Cleft palate genetics study finds no common variant link to neurodevelopmental risk

Children born with a cleft lip and/or palate face a higher likelihood of neurodevelopmental difficulties than their peers, including elevated rates of attention deficit hyperactivity disorder, autism spectrum disorder, and educational challenges. For years, researchers have puzzled over why. One leading hypothesis was that the same genetic variants that raise the risk of a cleft might also nudge brain development off course, creating a shared genetic pathway between facial malformation and neurodevelopmental vulnerability. A new study, published in BMC Medicine, puts that idea to one of its most rigorous tests yet, and the answer is a striking negative: common genetic variation does not appear to explain the excess neurodevelopmental risk seen in children with clefts.

The research, led by Alexandros Rammos and Evie Stergiakouli at the University of Bristol together with colleagues at Cardiff University and the University of Exeter, drew on two of the United Kingdom’s most valuable population resources. The team analysed genetic and phenotypic data from 2,313 children with cleft lip and/or palate recruited through the Cleft Collective, the world’s largest cleft-specific cohort study, and compared them with 7,913 unaffected children from the Millennium Cohort Study, a nationally representative birth cohort. This scale matters, because questions about subtle genetic correlations demand thousands of participants before any signal can be distinguished from statistical noise.

The investigators deployed a battery of complementary genomic techniques, each probing a different aspect of the relationship between cleft biology and neurodevelopment. First, they used linkage disequilibrium score regression, a method that estimates the overall genetic correlation between two traits by examining whether the same stretches of the genome show association signals in both. If cleft liability and psychiatric conditions shared a common genetic architecture, this technique would detect it across hundreds of thousands of genetic variants simultaneously. Instead, the analysis revealed little evidence of genetic correlations between cleft lip and/or palate and any of the eight traits examined, which spanned cognitive, neurodevelopmental, and psychiatric domains.

Second, the team constructed polygenic risk scores for each child. These scores summarise the cumulative effect of thousands of common variants, each contributing a tiny amount, into a single number that estimates an individual’s inherited liability to a given trait. The researchers calculated scores for ADHD, autism, depression, anxiety, schizophrenia, bipolar disorder, educational attainment, and intelligence, and then asked two separate questions. Did children with clefts carry higher polygenic risk than controls? And within the cleft population, did polygenic scores predict actual developmental and behavioural outcomes measured through validated instruments such as the Strengths and Difficulties Questionnaire, the Ages and Stages Questionnaire, and the Moods and Feelings Questionnaire?

The results were revealing precisely because they diverged. Children with cleft lip and/or palate did not show elevated polygenic risk scores for any of the psychiatric or neurodevelopmental traits compared with population controls, nor lower scores for educational attainment or intelligence. Yet within the cleft group itself, the polygenic scores behaved exactly as they do in the general population: children with higher inherited liability to ADHD, for example, showed more ADHD-type behaviours, and children with higher educational attainment scores performed better developmentally. In other words, the genetic factors that shape neurodevelopment in children with clefts appear to be the same ones that shape it in everyone else, operating independently of cleft status rather than through a shared cleft-neurodevelopment pathway.

Third, the researchers turned to Mendelian randomization, a technique that exploits the random allocation of genetic variants at conception to test whether an exposure plausibly causes an outcome. Because genetic variants are inherited independently of the environmental and social confounders that plague observational research, they can serve as natural proxies. The team used genetic variants associated with cleft liability to ask whether genetic predisposition to clefts causally influences neurodevelopmental outcomes. The analysis provided no robust evidence that it does, further undermining the hypothesis that the cleft itself, through shared genetic roots, drives the increased rates of neurodevelopmental difficulty.

The study also examined the relationship between common and rare genetic variation, an area where prior findings had been much more positive. Previous work has established that rare neurodevelopmental copy number variants, large deletions or duplications of DNA segments that remove or multiply dozens of genes at once, are enriched among children with clefts and are associated with poorer developmental outcomes. If common and rare variants were acting through convergent biological pathways, one might expect children carrying these rare variants to also carry a heavier burden of common risk alleles. The team found no such difference: neurodevelopmental copy number variant carriers did not differ from non-carriers in their polygenic burden, suggesting the two classes of variation contribute independently.

The implications for clinical practice are significant. Because polygenic risk scores predict behavioural and developmental outcomes within the cleft population just as they do in the general population, these scores may retain clinical relevance for children with clefts, potentially helping to identify those who would benefit from early developmental monitoring and support. At the same time, the findings make clear that screening for clefts alone does not identify a population with elevated common variant liability to psychiatric illness. Clinicians and families should instead understand the increased neurodevelopmental risk in this group as arising from other sources, which may include the rare variants already identified, environmental exposures, perinatal complications, the social and surgical burdens associated with cleft care, or factors yet to be discovered.

The negative result also carries a broader lesson for psychiatric genetics. Comorbidities between apparently distinct conditions are often assumed to reflect shared genetic architecture, and in many cases that assumption holds. But this study demonstrates that a well-documented clinical association, between a major congenital malformation and neurodevelopmental difficulty, can exist without any detectable common genetic overlap. The mechanisms linking clefts to neurodevelopmental outcomes may be heterogeneous, involving rare mutations in some children, environmental and medical factors in others, and possibly the cumulative experience of living with a visible craniofacial difference and repeated surgical interventions. Disentangling these threads will require longitudinal data of the kind the Cleft Collective was designed to provide.

The research was funded by the Medical Research Council, with additional support from The Scar Free Foundation, The Underwood Trust, and the Vocational Training Charitable Trust, and it relied on the participation of thousands of families and the United Kingdom’s NHS cleft teams. By rigorously ruling out one of the most plausible genetic explanations for neurodevelopmental comorbidity in cleft lip and/or palate, the study sharpens the field’s focus on the mechanisms that remain. For the roughly one in seven hundred children born with an orofacial cleft, the message is cautiously reassuring: their inherited common genetic risk for psychiatric and cognitive difficulties looks much like anyone else’s, and the developmental challenges some of them face are not written into the same variants that shaped their cleft. Finding what does explain that risk is now the field’s central task.

Subject of Research: Common and rare genetic variant contributions to neurodevelopmental risk in children with orofacial clefts

Article Title: Common variant contributions to neurodevelopmental risk in orofacial clefts

Article References: Common variant contributions to neurodevelopmental risk in orofacial clefts. (n.d.). https://doi.org/10.1186/s12916-026-05171-6

Image Credits: AI Generated

DOI: 10.1186/s12916-026-05171-6

Keywords: orofacial clefts, cleft lip and palate, neurodevelopmental disorders, polygenic risk scores, Mendelian randomization, copy number variants, genetic correlation, ADHD, autism spectrum disorder, Cleft Collective, psychiatric genetics, BMC Medicine