1. ¹Eastman Dental Institute, UCL, London, UK
2. ²Institute of Child Health, UCL, London, UK
3. ³Queen's University, Kingston, ON, Canada
4. ⁴Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
5. ⁵Department of Genetics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada
6. ⁶The Credit Valley Hospital, Mississauga, ON, Canada
7. ⁷Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada

Correspondence: Professor P Hammond, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: p.hammond@ucl.ac.uk; Dr MES Lewis, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V6H 3N1. E-mail: sume@interchange.ubc.ca

Received 18 June 2007; Revised 15 January 2008; Accepted 16 January 2008; Published online 4 March 2008.

Abstract

The heterogeneity of autism spectrum disorders (ASDs) confounds attempts to identify causes and pathogenesis. Identifiable endophenotypes and reliable biomarkers within ASDs would help to focus molecular research and uncover genetic causes and developmental mechanisms. We used dense surface-modelling techniques to compare the facial morphology of 72 boys with ASD and 128 first-degree relatives to that of 254 unrelated controls. Pattern-matching algorithms were able to discriminate between the faces of ASD boys and those of matched controls (AUC=0.82) and also discriminate between the faces of unaffected mothers of ASD children and matched female controls (AUC=0.76). We detected significant facial asymmetry in boys with ASD (P<0.01), notably depth-wise in the supra- and periorbital regions anterior to the frontal pole of the right hemisphere of the brain. Unaffected mothers of children with ASD display similar significant facial asymmetry, more exaggerated than that in matched controls (P<0.03) and, in particular, show vertical asymmetry of the periorbital region. Unaffected fathers of children with ASD did not show facial asymmetry to a significant degree compared to controls. Two thirds of unaffected male siblings tested were classified unseen as more facially similar to unrelated boys with ASD than to unrelated controls. These unaffected male siblings and two small groups of girls with ASD and female siblings, all show overall directional asymmetry, but without achieving statistical significance in two-tailed t-tests of individual asymmetry of ASD family and matched control groups. We conclude that previously identified right dominant asymmetry of the frontal poles of boys with ASD could explain their facial asymmetry through the direct effect of brain growth. The atypical facial asymmetry of unaffected mothers of children with ASD requires further brain studies before the same explanation can be proposed. An alternative explanation, not mutually exclusive, is a simultaneous and parallel action on face and brain growth by genetic factors. Both possibilities suggest the need for coordinated face and brain studies on ASD probands and their first-degree relatives, especially on unaffected mothers, given that their unusual facial asymmetry suggests an ASD susceptibility arising from maternal genes.