Advancing genotype-phenotype analysis through 3D facial morphometry: insights from Cri-du-Chat syndrome

Purpose Facial dysmorphism is a feature of many monogenic disorders and is important in diagnostics, variant interpretation and nosology. Nevertheless, comprehensively assessing the complex facial shape changes associated with specific syndromes remains challenging. Here, we present three-dimensional (3D) morphometric approaches to overcome these limitations, using Cri-du-Chat syndrome (CdCS) as a model. Methods We analysed 3D facial images from 24 participants with CdCS, 4540 unaffected controls and five participants with rare 5p15.33-15.32 deletions, incorporating two methods to account for age- and sex-related facial variation. We quantified phenotypic variation within and between groups and explored genotype-phenotype correlations in CdCS. Results We identified changes in the characteristic facial features of CdCS with age and found that facial shape in CdCS differed from controls in highly consistent directions, but with varying magnitudes of effect. 5p15.33-15.32 heterozygotes had non-specific dysmorphic features that were objectively different from those in CdCS, delineating multiple critical regions for facial dysmorphism on chromosome 5p. Conclusion This work explores 3D facial morphometry to complement the standard clinical assessment of facial dysmorphism. It provides insights into the genetic basis of facial shape in CdCS and highlights the potential of 3D morphometric techniques to facilitate clinical diagnostics, variant interpretation and delineation of syndrome nosology.