Craniofacial features and pathogenic variants in 1,252 children with neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) are a group of highly heterogeneous diseases with complex genetic etiology. Craniofacial anomalies are frequently observed in children with NDDs. This study aimed to identify craniofacial features in children with NDDs for early warning of genetic NDDs.

Peripheral blood samples were collected from children with NDDs and their parents for exome sequencing and copy number variation analysis. Typical clinical characteristics of children with NDDs, including craniofacial anomalies, limb malformations, and organ deformities, were thoroughly observed and recorded.

Among 1,252 children with NDDs, there were 283 cases with pathogenic variants and 219 cases of craniofacial abnormalities. The positive detection rate of pathogenic variants in the craniofacial anomaly group was significantly higher than that in the overall cohort and the cohort of non-craniofacial anomaly (P < 0.01). Eyes were the most common craniofacial region with anomalies in children with NDDs carrying pathogenic variants, followed by the head and oral cavity. Significant differences were observed in the rates of positive characteristics in the eight craniofacial regions between children with NDDs either carrying pathogenic variants or not. The craniofacial anomalies in ≥ 3 regions indicated a positive detection rate nearly 75% of pathogenic variants.

Craniofacial anomalies are highly predictive of pathogenic variants in children with NDDs. Moreover, the eyes, head and oral cavity are the most common craniofacial regions with anomalies in children with NDDs carrying pathogenic variants. For a definite diagnosis, genetic testing is recommended for children with unknown causes of NDDs and anomalies in three or more craniofacial regions.