Rammos Alexandros, Blakey Rachel, Dennison Charlotte A, Lewis Sarah J, Ali Nabila, Davies Amy, Wren Yvonne, Humphries Kerry, Sandy Jonathan, Rees Elliott, Kendall Kimberley Marie, Sharp Gemma C, Owen Michael J, van den Bree Marianne B M, Stergiakouli Evie
Cleft Collective, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom.
Population Health Sciences, Bristol Medical School, Oakfield House, Oakfield Grove, Bristol BS8 2BN, United Kingdom.
Hum Mol Genet. 2025 Sep 3;34(18):1563-1574. doi: 10.1093/hmg/ddaf115.
Cleft lip and/or palate (CL/P) is the most common craniofacial congenital anomaly and has been associated with higher risk of neurodevelopmental and behavioural problems indicating potential shared genetic factors between CL/P and neurodevelopmental disorders. In this study, we aimed to determine the prevalence of neurodevelopmental copy number variants (CNV) in children with CL/P and their link to early developmental and behavioural problems. Using data from the Cleft Collective, the largest UK-based national cohort study of children with CL/P, we determined the rates of neurodevelopmental CNVs in children with CL/P comparing them to the general population, explored differences by cleft type and investigated risk of developmental delays and behavioural problems among those with CL/P and neurodevelopmental CNVs. Children with CL/P had a higher prevalence of neurodevelopmental CNVs than participants in four population-based samples (3.7% vs 2.3% in the Avon Longitudinal Study of Parents and Children (ALSPAC), 2.0% in Born in Bradford (BiB), 2.3% in Millenium Cohort Study (MCS), 1.7% in UK Biobank, ORs(95%CIs): ALSPAC = 1.56(1.18-2.06), BiB = 1.84(1.37-2.45), MCS = 1.59(1.19-2.11), UK Biobank = 2.15(1.68-2.71). Children with cleft palate only were 3 times more likely to have a neurodevelopmental CNV (95%CIs1.50-6.59, p = 0.03) than children with cleft lip only. Furthermore, children with CL/P and neurodevelopmental CNVs were more likely to experience early developmental delays and behavioural problems by age 5 compared to children with CL/P and without neurodevelopmental CNVs. These findings highlight that genetic testing ascertaining the presence of neurodevelopmental CNVs might be helpful in early identification of developmental needs in children with CL/P.
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