Abstract
SUMMARYA copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood. To determine the influence of 16p11.2 genes on development, we investigated the effects of CNV on craniofacial structure in humans and model organisms. We show that deletion and duplication of 16p11.2 have “mirror” effects on specific craniofacial features that are conserved between human and rodent models of the CNV. By testing dosage effects of individual genes on the shape of the mandible in zebrafish, we identify seven genes with significant effects individually and find evidence for others when genes were tested in combination. The craniofacial phenotypes of 16p11.2 CNVs represent a model for studying the effects of genes on development, and our results suggest that the associated facial gestalts are attributable to the combined effects of multiple genes.
Highlights
Recent technological advances in genomics have facilitated the discovery of scores of new genetic disorders that have a complex and variable clinical presentation (Malhotra and Sebat, 2012)
Reciprocal Deletion and Duplication of 16p11.2 Have Mirror Effects on Craniofacial Structure 3D morphometric facial imaging was performed on subjects with 16p11.2 duplications or deletions and controls recruited to the Simons VIP study (Simons VIP Consortium, 2012; see STAR Methods)
Differences in deletion and duplication groups relative to controls were detected by linear regression, and covariates were included in the model to control for known factors that influence dimensions of head and face in this genetic disorder, including age, head circumference, BMI, sex, and ancestry principal components obtained from genetic data, with a random intercept allowed to account for within-family correlation
Summary
Recent technological advances in genomics have facilitated the discovery of scores of new genetic disorders that have a complex and variable clinical presentation (Malhotra and Sebat, 2012). Unlike Down syndrome (Roizen and Patterson, 2003) and Williams syndrome (Ewart et al, 1993), which have a distinguishable constellation of clinical features and facial gestalts, these new genetic disorders are notable for their lack of a clear pattern of congenital anomalies or dysmorphic features (Nevado et al, 2014). Deletion (Miller et al, 1993) and duplication (D’Angelo et al, 2016) of 30 genes are associated with variable degrees of cognitive impairment, epilepsy, and psychiatric disorders, including autism spectrum disorder and schizophrenia. The influence of CNV on psychiatric and morphometric traits alike is complex, and the underlying genetic mechanisms are not understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
