title: Atypical face shape and genomic structural variants in epilepsy.
abstract: Many pathogenic structural variants of the human genome are known to cause facial dysmorphism. During the past decade, pathogenic structural variants have also been found to be an important class of genetic risk factor for epilepsy. In other fields, face shape has been assessed objectively using 3D stereophotogrammetry and dense surface models. We hypothesized that computer-based analysis of 3D face images would detect subtle facial abnormality in people with epilepsy who carry pathogenic structural variants as determined by chromosome microarray. In 118 children and adults attending three European epilepsy clinics, we used an objective measure called Face Shape Difference to show that those with pathogenic structural variants have a significantly more atypical face shape than those without such variants. This is true when analysing the whole face, or the periorbital region or the perinasal region alone. We then tested the predictive accuracy of our measure in a second group of 63 patients. Using a minimum threshold to detect face shape abnormalities with pathogenic structural variants, we found high sensitivity (4/5, 80% for whole face; 3/5, 60% for periorbital and perinasal regions) and specificity (45/58, 78% for whole face and perinasal regions; 40/58, 69% for periorbital region). We show that the results do not seem to be affected by facial injury, facial expression, intellectual disability, drug history or demographic differences. Finally, we use bioinformatics tools to explore relationships between facial shape and gene expression within the developing forebrain. Stereophotogrammetry and dense surface models are powerful, objective, non-contact methods of detecting relevant face shape abnormalities. We demonstrate that they are useful in identifying atypical face shape in adults or children with structural variants, and they may give insights into the molecular genetics of facial development.
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Krishna
authors.initials: K
authors.lastname: Chinthapalli
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bartolini
authors.forename: Jan
authors.initials: J
authors.lastname: Novy
authors.forename: Michael
authors.initials: M
authors.lastname: Suttie
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Melania
authors.initials: M
authors.lastname: Falchi
authors.forename: Zoe
authors.initials: Z
authors.lastname: Fox
authors.forename: Lisa M S
authors.initials: LM
authors.lastname: Clayton
authors.forename: Josemir W
authors.initials: JW
authors.lastname: Sander
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Chantal
authors.initials: C
authors.lastname: Depondt
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.forename: Peter
authors.initials: P
authors.lastname: Hammond
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization / Q000379:methods; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology*; D005145:Face / Q000002:abnormalities*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010780:Photogrammetry; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D055815:Young Adult