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The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17–0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation., Author summary The human face is a highly variable trait composed of distinct features, each influenced by genetic and environmental factors. The strong genetic component is primarily evidenced by the facial similarity between identical twins and the clear facial resemblances within families. Over the past decade, a powerful methodological toolbox of computational and statistical genetics has been developed to study the genetic architecture of complex traits. However, these methods typically require one-dimensional phenotypic measurements (e.g. width of the nose or spacing between the eyes) that fail to accurately describe 3D facial shape. In this paper, we learn from 3D facial data itself, a series of relevant traits that are guided by the facial similarity observed between sibling pairs. Importantly, while preserving the structural convolution of the face, these traits also fit the requirements as input to the well-established statistical tools. In doing so, we have identified many genetic loci that are associated with a wide range of facial features. Some of these regions contained genes related to embryonic facial development, and craniofacial malformations. An improved understanding of the genetic basis of facial shape can have several important applications, for example in developmental biology, medical genetics and forensic sciences.

Congenital or neonatal cardiomyopathies are commonly associated with a poor prognosis and have multiple etiologies. In two siblings, a male and female, we identified an undescribed type of lethal congenital restrictive cardiomyopathy affecting the right ventricle. We hypothesized a novel autosomal recessive condition. To identify the cause, we performed genetic, in vitro and in vivo studies. Genome-wide SNP typing and parametric linkage analysis was done in a recessive model to identify candidate regions. Exome sequencing analysis was done in unaffected and affected siblings. In the linkage regions, we selected candidate genes that harbor two rare variants with predicted functional effects in the patients and for which the unaffected sibling is either heterozygous or homozygous reference. We identified two compound heterozygous variants in KIF20A; a maternal missense variant (c.544C>T: p.R182W) and a paternal frameshift mutation (c.1905delT: p.S635Tfs*15). Functional studies confirmed that the R182W mutation creates an ATPase defective form of KIF20A which is not able to support efficient transport of Aurora B as part of the chromosomal passenger complex. Due to this, Aurora B remains trapped on chromatin in dividing cells and fails to translocate to the spindle midzone during cytokinesis. Translational blocking of KIF20A in a zebrafish model resulted in a cardiomyopathy phenotype. We identified a novel autosomal recessive congenital restrictive cardiomyopathy, caused by a near complete loss-of-function of KIF20A. This finding further illustrates the relationship of cytokinesis and congenital cardiomyopathy., Author summary Inborn heart defects can be divided into structural heart defects and diseases affecting the heart muscle, called cardiomyopathies. Congenital or neonatal cardiomyopathies are commonly associated with a poor prognosis and have multiple etiologies. In two siblings, a male and female, we identified an undescribed type of lethal congenital restrictive cardiomyopathy affecting the right ventricle. We hypothesized that this was most likely due to a novel autosomal recessive condition. To identify the cause, we used powerful genetic tools; linkage analysis combined to Whole Exome Sequencing (WES), which analyses the protein coding parts of the human genome. A compound heterozygous mutation was found in KIF20A, a gene which has never been associated with human pathology previously. Further functional studies confirmed that the found variants resulted in a loss-of-function of KIF20A. Studies in zebrafish as an animal model were consistent with a role of KIF20A in cardiac development and function. These findings provide a functional link between cytokinesis and cardiomyopathy, opening a new mechanism for future research in genes involved in cell division.