Browsing by Author "Shriver, Mark"

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    Advancing Genotype-Phenotype Analysis through 3D Facial Morphometry: Insights from Cri-du-Chat Syndrome
    (medRxiv, 2025-06-01) Vanneste, Michiel; Matthews, Harold; Sleyp, Yoeri; Hammond, Peter; Shriver, Mark; Weinberg, Seth M.; Marazita, Mary L.; Walsh, Susan; Hallgrímsson, Benedikt; Klein, Ophir D.; Spritz, Richard A.; Van Den Bogaert, Kris; Claes, Peter; Peeters, Hilde; Biology, School of Science
    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 3D morphometric approaches to overcome these limitations, utilizing Cri-du-Chat syndrome (CdCS) as a model. Methods: We analyzed 3D facial photos from 24 individuals with CdCS, 4540 unaffected controls and 5 individuals 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.
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    Large-scale open-source three-dimensional growth curves for clinical facial assessment and objective description of facial dysmorphism
    (Springer Nature, 2021-06-09) Matthews, Harold S.; Palmer, Richard L.; Baynam, Gareth S.; Quarrell, Oliver W.; Klein, Ophir D.; Spritz, Richard A.; Hennekam, Raoul C.; Walsh, Susan; Shriver, Mark; Weinberg, Seth M.; Hallgrimsson, Benedikt; Hammond, Peter; Penington, Anthony J.; Peeters, Hilde; Claes, Peter D.; Biology, School of Science
    Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype–phenotype relations.
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    Syndrome-informed phenotyping identifies a polygenic background for achondroplasia-like facial variation in the general population
    (Springer Nature, 2024-12-02) Vanneste, Michiel; Hoskens, Hanne; Goovaerts, Seppe; Matthews, Harold; Devine, Jay; Aponte, Jose D.; Cole, Joanne; Shriver, Mark; Marazita, Mary L.; Weinberg, Seth M.; Walsh, Susan; Richmond, Stephen; Klein, Ophir D.; Spritz, Richard A.; Peeters, Hilde; Hallgrímsson, Benedikt; Claes, Peter; Biology, School of Science
    Human craniofacial shape is highly variable yet highly heritable with numerous genetic variants interacting through multiple layers of development. Here, we hypothesize that Mendelian phenotypes represent the extremes of a phenotypic spectrum and, using achondroplasia as an example, we introduce a syndrome-informed phenotyping approach to identify genomic loci associated with achondroplasia-like facial variation in the general population. We compare three-dimensional facial scans from 43 individuals with achondroplasia and 8246 controls to calculate achondroplasia-like facial scores. Multivariate GWAS of the control scores reveals a polygenic basis for facial variation along an achondroplasia-specific shape axis, identifying genes primarily involved in skeletal development. Jointly modeling these genes in two independent control samples, both human and mouse, shows craniofacial effects approximating the characteristic achondroplasia phenotype. These findings suggest that both complex and Mendelian genetic variation act on the same developmentally determined axes of facial variation, providing insights into the genetic intersection of complex traits and Mendelian disorders.