Impact of low-frequency coding variants on human facial shape.

The contribution of low-frequency variants to the genetic architecture of normal-range facial traits is unknown. We studied the influence of low-frequency coding variants (MAF < 1%) in 8091 genes on multi-dimensional facial shape phenotypes in a European cohort of 2329 healthy individuals. Using three-dimensional images, we partitioned the full face into 31 hierarchically arranged segments to model facial morphology at multiple levels, and generated multi-dimensional phenotypes representing the shape variation within each segment.

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.

Mutant COMP shapes growth and development of skull and facial structures in mice and humans.

Background: Cartilage oligomeric matrix protein (COMP) is an important extracellular matrix protein primarily functioning in the musculoskeletal tissues and especially endochondral bone growth. Mutations in COMP cause the skeletal dysplasia pseudoachondroplasia (PSACH) that is characterized by short limbs and fingers, joint laxity, and abnormalities but a striking lack of skull and facial abnormalities.

Methods: This study examined both mice and humans to determine how mutant-COMP affects face and skull growth.

Hunting for genes that shape human faces: Initial successes and challenges for the future.

There is ample evidence from heritability studies, genetic syndromes and experimental animal models that facial morphology is strongly influenced by genes. In this brief review, we present an up-to-date overview of the efforts to identify genes associated with the size and shape of human facial features. We discuss recent methodological advances that have led to breakthroughs, but also the multitude of challenges facing the field.

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.

Olfactory function in patients with nonsyndromic orofacial clefts and their unaffected relatives.

Nonsyndromic orofacial clefting is one of the most frequently occurring congenital conditions. The aim of the study was to investigate the prevalence and nature of reduced olfactory function in patients with nonsyndromic cleft lip and/or cleft palate (NSCL/P) and their unaffected first-degree relatives. Olfactory function was tested using the Sniffin' Sticks identification test in patients with NSCL/P, in their unaffected relatives, and in control subjects.

GWAS reveals loci associated with velopharyngeal dysfunction.

Velopharyngeal dysfunction (VPD) occurs when the muscular soft palate (velum) and lateral pharyngeal walls are physically unable to separate the oral and nasal cavities during speech production leading to hypernasality and abnormal speech reduction. Because VPD is often associated with overt or submucous cleft palate, it could be present as a subclinical phenotype in families with a history of orofacial clefting. A key assumption to this model is that the overt and subclinical manifestations of the orofacial cleft phenotype exist on a continuum and therefore share common etiological factors.

Mapping genetic variants for cranial vault shape in humans.

The shape of the cranial vault, a region comprising interlocking flat bones surrounding the cerebral cortex, varies considerably in humans. Strongly influenced by brain size and shape, cranial vault morphology has both clinical and evolutionary relevance. However, little is known about the genetic basis of normal vault shape in humans.

Soft tissue nasal asymmetry as an indicator of orofacial cleft predisposition.

The biological relatives of offspring with nonsyndromic orofacial clefts have been shown to exhibit distinctive facial features, including excess asymmetry, which are hypothesized to indicate the presence of genetic risk factors. The significance of excess soft tissue nasal asymmetry in at-risk relatives is unclear and was examined in the present study. Our sample included 164 unaffected parents from families with a history of orofacial clefting and 243 adult controls.

Genome-wide mapping of global-to-local genetic effects on human facial shape.

Genome-wide association scans of complex multipartite traits like the human face typically use preselected phenotypic measures. Here we report a data-driven approach to phenotyping facial shape at multiple levels of organization, allowing for an open-ended description of facial variation while preserving statistical power. In a sample of 2,329 persons of European ancestry, we identified 38 loci, 15 of which replicated in an independent European sample (n = 1,719).

Multiethnic GWAS Reveals Polygenic Architecture of Earlobe Attachment.

The genetic basis of earlobe attachment has been a matter of debate since the early 20 century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported).

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.

Exploring the Underlying Genetics of Craniofacial Morphology through Various Sources of Knowledge.

The craniofacial complex is the billboard of sorts containing information about sex, health, ancestry, kinship, genes, and environment. A thorough knowledge of the genes underlying craniofacial morphology is fundamental to understanding craniofacial biology and evolution. These genes can also provide an important foundation for practical efforts like predicting faces from DNA and phenotype-based facial diagnostics.

Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.

Purpose: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.

Methods: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls.

AGORA, a data- and biobank for birth defects and childhood cancer.

Background: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection.

Secondary cleft rhinoplasty: impact on self-esteem and quality of life.

Background: Rhinoplasty is one of the most challenging facial plastic procedures. Although patient satisfaction is the real outcome parameter in rhinoplasty, most authors have studied objective outcomes evaluated by professionals. The purpose of this study was to determine patient satisfaction after rhinoplasty in patients born with a cleft lip compared with outcome assessment by professionals, and to assess the impact of the procedure on appearance-related distress and generic quality of life.