Cleft lip has a strong genetic component, but it is not caused by a single gene acting alone. Most cases result from a combination of multiple genes and environmental factors during early pregnancy. About 1 in every 1,000 to 1,500 babies worldwide is born with some form of orofacial cleft, and the risk rises significantly when a close family member is affected.
How Genetics Contributes to Cleft Lip
Roughly 70% of cleft lip cases are classified as “non-syndromic,” meaning the cleft occurs on its own without being part of a broader genetic condition. These cases follow what geneticists call multifactorial inheritance: several genes each contribute a small amount of risk, and environmental triggers during pregnancy can tip the balance.
The genes involved play roles in how cells migrate, stick together, and multiply during the earliest weeks of facial development. Some of the most studied include IRF6 and GRHL3, both of which help regulate how tissues form and fuse in the developing face. Variations in these genes don’t guarantee a cleft will occur, but they raise the likelihood, especially when combined with other genetic or environmental risk factors.
Family Risk by the Numbers
If one parent has a cleft lip, the chance of their child being born with one is roughly 3.6% to 4.7%, compared to about 0.2% in the general population. When a sibling has a cleft, the risk for a subsequent child is similarly elevated at around 4.6%. A large population study estimated that having a first-degree relative with cleft lip increases recurrence risk about 32-fold compared to families with no history.
Those numbers can sound alarming, but context matters. A 32-fold increase over a baseline of 0.2% still means the absolute risk stays in the range of 4% to 5%. The vast majority of children born into families with a history of clefting will not have a cleft themselves.
When the Cleft Is Part of a Syndrome
About 30% of cleft lip cases occur alongside other physical or developmental differences as part of a recognized genetic syndrome. In these cases, the genetic link is often more direct and predictable.
- Van der Woude syndrome is one of the most common. It follows an autosomal dominant pattern, meaning a single copy of the altered gene from one parent can cause it. The hallmark is small pits or mounds on the lower lip, sometimes accompanied by missing teeth or heart defects.
- Velocardiofacial syndrome (also called 22q11.2 deletion syndrome) occurs in about 1 in 2,000 births. It involves a missing piece of chromosome 22 and can cause cleft palate along with heart anomalies, distinctive facial features, and learning differences.
- Pierre Robin sequence features a small lower jaw, a tongue that falls back into the airway, and cleft palate. It can occur on its own or as part of other genetic conditions.
- Treacher Collins syndrome and chromosomal conditions like trisomy 13 and trisomy 18 also include orofacial clefts among their features.
What Happens During Development
The face forms remarkably early. By the 6th week of pregnancy, separate tissue structures in the embryo’s face begin fusing together to form the upper lip and primary palate. The secondary palate, which becomes the roof of the mouth, develops during weeks 7 and 8. By the end of week 8, these structures have normally joined into a continuous surface.
A cleft lip occurs when the tissues that should fuse around the upper lip fail to come together completely during this narrow window. Because the process unfolds so early, many of the environmental risk factors that matter most are exposures that happen during the first trimester, often before a person even knows they’re pregnant.
Environmental Factors That Raise Risk
Even with a genetic predisposition, environmental exposures during early pregnancy can influence whether a cleft actually develops. Maternal smoking during the first trimester raises the risk of cleft lip by about 79%, and the risk climbs with the number of cigarettes smoked per day. Alcohol consumption during the first trimester roughly doubles the risk of cleft palate.
The body’s ability to process certain nutrients also plays a role. Folate (the B vitamin critical to early development) is one of the best-studied protective factors. Women of childbearing age are advised to take 400 micrograms of folic acid daily starting at least four weeks before conception and continuing through the first 12 weeks of pregnancy. This supplementation is already standard guidance for preventing neural tube defects, and it offers some protection against orofacial clefts as well.
Genetic Testing Options for Families
If you have a family history of clefting, genetic testing can help clarify whether a specific inherited condition is involved. The first-line test for syndromic clefting is typically a chromosomal microarray, which scans the genome for missing or extra segments of DNA. In settings where microarrays aren’t available, a standard chromosome analysis combined with targeted testing for the 22q11.2 deletion is recommended.
For families where a specific gene mutation has already been identified, prenatal testing is an option. Chorionic villus sampling can be performed after 11 weeks of pregnancy to check the fetus for the same familial variant. Amniocentesis is another route, testing fetal cells in the amniotic fluid for chromosomal anomalies and, if needed, running more detailed sequencing.
Whole genome sequencing is now available and can analyze a panel of genes associated with clefting all at once. This is most useful when a child is born with a cleft alongside other features that suggest a syndrome, or when a family wants a clearer picture of recurrence risk for future pregnancies.
Detection During Pregnancy
Cleft lip can often be seen on ultrasound beginning around the 13th week of pregnancy, and 3D ultrasound techniques sometimes pick it up even earlier. Cleft palate alone, without an accompanying lip cleft, is harder to detect on imaging because it involves the roof of the mouth rather than an external facial structure. Many isolated cleft palates are not identified until after birth.
A prenatal diagnosis gives families time to connect with surgical teams and plan for any feeding support the baby may need. Cleft lip repair surgery is typically performed in the first few months of life, and cleft palate repair usually follows before a child’s first birthday.