rather than assuming one genetics for all clefts.
Orofacial clefts are diagnosed by examination (often on prenatal ultrasound) and treated surgically, not by genotype. These three variants are risk-region findings from one study of one subtype; they are not a prenatal test and do not distinguish syndromic from non-syndromic clefts.
The study's own lesson for reading any cleft genetics result: a locus found for one subtype may not apply to another, and three of its loci pushed in opposite directions between cleft lip and Pierre Robin Sequence. A page like this one covers a single subtype for that reason.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Cleft Lip with Cleft Palate comes down to these specific, well-studied positions — not a diagnosis.
ARHGEF18 · rs12971753
See detailed info →near ARHGEF19 · rs61769781
See detailed info →The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 1 of 11 linked studies with a resolved discovery ancestry.
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Cleft Lip with Cleft Palate. MyGeneLog™. https://www.mygenelog.com/conditions/cleft-lip-with-cleft-palate
One of the orofacial cleft subtypes, in which both the lip and the palate are affected. Others include cleft lip alone, cleft palate alone and Pierre Robin Sequence; a 2025 study showed these subtypes only partly share their genetics.
Only partly. A 2025 genome-wide study of 2,268 cases found some risk loci with similar effects across every subtype, some specific to one subtype, and three that had opposite effects on cleft lip and Pierre Robin Sequence.
The 2025 Cleft Collective study identified 27 regions at genome-wide significance across all cleft subtypes, 8 of them not previously reported. Three variants from its cleft-lip-with-cleft-palate subgroup are on this page.
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