Toward 3D facial analysis for recognizing Mendelian causes of autism spectrum disorder.

Recognizing Mendelian causes is crucial in molecular diagnostics and counseling for patients with autism spectrum disorder (ASD). We explored facial dysmorphism and facial asymmetry in relation to genetic causes in ASD patients and studied the potential of objective facial phenotyping in discriminating between Mendelian and multifactorial ASD. In a cohort of 152 ASD patients, 3D facial images were used to calculate three metrics: a computational dysmorphism score, a computational asymmetry score, and an expert dysmorphism score.

Determination of craniofacial and dental characteristics of individuals with Williams-Beuren syndrome by using 3D facial scans and radiographs.

Background: Williams-Beuren syndrome (WBS) is caused by a microdeletion on chromosome 7q11-23 and clusters a variety of systemic affectations.

Aim: To investigate whether 3D facial scans can detect WBS by objectively addressing their craniofacial, skeletal and dental characteristics, compared with those of a non-affected control group.

Materials And Methods: 3D facial surface scans of 17 WBS individuals and 33 normal developing patients were analysed.

Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations.

Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups.

3D facial phenotyping by biometric sibling matching used in contemporary genomic methodologies.

The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height).

Shared heritability of human face and brain shape.

Evidence from model organisms and clinical genetics suggests coordination between the developing brain and face, but the role of this link in common genetic variation remains unknown. We performed a multivariate genome-wide association study of cortical surface morphology in 19,644 individuals of European ancestry, identifying 472 genomic loci influencing brain shape, of which 76 are also linked to face shape. Shared loci include transcription factors involved in craniofacial development, as well as members of signaling pathways implicated in brain-face cross-talk.

The PAX1 locus at 20p11 is a potential genetic modifier for bilateral cleft lip.

Nonsyndromic orofacial clefts (OFCs) are a common birth defect and are phenotypically heterogenous in the structure affected by the cleft - cleft lip (CL) and cleft lip and palate (CLP) - as well as other features, such as the severity of the cleft. Here, we focus on bilateral and unilateral clefts as one dimension of OFC severity, because the genetic architecture of these subtypes is not well understood. We tested for subtype-specific genetic associations in 44 bilateral CL (BCL) cases, 434 unilateral CL (UCL) cases, 530 bilateral CLP cases (BCLP), 1123 unilateral CLP (UCLP) cases, and unrelated controls (N = 1626), using a mixed-model approach.

The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation.

Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls.

Insights into the genetic architecture of the human face.

The human face is complex and multipartite, and characterization of its genetic architecture remains challenging. Using a multivariate genome-wide association study meta-analysis of 8,246 European individuals, we identified 203 genome-wide-significant signals (120 also study-wide significant) associated with normal-range facial variation. Follow-up analyses indicate that the regions surrounding these signals are enriched for enhancer activity in cranial neural crest cells and craniofacial tissues, several regions harbor multiple signals with associations to different facial phenotypes, and there is evidence for potential coordinated actions of variants.

Robust genome-wide ancestry inference for heterogeneous datasets: illustrated using the 1,000 genome project with 3D facial images.

Estimates of individual-level genomic ancestry are routinely used in human genetics, and related fields. The analysis of population structure and genomic ancestry can yield insights in terms of modern and ancient populations, allowing us to address questions regarding admixture, and the numbers and identities of the parental source populations. Unrecognized population structure is also an important confounder to correct for in genome-wide association studies.

Sources of variation in the 3dMDface and Vectra H1 3D facial imaging systems.

As technology advances and collaborations grow, our ability to finely quantify and explore morphological variation in 3D structures can enable important discoveries and insights into clinical, evolutionary, and genetic questions. However, it is critical to explore and understand the relative contribution of potential sources of error to the structures under study. In this study, we isolated the level of error in 3D facial images attributable to four sources, using the 3dMDface and Vectra H1 camera systems.

Spatially Dense 3D Facial Heritability and Modules of Co-heritability in a Father-Offspring Design.

The human face is a complex trait displaying a strong genetic component as illustrated by various studies on facial heritability. Most of these start from sparse descriptions of facial shape using a limited set of landmarks. Subsequently, facial features are preselected as univariate measurements or principal components and the heritability is estimated for each of these features separately.

Six NSCL/P Loci Show Associations With Normal-Range Craniofacial Variation.

Orofacial clefting is one of the most prevalent craniofacial malformations. Previous research has demonstrated that unaffected relatives of patients with non-syndromic cleft lip with/without cleft palate (NSCL/P) show distinctive facial features, which can be an expression of underlying NSCL/P susceptibility genes. These results support the hypothesis that genes involved in the occurrence of a cleft also play a role in normal craniofacial development.

SNPs Associated With Testosterone Levels Influence Human Facial Morphology.

Many factors influence human facial morphology, including genetics, age, nutrition, biomechanical forces, and endocrine factors. Moreover, facial features clearly differ between males and females, and these differences are driven primarily by the influence of sex hormones during growth and development. Specific genetic variants are known to influence circulating sex hormone levels in humans, which we hypothesize, in turn, affect facial features.

Testing the face shape hypothesis in twins discordant for nonsyndromic orofacial clefting.

Nonsyndromic orofacial clefts (OFCs) are complex traits characterized by multifactorial inheritance and wide phenotypic variability. Numerous studies have shown subtle differences in the faces of unaffected relatives from cleft families compared to controls, the implication being that such outward differences are an incomplete expression reflecting an underlying genetic predisposition. Twins discordant for OFCs provide a unique opportunity to further test this idea, as the unaffected co-twin shares on average 50% (for dizygotic twins) and 100% (for monozygotic twins) of the genetic risk factors as the affected twin.