Benedikt Hallgrimsson

RESEARCH, TEACHING, or OTHER INTERESTS

Animal Science and Zoology, Genetics, Developmental Biology, Ecology, Evolution, Behavior and Systematics

Scopus Publications

A 3D Clinical Face Phenotype Space of Genetic Syndromes Using a Triplet-Based Singular Geometric Autoencoder
Soha S. Mahdi, Eduarda Caldeira, Harold Matthews, Michiel Vanneste, Nele Nauwelaers, Meng Yuan, Giorgos Bouritsas, Gareth S. Baynam, Peter Hammond, Richard Spritz,et al.
Institute of Electrical and Electronics Engineers (IEEE)
Clinical diagnosis of syndromes benefits strongly from objective facial phenotyping. This study introduces a novel approach to enhance clinical diagnosis through the development and exploration of a low-dimensional metric space referred to as the clinical face phenotypic space (CFPS). As a facial matching tool for clinical genetics, such CFPS can enhance clinical diagnosis. It helps to interpret facial dysmorphisms of a subject by placing them within the space of known dysmorphisms. In this paper, a triplet loss-based autoencoder developed by geometric deep learning (GDL) is trained using multi-task learning, which combines supervised and unsupervised learning approaches. Experiments are designed to illustrate the following properties of CFPSs that can aid clinicians in narrowing down their search space: a CFPS can 1) classify syndromes accurately, 2) generalize to novel syndromes, and 3) preserve the relatedness of genetic diseases, meaning that clusters of phenotypically similar disorders reflect functional relationships between genes. The proposed model consists of three main components: an encoder based on GDL optimizing distances between groups of individuals in the CFPS, a decoder enhancing classification by reconstructing faces, and a singular value decomposition layer maintaining orthogonality and optimal variance distribution across dimensions. This allows for the selection of an optimal number of CFPS dimensions as well as improving the classification capacity of the CFPS.


Quantitative analysis of facial shape in children to support respirator design
Christopher Nemeth, Hanne Hoskens, Graham Wilson, Mike Jones, Josef DiPietrantonio, Bukola Salami, Del Harnish, Peter Claes, Seth M. Weinberg, Mark D. Shriver,et al.
Elsevier BV



Mapping genes for human face shape: Exploration of univariate phenotyping strategies
Meng Yuan, Seppe Goovaerts, Michiel Vanneste, Harold Matthews, Hanne Hoskens, Stephen Richmond, Ophir D. Klein, Richard A. Spritz, Benedikt Hallgrimsson, Susan Walsh,et al.
Public Library of Science (PLoS)
Human facial shape, while strongly heritable, involves both genetic and structural complexity, necessitating precise phenotyping for accurate assessment. Common phenotyping strategies include simplifying 3D facial features into univariate traits such as anthropometric measurements (e.g., inter-landmark distances), unsupervised dimensionality reductions (e.g., principal component analysis (PCA) and auto-encoder (AE) approaches), and assessing resemblance to particular facial gestalts (e.g., syndromic facial archetypes). This study provides a comparative assessment of these strategies in genome-wide association studies (GWASs) of 3D facial shape. Specifically, we investigated inter-landmark distances, PCA and AE-derived latent dimensions, and facial resemblance to random, extreme, and syndromic gestalts within a GWAS of 8,426 individuals of recent European ancestry. Inter-landmark distances exhibit the highest SNP-based heritability as estimated via LD score regression, followed by AE dimensions. Conversely, resemblance scores to extreme and syndromic facial gestalts display the lowest heritability, in line with expectations. Notably, the aggregation of multiple GWASs on facial resemblance to random gestalts reveals the highest number of independent genetic loci. This novel, easy-to-implement phenotyping approach holds significant promise for capturing genetically relevant morphological traits derived from complex biomedical imaging datasets, and its applications extend beyond faces. Nevertheless, these different phenotyping strategies capture different genetic influences on craniofacial shape. Thus, it remains valuable to explore these strategies individually and in combination to gain a more comprehensive understanding of the genetic factors underlying craniofacial shape and related traits.


Syndrome-informed phenotyping identifies a polygenic background for achondroplasia-like facial variation in the general population
Michiel Vanneste, Hanne Hoskens, Seppe Goovaerts, Harold Matthews, Jay Devine, Jose D. Aponte, Joanne Cole, Mark Shriver, Mary L. Marazita, Seth M. Weinberg,et al.
Springer Science and Business Media LLC



Genetic architecture of trait variance in craniofacial morphology
Fernando Andrade, Lisa Howell, Christopher J Percival, Joan T Richtsmeier, Ralph S Marcucio, Benedikt Hallgrímsson, and James M Cheverud
Oxford University Press (OUP)
Abstract The genetic architecture of trait variance has long been of interest in genetics and evolution. One of the earliest attempts to understand this architecture was presented in Lerner's Genetic Homeostasis (1954). Lerner proposed that heterozygotes should be better able to tolerate environmental perturbations because of functional differences between the alleles at a given locus, with each allele optimal for slightly different environments. This greater robustness to environmental variance, he argued, would result in smaller trait variance for heterozygotes. The evidence for Lerner's hypothesis has been inconclusive. To address this question using modern genomic methods, we mapped loci associated with differences in trait variance (vQTL) on 1,101 individuals from the F34 of an advanced intercross between LG/J and SM/J mice. We also mapped epistatic interactions for these vQTL in order to understand the influence of epistasis for the architecture of trait variance. We did not find evidence supporting Lerner's hypothesis, that heterozygotes tend to have smaller trait variances than homozygotes. We further show that the effects of most mapped loci on trait variance are produced by epistasis affecting trait means and that those epistatic effects account for about a half of the differences in genotypic-specific trait variances. Finally, we propose a model where the different interactions between the additive and dominance effects of the vQTL and their epistatic partners can explain Lerner's original observations but can also be extended to include other conditions where heterozygotes are not the least variable genotype.


An interactive atlas of three-dimensional syndromic facial morphology
J. David Aponte, Jordan J. Bannister, Hanne Hoskens, Harold Matthews, Kaitlin Katsura, Cassidy Da Silva, Tim Cruz, Julie H.M. Pilz, Richard A. Spritz, Nils D. Forkert,et al.
Elsevier BV



Dosage-dependent effects of FGFR2^W290R mutation on craniofacial shape and cellular dynamics of the basicranial synchondroses
Heather A. Richbourg, Marta Vidal‐García, Katherine A. Brakora, Jay Devine, Risa Takenaka, Nathan M. Young, Siew‐Ging Gong, Amanda Neves, Benedikt Hallgrímsson, and Ralph S. Marcucio
Wiley
AbstractCraniosynostosis is a common yet complex birth defect, characterized by premature fusion of the cranial sutures that can be syndromic or nonsyndromic. With over 180 syndromic associations, reaching genetic diagnoses and understanding variations in underlying cellular mechanisms remains a challenge. Variants of FGFR2 are highly associated with craniosynostosis and warrant further investigation. Using the missense mutation FGFR2W290R, an effective mouse model of Crouzon syndrome, craniofacial features were analyzed using geometric morphometrics across developmental time (E10.5—adulthood, n = 665 total). Given the interrelationship between the cranial vault and basicranium in craniosynostosis patients, the basicranium and synchondroses were analyzed in perinates. Embryonic time points showed minimal significant shape differences. However, hetero‐ and homozygous mutant perinates and adults showed significant differences in shape and size of the cranial vault, face, and basicranium, which were associated with cranial doming and shortening of the basicranium and skull. Although there were also significant shape and size differences associated with the basicranial bones and clear reductions in basicranial ossification in cleared whole‐mount samples, there were no significant alterations in chondrocyte cell shape, size, or orientation along the spheno‐occipital synchondrosis. Finally, shape differences in the cranial vault and basicranium were interrelated at perinatal stages. These results point toward the possibility that facial shape phenotypes in craniosynostosis may result in part from pleiotropic effects of the causative mutations rather than only from the secondary consequences of the sutural defects, indicating a novel direction of research that may shed light on the etiology of the broad changes in craniofacial morphology observed in craniosynostosis syndromes.


Response to Jacobs and Flaherty re: ‘‘Sex Differences in Adult Facial Three-Dimensional Morphology: Application to Gender-Affirming Facial Surgery’’
Rahul Seth, Jordan J. Bannister, David C. Katz, P. Daniel Knott, Nils D. Forkert, and Benedikt Hallgrimsson
Mary Ann Liebert Inc



Rapid and biased evolution of canalization during adaptive divergence revealed by dominance in gene expression variability during Arctic charr early development
Quentin Jean-Baptiste Horta-Lacueva, Zophonías Oddur Jónsson, Dagny A. V. Thorholludottir, Benedikt Hallgrímsson, and Kalina Hristova Kapralova
Springer Science and Business Media LLC
AbstractAdaptive evolution may be influenced by canalization, the buffering of developmental processes from environmental and genetic perturbations, but how this occurs is poorly understood. Here, we explore how gene expression variability evolves in diverging and hybridizing populations, by focusing on the Arctic charr (Salvelinus alpinus) of Thingvallavatn, a classic case of divergence between feeding habitats. We report distinct profiles of gene expression variance for both coding RNAs and microRNAs between the offspring of two contrasting morphs (benthic/limnetic) and their hybrids reared in common conditions and sampled at two key points of cranial development. Gene expression variance in the hybrids is substantially affected by maternal effects, and many genes show biased expression variance toward the limnetic morph. This suggests that canalization, as inferred by gene expression variance, can rapidly diverge in sympatry through multiple gene pathways, which are associated with dominance patterns possibly biasing evolutionary trajectories and mitigating the effects of hybridization on adaptive evolution.


Author Correction: MusMorph, a database of standardized mouse morphology data for morphometric meta-analyses (Scientific Data, (2022), 9, 1, (230), 10.1038/s41597-022-01338-x)
Jay Devine, Marta Vidal-García, Wei Liu, Amanda Neves, Lucas D. Lo Vercio, Rebecca M. Green, Heather A. Richbourg, Marta Marchini, Colton M. Unger, Audrey C. Nickle,et al.
Springer Science and Business Media LLC



Defects in placental syncytiotrophoblast cells are a common cause of developmental heart disease
Bethany N. Radford, Xiang Zhao, Tali Glazer, Malcolm Eaton, Danielle Blackwell, Shuhiba Mohammad, Lucas Daniel Lo Vercio, Jay Devine, Tali Shalom-Barak, Benedikt Hallgrimsson,et al.
Springer Science and Business Media LLC
AbstractPlacental abnormalities have been sporadically implicated as a source of developmental heart defects. Yet it remains unknown how often the placenta is at the root of congenital heart defects (CHDs), and what the cellular mechanisms are that underpin this connection. Here, we selected three mouse mutant lines, Atp11a, Smg9 and Ssr2, that presented with placental and heart defects in a recent phenotyping screen, resulting in embryonic lethality. To dissect phenotype causality, we generated embryo- and trophoblast-specific conditional knockouts for each of these lines. This was facilitated by the establishment of a new transgenic mouse, Sox2-Flp, that enables the efficient generation of trophoblast-specific conditional knockouts. We demonstrate a strictly trophoblast-driven cause of the CHD and embryonic lethality in one of the three lines (Atp11a) and a significant contribution of the placenta to the embryonic phenotypes in another line (Smg9). Importantly, our data reveal defects in the maternal blood-facing syncytiotrophoblast layer as a shared pathology in placentally induced CHD models. This study highlights the placenta as a significant source of developmental heart disorders, insights that will transform our understanding of the vast number of unexplained congenital heart defects.


Comparing 2D and 3D representations for face-based genetic syndrome diagnosis
Jordan J. Bannister, Matthias Wilms, J. David Aponte, David C. Katz, Ophir D. Klein, Francois P. Bernier, Richard A. Spritz, Benedikt Hallgrímsson, and Nils D. Forkert
Springer Science and Business Media LLC



Privacy, bias and the clinical use of facial recognition technology: A survey of genetics professionals
Elias Aboujaoude, Janice Light, Julia E. H. Brown, W. John Boscardin, Benedikt Hallgrímsson, and Ophir D. Klein
Wiley
AbstractFacial recognition technology (FRT) has been adopted as a precision medicine tool. The medical genetics field highlights both the clinical potential and privacy risks of this technology, putting the discipline at the forefront of a new digital privacy debate. Investigating how geneticists perceive the privacy concerns surrounding FRT can help shape the evolution and regulation of the field, and provide lessons for medicine and research more broadly. Five hundred and sixty‐two genetics clinicians and researchers were approached to fill out a survey, 105 responded, and 80% of these completed. The survey consisted of 48 questions covering demographics, relationship to new technologies, views on privacy, views on FRT, and views on regulation. Genetics professionals generally placed a high value on privacy, although specific views differed, were context‐specific, and covaried with demographic factors. Most respondents (88%) agreed that privacy is a basic human right, but only 37% placed greater weight on it than other values such as freedom of speech. Most respondents (80%) supported FRT use in genetics, but not necessarily for broader clinical use. A sizeable percentage (39%) were unaware of FRT's lower accuracy rates in marginalized communities and of the mental health effects of privacy violations (62%), but most (76% and 75%, respectively) expressed concern when informed. Overall, women and those who self‐identified as politically progressive were more concerned about the lower accuracy rates in marginalized groups (88% vs. 64% and 83% vs. 63%, respectively). Younger geneticists were more wary than older geneticists about using FRT in genetics (28% compared to 56% “strongly” supported such use). There was an overall preference for more regulation, but respondents had low confidence in governments' or technology companies' ability to accomplish this. Privacy views are nuanced and context‐dependent. Support for privacy was high but not absolute, and clear deficits existed in awareness of crucial FRT‐related discrimination potential and mental health impacts. Education and professional guidelines may help to evolve views and practices within the field.


Precise modulation of transcription factor levels identifies features underlying dosage sensitivity
Sahin Naqvi, Seungsoo Kim, Hanne Hoskens, Harold S. Matthews, Richard A. Spritz, Ophir D. Klein, Benedikt Hallgrímsson, Tomek Swigut, Peter Claes, Jonathan K. Pritchard,et al.
Springer Science and Business Media LLC
AbstractTranscriptional regulation exhibits extensive robustness, but human genetics indicates sensitivity to transcription factor (TF) dosage. Reconciling such observations requires quantitative studies of TF dosage effects at trait-relevant ranges, largely lacking so far. TFs play central roles in both normal-range and disease-associated variation in craniofacial morphology; we therefore developed an approach to precisely modulate TF levels in human facial progenitor cells and applied it to SOX9, a TF associated with craniofacial variation and disease (Pierre Robin sequence (PRS)). Most SOX9-dependent regulatory elements (REs) are buffered against small decreases in SOX9 dosage, but REs directly and primarily regulated by SOX9 show heightened sensitivity to SOX9 dosage; these RE responses partially predict gene expression responses. Sensitive REs and genes preferentially affect functional chondrogenesis and PRS-like craniofacial shape variation. We propose that such REs and genes underlie the sensitivity of specific phenotypes to TF dosage, while buffering of other genes leads to robust, nonlinear dosage-to-phenotype relationships.


Refining nosology by modelling variation among facial phenotypes: the RASopathies
Harold Matthews, Michiel Vanneste, Kaitlin Katsura, David Aponte, Michael Patton, Peter Hammond, Gareth Baynam, Richard Spritz, Ophir D Klein, Benedikt Hallgrimsson,et al.
BMJ
BackgroundIn clinical genetics, establishing an accurate nosology requires analysis of variations in both aetiology and the resulting phenotypes. At the phenotypic level, recognising typical facial gestalts has long supported clinical and molecular diagnosis; however, the objective analysis of facial phenotypic variation remains underdeveloped. In this work, we propose exploratory strategies for assessing facial phenotypic variation within and among clinical and molecular disease entities and deploy these techniques on cross-sectional samples of four RASopathies: Costello syndrome (CS), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC) and neurofibromatosis type 1 (NF1).MethodsFrom three-dimensional dense surface scans, we model the typical phenotypes of the four RASopathies as average ‘facial signatures’ and assess individual variation in terms of direction (what parts of the face are affected and in what ways) and severity of the facial effects. We also derive a metric of phenotypic agreement between the syndromes and a metric of differences in severity along similar phenotypes.ResultsCFC shows a relatively consistent facial phenotype in terms of both direction and severity that is similar to CS and NS, consistent with the known difficulty in discriminating CFC from NS based on the face. CS shows a consistent directional phenotype that varies in severity. Although NF1 is highly variable, on average, it shows a similar phenotype to CS.ConclusionsWe established an approach that can be used in the future to quantify variations in facial phenotypes between and within clinical and molecular diagnoses to objectively define and support clinical nosologies.


Micro-CT Imaging and Morphometric Analysis of Mouse Neonatal Brains
Jimena Barbeito-Andrés, Laura Andrini, Mariana Vallejo-Azar, Sara Seguel, Jay Devine, Benedikt Hallgrímsson, and Paula Gonzalez
MyJove Corporation
Neuroimages are a valuable tool for studying brain morphology in experiments using animal models. Magnetic resonance imaging (MRI) has become the standard method for soft tissues, although its low spatial resolution poses some limits for small animals. Here, we describe a protocol for obtaining high-resolution three-dimensional (3D) information on mouse neonate brains and skulls using micro-computed tomography (micro-CT). The protocol includes those steps needed to dissect the samples, stain and scan the brain, and obtain morphometric measurements of the whole organ and regions of interest (ROIs). Image analysis includes the segmentation of structures and the digitization of point coordinates. In sum, this work shows that the combination of micro-CT and Lugol's solution as a contrast agent is a suitable alternative for imaging the perinatal brains of small animals. This imaging workflow has applications in developmental biology, biomedicine, and other sciences interested in assessing the effect of diverse genetic and environmental factors on brain development.


Bite Force Performance from wild Derived mice has Undetectable Heritability Despite Having Heritable Morphological Components
Samuel Ginot, Benedikt Hallgrímsson, Sylvie Agret, and Julien Claude
Springer Science and Business Media LLC
AbstractFitness-related traits tend to have low heritabilities. Conversely, morphology tends to be highly heritable. Yet, many fitness-related performance traits such as running speed or bite force depend critically on morphology. Craniofacial morphology correlates with bite performance in several groups including rodents. However, within species, this relationship is less clear, and the genetics of performance, morphology and function are rarely analyzed in combination. Here, we use a half-sib design in outbred wild-derivedMus musculusto study the morphology-bite force relationship and determine whether there is additive genetic (co-)variance for these traits. Results suggest that bite force has undetectable additive genetic variance and heritability in this sample, while morphological traits related mechanically to bite force exhibit varying levels of heritability. The most heritable traits include the length of the mandible which relates to bite force. Despite its correlation with morphology, realized bite force was not heritable, which suggests it is less responsive to selection in comparison to its morphological determinants. We explain this paradox with a non-additive, many-to-one mapping hypothesis of heritable change in complex traits. We furthermore propose that performance traits could evolve if pleiotropic relationships among the determining traits are modified.


Detecting 3D syndromic faces as outliers using unsupervised normalizing flow models
Jordan J. Bannister, Matthias Wilms, J. David Aponte, David C. Katz, Ophir D. Klein, Francois P.J. Bernier, Richard A. Spritz, Benedikt Hallgrímsson, and Nils D. Forkert
Elsevier BV



MusMorph, a database of standardized mouse morphology data for morphometric meta-analyses
Jay Devine, Marta Vidal-García, Wei Liu, Amanda Neves, Lucas D. Lo Vercio, Rebecca M. Green, Heather A. Richbourg, Marta Marchini, Colton M. Unger, Audrey C. Nickle,et al.
Springer Science and Business Media LLC
AbstractComplex morphological traits are the product of many genes with transient or lasting developmental effects that interact in anatomical context. Mouse models are a key resource for disentangling such effects, because they offer myriad tools for manipulating the genome in a controlled environment. Unfortunately, phenotypic data are often obtained using laboratory-specific protocols, resulting in self-contained datasets that are difficult to relate to one another for larger scale analyses. To enable meta-analyses of morphological variation, particularly in the craniofacial complex and brain, we created MusMorph, a database of standardized mouse morphology data spanning numerous genotypes and developmental stages, including E10.5, E11.5, E14.5, E15.5, E18.5, and adulthood. To standardize data collection, we implemented an atlas-based phenotyping pipeline that combines techniques from image registration, deep learning, and morphometrics. Alongside stage-specific atlases, we provide aligned micro-computed tomography images, dense anatomical landmarks, and segmentations (if available) for each specimen (N = 10,056). Our workflow is open-source to encourage transparency and reproducible data collection. The MusMorph data and scripts are available on FaceBase (www.facebase.org, https://doi.org/10.25550/3-HXMC) and GitHub (https://github.com/jaydevine/MusMorph).


Sex Differences in Adult Facial Three-Dimensional Morphology: Application to Gender-Affirming Facial Surgery
Jordan J. Bannister, Hailey Juszczak, Jose David Aponte, David C. Katz, P. Daniel Knott, Seth M. Weinberg, Benedikt Hallgrímsson, Nils D. Forkert, and Rahul Seth
Mary Ann Liebert Inc
Background: Gender-affirming facial surgery (GFS) is pursued by transgender individuals who desire facial features that better reflect their gender identity. Currently, there are a few objective guidelines to justify and facilitate effective surgical decision making. Objective: To quantify the effect of sex on adult facial size and shape through an analysis of three-dimensional (3D) facial surface images. Materials and Methods: Facial measurements were obtained by registering an atlas facial surface to 3D surface scans of 545 males and 1028 females older than 20 years of age. The differences between male and female faces were analyzed and visualized for a set of predefined surgically relevant facial regions. Results: On average, male faces are 7.3% larger than female faces (Cohen's D = 2.17). Sex is associated with significant facial shape differences (p < 0.0001) in the entire face as well as in each sub-region considered in this study. The facial regions in which sex has the largest effect on shape are the brow, jaw, nose, and cheek. Conclusions: These findings provide biologic data-driven anatomic guidance and justification for GFS, particularly forehead contouring cranioplasty, mandible and chin alterations, rhinoplasty, and cheek modifications.


Fgf8 dosage regulates jaw shape and symmetry through pharyngeal-cardiac tissue relationships
Nathaniel Zbasnik, Katie Dolan, Stephanie A. Buczkowski, Rebecca M. Green, Benedikt Hallgrímsson, Ralph S. Marcucio, Anne M. Moon, and Jennifer L. Fish
Wiley
AbstractBackgroundAsymmetries in craniofacial anomalies are commonly observed. In the facial skeleton, the left side is more commonly and/or severely affected than the right. Such asymmetries complicate treatment options. Mechanisms underlying variation in disease severity between individuals as well as within individuals (asymmetries) are still relatively unknown.ResultsDevelopmental reductions in fibroblast growth factor 8 (Fgf8) have a dosage dependent effect on jaw size, shape, and symmetry. Further, Fgf8 mutants have directionally asymmetric jaws with the left side being more affected than the right. Defects in lower jaw development begin with disruption to Meckel's cartilage, which is discontinuous. All skeletal elements associated with the proximal condensation are dysmorphic, exemplified by a malformed and misoriented malleus. At later stages, Fgf8 mutants exhibit syngnathia, which falls into two broad categories: bony fusion of the maxillary and mandibular alveolar ridges and zygomatico‐mandibular fusion. All of these morphological defects exhibit both inter‐ and intra‐specimen variation.ConclusionsWe hypothesize that these asymmetries are linked to heart development resulting in higher levels of Fgf8 on the right side of the face, which may buffer the right side to developmental perturbations. This mouse model may facilitate future investigations of mechanisms underlying human syngnathia and facial asymmetry.


The genetic basis of neurocranial size and shape across varied lab mouse populations
Christopher J. Percival, Jay Devine, Chaudhry Raza Hassan, Marta Vidal‐Garcia, Christopher J. O'Connor‐Coates, Eva Zaffarini, Charles Roseman, David Katz, and Benedikt Hallgrimsson
Wiley
AbstractBrain and skull tissues interact through molecular signalling and mechanical forces during head development, leading to a strong correlation between the neurocranium and the external brain surface. Therefore, when brain tissue is unavailable, neurocranial endocasts are often used to approximate brain size and shape. Evolutionary changes in brain morphology may have resulted in secondary changes to neurocranial morphology, but the developmental and genetic processes underlying this relationship are not well understood. Using automated phenotyping methods, we quantified the genetic basis of endocast variation across large genetically varied populations of laboratory mice in two ways: (1) to determine the contributions of various genetic factors to neurocranial form and (2) to help clarify whether a neurocranial variation is based on genetic variation that primarily impacts bone development or on genetic variation that primarily impacts brain development, leading to secondary changes in bone morphology. Our results indicate that endocast size is highly heritable and is primarily determined by additive genetic factors. In addition, a non‐additive inbreeding effect led to founder strains with lower neurocranial size, but relatively large brains compared to skull size; suggesting stronger canalization of brain size and/or a general allometric effect. Within an outbred sample of mice, we identified a locus on mouse chromosome 1 that is significantly associated with variation in several positively correlated endocast size measures. Because the protein‐coding genes at this locus have been previously associated with brain development and not with bone development, we propose that genetic variation at this locus leads primarily to variation in brain volume that secondarily leads to changes in neurocranial globularity. We identify a strain‐specific missense mutation within Akt3 that is a strong causal candidate for this genetic effect. Whilst it is not appropriate to generalize our hypothesis for this single locus to all other loci that also contribute to the complex trait of neurocranial skull morphology, our results further reveal the genetic basis of neurocranial variation and highlight the importance of the mechanical influence of brain growth in determining skull morphology.


HDAC9 structural variants disrupting TWIST1 transcriptional regulation lead to craniofacial and limb malformations
Naama Hirsch, Idit Dahan, Eva D'haene, Matan Avni, Sarah Vergult, Marta Vidal-García, Pamela Magini, Claudio Graziano, Giulia Severi, Elena Bonora,et al.
Cold Spring Harbor Laboratory
Structural variants (SVs) can affect protein-coding sequences as well as gene regulatory elements. However, SVs disrupting protein-coding sequences that also function ascis-regulatory elements remain largely uncharacterized. Here, we show that craniosynostosis patients with SVs containing the histone deacetylase 9(HDAC9) protein-coding sequence are associated with disruption ofTWIST1regulatory elements that reside within theHDAC9sequence. Based on SVs within theHDAC9‐TWIST1locus, we defined the 3′-HDAC9sequence as a criticalTWIST1regulatory region, encompassing craniofacialTWIST1enhancers and CTCF sites. Deletions of eitherTwist1enhancers (eTw5-7Δ/Δ) or CTCF site (CTCF-5Δ/Δ) within theHdac9protein-coding sequence led to decreasedTwist1expression and altered anterior/posterior limb expression patterns of SHH pathway genes. This decreasedTwist1expression results in a smaller sized and asymmetric skull and polydactyly that resemblesTwist1+/−mouse phenotype. Chromatin conformation analysis revealed that theTwist1promoter interacts withHdac9sequences that encompassTwist1enhancers and a CTCF site, and that interactions depended on the presence of both regulatory regions. Finally, a large inversion of the entireHdac9sequence (Hdac9INV/+) in mice that does not disruptHdac9expression but repositionsTwist1regulatory elements showed decreasedTwist1expression and led to a craniosynostosis-like phenotype and polydactyly. Thus, our study elucidates essential components ofTWIST1transcriptional machinery that reside within theHDAC9sequence. It suggests that SVs encompassing protein-coding sequences could lead to a phenotype that is not attributed to its protein function but rather to a disruption of the transcriptional regulation of a nearby gene.


A Deep Invertible 3-D Facial Shape Model for Interpretable Genetic Syndrome Diagnosis
Jordan J. Bannister, Matthias Wilms, J. David Aponte, David C. Katz, Ophir D. Klein, Francois P. J. Bernier, Richard A. Spritz, Benedikt Hallgrimsson, and Nils D. Forkert
Institute of Electrical and Electronics Engineers (IEEE)
One of the primary difficulties in treating patients with genetic syndromes is diagnosing their condition. Many syndromes are associated with characteristic facial features that can be imaged and utilized by computer-assisted diagnosis systems. In this work, we develop a novel 3D facial surface modeling approach with the objective of maximizing diagnostic model interpretability within a flexible deep learning framework. Therefore, an invertible normalizing flow architecture is introduced to enable both inferential and generative tasks in a unified and efficient manner. The proposed model can be used (1) to infer syndrome diagnosis and other demographic variables given a 3D facial surface scan and (2) to explain model inferences to non-technical users via multiple interpretability mechanisms. The model was trained and evaluated on more than 4700 facial surface scans from subjects with 47 different syndromes. For the challenging task of predicting syndrome diagnosis given a new 3D facial surface scan, age, and sex of a subject, the model achieves a competitive overall top-1 accuracy of 71%, and a mean sensitivity of 43% across all syndrome classes. We believe that invertible models such as the one presented in this work can achieve competitive inferential performance while greatly increasing model interpretability in the domain of medical diagnosis.


Morphological correspondence between brain and endocranial surfaces in mice exposed to undernutrition during development
Noelia Bonfili, Jimena Barbeito‐Andrés, Valeria Bernal, Benedikt Hallgrímsson, and Paula N. Gonzalez
Wiley
AbstractThe morphological changes of the brain and the skull are highly integrated as a result of shared developmental pathways and different types of interactions between them. Shared developmental trajectories between these two structures might be influenced by genetic and environmental factors. Although the effect of environmental factors on neural and craniofacial traits has been extensively studied, less is known about the specific impact of stressful conditions on the coordinated variation between these structures. Here, we test the effect of early nutrient restriction on morphological correspondence between the brain and the endocast. For this purpose, mice exposed to protein or calorie‐protein restriction during gestation and lactation were compared with a control group in which dams were fed standard food ad libitum. High‐resolution images were obtained after weaning to describe brain and endocranial morphology. By magnetic resonance imaging (MRI), brain volumes were obtained and endocasts were segmented from skull reconstructions derived from micro‐computed tomography (microCT). Brain and endocranial volumes were compared to assess the correspondence in size. Shape changes were analyzed using a set of landmarks and semilandmarks on 3D surfaces. Results indicated that brain volume is relatively less affected by undernutrition during development than endocast volume. Shape covariation between the brain and the endocast was found to be quite singular for protein‐restricted animals. Procrustes distances were larger between the brain and the endocast of the same specimens than between brains or endocasts of different animals, which means that the greatest similarity is by type of structure and suggests that the use of the endocast as a direct proxy of the brain at this intraspecific scale could have some limitations. In the same line, patterns of brain shape asymmetry were not directly estimated from endocranial surfaces. In sum, our findings indicate that morphological variation and association between the brain and the endocast is modulated by environmental factors and support the idea that head morphogenesis results from complex processes that are sensitive to the pervasive influence of nutrient intake.

RECENT SCHOLAR PUBLICATIONS

Quantifying the relationship between cell proliferation and morphology during development of the face
LD Lo Vercio, RM Green, A Dauter, EC Barretto, M Vidal-Garca, J Devine, ...
Development, dev. 204511 2025



P263: HNRNP-related neurodevelopmental disorders: Expanding knowledge of known conditions and prompting novel studies into candidate genes
M Gillentine, A Hansen, C Da Silva, L Phillips, SP Maricic, A Beaudet, ...
Genetics in Medicine Open 3 2025



Quantitative analysis of facial shape in children to support respirator design
C Nemeth, H Hoskens, G Wilson, M Jones, J DiPietrantonio, B Salami, ...
Applied Ergonomics 122, 104375 2025



A 3D clinical face phenotype space of genetic syndromes using a triplet-based singular geometric autoencoder
SS Mahdi, E Caldeira, H Matthews, M Vanneste, N Nauwelaers, M Yuan, ...
Ieee Access 2024



Mapping genes for human face shape: Exploration of univariate phenotyping strategies
M Yuan, S Goovaerts, M Vanneste, H Matthews, H Hoskens, S Richmond, ...
PLoS computational biology 20 (12), e1012617 2024



Syndrome-informed phenotyping identifies a polygenic background for achondroplasia-like facial variation in the general population
M Vanneste, H Hoskens, S Goovaerts, H Matthews, J Devine, JD Aponte, ...
Nature communications 15 (1), 1-13 2024



SA29 Pathways to Value and Impact for Child Health and Wellness
D Marshall, F MacKenzie, K Graham, K Bernie, S El-Hassar, ...
Value in Health 27 (12), S618-S619 2024



Genetic architecture of trait variance in craniofacial morphology
F Andrade, L Howell, CJ Percival, JT Richtsmeier, RS Marcucio, ...
Genetics 226 (4), iyae028 2024



Dosage‐dependent effects of FGFR2^W290R mutation on craniofacial shape and cellular dynamics of the basicranial synchondroses
HA Richbourg, M Vidal‐Garca, KA Brakora, J Devine, R Takenaka, ...
The Anatomical Record 2024



An interactive atlas of three-dimensional syndromic facial morphology
JD Aponte, JJ Bannister, H Hoskens, H Matthews, K Katsura, C Da Silva, ...
The American Journal of Human Genetics 111 (1), 39-47 2024



Downstream branches of receptor tyrosine kinase signaling act interdependently to shape the face
N Hanne, D Hu, M Vidal-Garca, C Allen, MB Shakir, W Liu, ...
bioRxiv, 2024.12. 10.627829 2024



Automated syndrome classification across ethnicities
H Hoskens, J Aponte, M Shriver, P Claes, B Hallgrimsson
European Journal Of Human Genetics 32, 665-665 2024



Multivariate GWAS on achondroplasia-like craniofacial shape variation in healthy human individuals
M Vanneste, H Hoskens, H Matthews, J Aponte, S Goovaerts, O Klein, ...
European Journal Of Human Genetics 32, 790-790 2024



Response to Jacobs and Flaherty re:“Sex Differences in Adult Facial Three-Dimensional Morphology: Application to Gender-Affirming Facial Surgery”
R Seth, JJ Bannister, DC Katz, PD Knott, ND Forkert, B Hallgrimsson
Facial Plastic Surgery & Aesthetic Medicine 25 (6), 456-456 2023



Comparing 2D and 3D representations for face-based genetic syndrome diagnosis
JJ Bannister, M Wilms, JD Aponte, DC Katz, OD Klein, FP Bernier, ...
European Journal of Human Genetics 31 (9), 1010-1016 2023



Privacy, bias and the clinical use of facial recognition technology: A survey of genetics professionals
E Aboujaoude, J Light, JEH Brown, WJ Boscardin, B Hallgrmsson, ...
American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2023



Rapid and biased evolution of canalization during adaptive divergence revealed by dominance in gene expression variability during Arctic charr early development
QJB Horta-Lacueva, ZO Jnsson, DAV Thorholludottir, B Hallgrmsson, ...
Communications Biology 6 (1), 897 2023



MusMorph, a database of standardized mouse morphology data for morphometric meta-analyses (vol 9, 230, 2022)
J Devine, M Vidal-Garcia, W Liu, A Neves, LD Lo Vercio, RM Green, ...
SCIENTIFIC DATA 10 (1) 2023



Assessing univariate facial phenotyping approaches in GWAS
M Yuan, S Goovaerts, M Vanneste, H Matthews, H Hoskens, OD Klein, ...
56th annual European Human Genetics Conference 2023, Date: 2023/06/10-2023 2023



Classifying high-dimensional phenotypes with ensemble learning
J Devine, HK Kurki, JR Epp, PN Gonzalez, P Claes, B Hallgrmsson
bioRxiv 2023

MOST CITED SCHOLAR PUBLICATIONS

The genome architecture of the Collaborative Cross mouse genetic reference population
CC Consortium
Genetics 190 (2), 389-401 2012
Citations: 478



Deciphering the palimpsest: studying the relationship between morphological integration and phenotypic covariation
B Hallgrmsson, H Jamniczky, NM Young, C Rolian, TE Parsons, ...
Evolutionary biology 36, 355-376 2009
Citations: 468



Canalization, developmental stability, and morphological integration in primate limbs
B Hallgrmsson, K Willmore, BK Hall
American Journal of Physical Anthropology: The Official Publication of the 2002
Citations: 455



Variation: a central concept in biology
B Hallgrmsson, BK Hall
Elsevier 2005
Citations: 397



Serial homology and the evolution of mammalian limb covariation structure
NM Young, B Hallgrmsson
Evolution 59 (12), 2691-2704 2005
Citations: 343



Evolvability as the proper focus of evolutionary developmental biology
JL Hendrikse, TE Parsons, B Hallgrmsson
Evolution & development 9 (4), 393-401 2007
Citations: 337



Multiple Organ System Defects and Transcriptional Dysregulation in the Nipbl^+/− Mouse, a Model of Cornelia de Lange Syndrome
S Kawauchi, AL Calof, R Santos, ME Lopez-Burks, CM Young, MP Hoang, ...
PLoS genetics 5 (9), e1000650 2009
Citations: 296



Development and the evolvability of human limbs
NM Young, GP Wagner, B Hallgrmsson
Proceedings of the National Academy of Sciences 107 (8), 3400–3405 2010
Citations: 291



Fine tuning of craniofacial morphology by distant-acting enhancers
C Attanasio, AS Nord, Y Zhu, MJ Blow, Z Li, DK Liberton, H Morrison, ...
Science 342 (6157), 1241006 2013
Citations: 288



Quantitative 3D analysis of the canal network in cortical bone by micro‐computed tomography
DML Cooper, AL Turinsky, CW Sensen, B Hallgrmsson
The Anatomical Record Part B: The New Anatomist: An Official Publication of 2003
Citations: 275



Anatomy and histology of the human urinary system
B Hallgrmsson, H Benediktsson, PD Vize
The Kidney, 149-164 2003
Citations: 272



Strickberger's evolution
B Hall, B Hallgrimsson
Jones & Bartlett Learning 2008
Citations: 271



Age-dependent change in the 3D structure of cortical porosity at the human femoral midshaft
DML Cooper, CDL Thomas, JG Clement, AL Turinsky, CW Sensen, ...
Bone 40 (4), 957-965 2007
Citations: 269



Epigenetic interactions and the structure of phenotypic variation in the cranium
B Hallgrmsson, DE Lieberman, W Liu, AF Ford‐Hutchinson, FR Jirik
Evolution & development 9 (1), 76-91 2007
Citations: 251



Stem cell–derived endochondral cartilage stimulates bone healing by tissue transformation
CS Bahney, DP Hu, AJ Taylor, F Ferro, HM Britz, B Hallgrimsson, ...
Journal of Bone and Mineral Research 29 (5), 1269-1282 2014
Citations: 231



Trabecular bone in the bird knee responds with high sensitivity to changes in load orientation
H Pontzer, DE Lieberman, E Momin, MJ Devlin, JD Polk, B Hallgrimsson, ...
Journal of Experimental Biology 209 (1), 57-65 2006
Citations: 218



Genome-wide association study reveals multiple loci influencing normal human facial morphology
JR Shaffer, E Orlova, MK Lee, EJ Leslie, ZD Raffensperger, CL Heike, ...
PLoS genetics 12 (8), e1006149 2016
Citations: 216



The lysyl oxidase inhibitor, β-aminopropionitrile, diminishes the metastatic colonization potential of circulating breast cancer cells
A Bondareva, CM Downey, F Ayres, W Liu, SK Boyd, B Hallgrimsson, ...
PloS one 4 (5), e5620 2009
Citations: 213



Genetics and evolution of functionvalued traits: understanding environmentally responsive phenotypes
MK Stinchcombe, J. J. Beder, P. A. Carter, G. W. Gilchrist, D. Gervini, R ...
Trends in Ecology and Evolution 27 (11), 637-647 2012
Citations: 206



Comparison of microcomputed tomographic and microradiographic measurements of cortical bone porosity
DML Cooper, JR Matyas, MA Katzenberg, B Hallgrimsson
Calcified tissue international 74 (5), 437-447 2004
Citations: 200