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1.  Large-scale objective phenotyping of 3D facial morphology 
Human Mutation  2012;33(5):817-825.
Abnormal phenotypes have played significant roles in the discovery of gene function, but organized collection of phenotype data has been overshadowed by developments in sequencing technology. In order to study phenotypes systematically, large-scale projects with standardized objective assessment across populations are considered necessary. The report of the 2006 Human Variome Project meeting recommended documentation of phenotypes through electronic means by collaborative groups of computational scientists and clinicians using standard, structured descriptions of disease-specific phenotypes. In this report, we describe progress over the past decade in 3D digital imaging and shape analysis of the face, and future prospects for large-scale facial phenotyping. Illustrative examples are given throughout using a collection of 1107 3D face images of healthy controls and individuals with a range of genetic conditions involving facial dysmorphism.
PMCID: PMC3327801  PMID: 22434506
3D imaging; facial phenotyping; morphometrics; dysmorphology
2.  Presence of epilepsy-associated variants in large exome databases 
Journal of neurogenetics  2013;27(0):1-4.
Mutations in more than twenty genes have been found to cause idiopathic epilepsies, and screening for these variants could facilitate the clinical diagnosis of epilepsy. However, many of the studies that reported putative pathogenic variants for epilepsy tested a relatively small number of control samples making it more likely that a rare non-pathogenic variant could be mistaken as causal. To test the robustness of inferences based on small sample sizes, we investigated whether variants previously reported to cause epilepsy were present in the resequencing data from the large control populations of the 1000 Genomes Project and the NHLBI Exome Sequencing Project. A list of variants associated with epilepsy was compiled using a manual review of the literature for genes associated with epilepsy from a recent International League Against Epilepsy (ILAE) report and two comprehensive genetic studies. We checked for the presence of those variants in the 1000 Genomes Project database and the NHLBI Exome Variant Server (EVS). Of 208 epilepsy-associated variants that we identified from our literature review, only seven were found among 17 thousand chromosomes across 1000 Genomes and the EVS. Consistent with recent published reports, we also found many variants with predicted pathogenicity in epilepsy associated genes in the genomic databases. Our findings suggest that the 1000 Genomes and the EVS datasets may be a valuable resource of control data in research aimed at identifying genes for epilepsy specifically when the model predicts a highly penetrant allele. These databases also elucidate the array of genetic variation in putative epilepsy genes in the general population.
PMCID: PMC3672316  PMID: 23527921
3.  Left ventricular hypertrabeculation/noncompaction with epilepsy, other heart defects, minor facial anomalies and new copy number variants 
BMC Medical Genetics  2012;13:60.
Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality of unknown etiology which has been described in children as well as in adults with and without chromosomal aberrations. LVHT has been reported in association with various cardiac and extracardiac abnormalities like epilepsy and facial dysmorphism.
Case presentation
A unique combination of LVHT, atrial septal defect, pulmonary valve stenosis, aortic stenosis, epilepsy and minor facial anomalies is presented in a 5.5 years old girl. Microarray-based genomic hybridization (array-CGH) detected six previously not described copy number variants (CNVs) inherited from a clinically unaffected father and minimally affected mother, thus, most likely, not clinically significant but rare benign variants.
Despite this complex phenotype de novo microdeletions or microduplications were not detected by array CGH. Further investigations, such as whole exome sequencing, could reveal point mutations and small indels as the possible cause.
PMCID: PMC3490829  PMID: 22830313
Cardiomyopathy; Congenital heart disease; Neurology; Pediatrics; Array CGH; Hypertrabeculation; Seizures
4.  Facial Dysmorphism Across the Fetal Alcohol Spectrum 
Pediatrics  2013;131(3):e779-e788.
Classic facial characteristics of fetal alcohol syndrome (FAS) are shortened palpebral fissures, smooth philtrum, and thin upper vermillion. We aim to help pediatricians detect facial dysmorphism across the fetal alcohol spectrum, especially among nonsyndromal heavily exposed (HE) individuals without classic facial characteristics.
Of 192 Cape Coloured children recruited, 69 were born to women who reported abstaining from alcohol during pregnancy. According to multifaceted criteria, the remainder were allocated clinically to the FAS (n = 22), partial FAS (n = 26) or nonsyndromal HE (n = 75) categories. We used dense surface modeling and signature analyses of 3-dimensional facial photographs to determine agreement between clinical categorization and classifications induced from face shape alone, to visualize facial differences, and to consider predictive links between face shape and neurobehavior.
Face classification achieved significant agreement with clinical categories for discrimination of nonexposed from FAS alone (face: 0.97–1.00; profile: 0.92) or with the addition of partial FAS (face: 0.90; profile: 0.92). Visualizations of face signatures delineated dysmorphism across the fetal alcohol spectrum and in half of the nonsyndromal HE category face signature graphs detected facial characteristics consistent with prenatal alcohol exposure. This subgroup performed less well on IQ and learning tests than did nonsyndromal subjects without classic facial characteristics.
Heat maps and morphing visualizations of face signatures may help clinicians detect facial dysmorphism across the fetal alcohol spectrum. Face signature graphs show potential for identifying nonsyndromal heavily exposed children who lack the classic facial phenotype but have cognitive impairment.
PMCID: PMC3581841  PMID: 23439907
facial dysmorphism; fetal alcohol spectrum disorders; fetal alcohol syndrome; dense surface modeling; signature graphs; prenatal alcohol exposure; alcohol-related neurodevelopmental disorder
5.  Clinical and molecular delineation of the 17q21.31 microdeletion syndrome 
Journal of medical genetics  2008;45(11):710-720.
The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.
We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.
We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729–41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10–5).
Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.
PMCID: PMC3071570  PMID: 18628315
6.  How Category Structure Influences the Perception of Object Similarity: The Atypicality Bias 
Why do some faces appear more similar than others? Beyond structural factors, we speculate that similarity is governed by the organization of faces located in a multi-dimensional face space. To test this hypothesis, we morphed a typical face with an atypical face. If similarity judgments are guided purely by their physical properties, the morph should be perceived to be equally similar to its typical parent as its atypical parent. However, contrary to the structural prediction, our results showed that the morph face was perceived to be more similar to the atypical face than the typical face. Our empirical studies show that the atypicality bias is not limited to faces, but extends to other object categories (birds) whose members share common shape properties. We also demonstrate atypicality bias is malleable and can change subject to category learning and experience. Collectively, the empirical evidence indicates that perceptions of face and object similarity are affected by the distribution of stimuli in a face or object space. In this framework, atypical stimuli are located in a sparser region of the space where there is less competition for recognition and therefore, these representations capture a broader range of inputs. In contrast, typical stimuli are located in a denser region of category space where there is increased competition for recognition and hence, these representation draw a more restricted range of face inputs. These results suggest that the perceived likeness of an object is influenced by the organization of surrounding exemplars in the category space.
PMCID: PMC3368386  PMID: 22685441
face perception; object perception; categorization; morphing; perceptual similarity
7.  Modeling 3D Facial Shape from DNA 
PLoS Genetics  2014;10(3):e1004224.
Human facial diversity is substantial, complex, and largely scientifically unexplained. We used spatially dense quasi-landmarks to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). Using bootstrapped response-based imputation modeling (BRIM), we uncover the relationships between facial variation and the effects of sex, genomic ancestry, and a subset of craniofacial candidate genes. The facial effects of these variables are summarized as response-based imputed predictor (RIP) variables, which are validated using self-reported sex, genomic ancestry, and observer-based facial ratings (femininity and proportional ancestry) and judgments (sex and population group). By jointly modeling sex, genomic ancestry, and genotype, the independent effects of particular alleles on facial features can be uncovered. Results on a set of 20 genes showing significant effects on facial features provide support for this approach as a novel means to identify genes affecting normal-range facial features and for approximating the appearance of a face from genetic markers.
Author Summary
The face is perhaps the most inherently fascinating and aesthetic feature of the human body. It is a principle subject of art throughout human history and across cultures and populations. It provides the most significant means by which we communicate our emotions and intentions in addition to health, sex, and age. And yet features such as the strength of the brow ridge, the spacing between the eyes, the width of the nose, and the shape of the philtrum are largely scientifically unexplained. Here, we use a novel method to measure face shape in population samples with mixed West African and European ancestry from three locations (United States, Brazil, and Cape Verde). We show that facial variation with regard to sex, ancestry, and genes can be systematically studied with our methods, allowing us to lay the foundation for predictive modeling of faces. Such predictive modeling could be forensically useful; for example, DNA left at crime scenes could be tested and faces predicted in order to help to narrow the pool of potential suspects. Further, our methods could be used to predict the facial features of descendants, deceased ancestors, and even extinct human species. In addition, these methods could prove to be useful diagnostic tools.
PMCID: PMC3961191  PMID: 24651127
8.  The face-specific N170 component is modulated by emotional facial expression 
According to the traditional two-stage model of face processing, the face-specific N170 event-related potential (ERP) is linked to structural encoding of face stimuli, whereas later ERP components are thought to reflect processing of facial affect. This view has recently been challenged by reports of N170 modulations by emotional facial expression. This study examines the time-course and topography of the influence of emotional expression on the N170 response to faces.
Dense-array ERPs were recorded in response to a set (n = 16) of fear and neutral faces. Stimuli were normalized on dimensions of shape, size and luminance contrast distribution. To minimize task effects related to facial or emotional processing, facial stimuli were irrelevant to a primary task of learning associative pairings between a subsequently presented visual character and a spoken word.
N170 to faces showed a strong modulation by emotional facial expression. A split half analysis demonstrates that this effect was significant both early and late in the experiment and was therefore not associated with only the initial exposures of these stimuli, demonstrating a form of robustness against habituation. The effect of emotional modulation of the N170 to faces did not show significant interaction with the gender of the face stimulus, or hemisphere of recording sites. Subtracting the fear versus neutral topography provided a topography that itself was highly similar to the face N170.
The face N170 response can be influenced by emotional expressions contained within facial stimuli. The topography of this effect is consistent with the notion that fear stimuli exaggerates the N170 response itself. This finding stands in contrast to previous models suggesting that N170 processes linked to structural analysis of faces precede analysis of emotional expression, and instead may reflect early top-down modulation from neural systems involved in rapid emotional processing.
PMCID: PMC1794418  PMID: 17244356
9.  Rare copy number variants are an important cause of epileptic encephalopathies 
Annals of neurology  2011;70(6):974-985.
Rare copy number variants (CNVs) – deletions and duplications – have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure, group of epilepsies, has not been performed.
We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high-density, exon-focused whole-genome oligonucleotide array.
We found that 25/315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least half being clearly or likely pathogenic. We identified two patients with overlapping deletions at 7q21 and two patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and four patients harbored two rare CNVs. We screened two novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions.
Our data highlight the significance of rare copy number variants in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study.
PMCID: PMC3245646  PMID: 22190369
10.  A Novel Two-Stage Illumination Estimation Framework for Expression Recognition 
The Scientific World Journal  2014;2014:565389.
One of the critical issues for facial expression recognition is to eliminate the negative effect caused by variant poses and illuminations. In this paper a two-stage illumination estimation framework is proposed based on three-dimensional representative face and clustering, which can estimate illumination directions under a series of poses. First, 256 training 3D face models are adaptively categorized into a certain amount of facial structure types by k-means clustering to group people with similar facial appearance into clusters. Then the representative face of each cluster is generated to represent the facial appearance type of that cluster. Our training set is obtained by rotating all representative faces to a certain pose, illuminating them with a series of different illumination conditions, and then projecting them into two-dimensional images. Finally the saltire-over-cross feature is selected to train a group of SVM classifiers and satisfactory performance is achieved when estimating a number of test sets including images generated from 64 3D face models kept for testing, CAS-PEAL face database, CMU PIE database, and a small test set created by ourselves. Compared with other related works, our method is subject independent and has less computational complexity O(C × N) without 3D facial reconstruction.
PMCID: PMC4009132  PMID: 24977212
11.  Looking Like a Leader–Facial Shape Predicts Perceived Height and Leadership Ability 
PLoS ONE  2013;8(12):e80957.
Judgments of leadership ability from face images predict the outcomes of actual political elections and are correlated with leadership success in the corporate world. The specific facial cues that people use to judge leadership remain unclear, however. Physical height is also associated with political and organizational success, raising the possibility that facial cues of height contribute to leadership perceptions. Consequently, we assessed whether cues to height exist in the face and, if so, whether they are associated with perception of leadership ability. We found that facial cues to perceived height had a strong relationship with perceived leadership ability. Furthermore, when allowed to manually manipulate faces, participants increased facial cues associated with perceived height in order to maximize leadership perception. A morphometric analysis of face shape revealed that structural facial masculinity was not responsible for the relationship between perceived height and perceived leadership ability. Given the prominence of facial appearance in making social judgments, facial cues to perceived height may have a significant influence on leadership selection.
PMCID: PMC3851990  PMID: 24324651
12.  A Case of Prosopometamorphopsia Restricted to the Nose and Mouth with Right Medial Temporooccipital Lobe Infarction that Included the Fusiform Face Area 
Metamorphopsia includes a broad spectrum of visual perceptual distortions, such as alteration of perceived object size or, rarely, altered perception of faces, termed prosopometamorphopsia.
Case Report
This report describes a patient who complained of metamorphopsia restricted to the center of the face, particularly the lower part of the face (nose and mouth), following infarction of the right medial temporooccipital lobe that included the fusiform face area.
The fusiform face area is commonly believed to be a face-selective cortical region dedicated to the visual analysis of face stimuli. We speculate that any injury to this brain area could bring about prosopometamorphopsia involving whole or unilateral face perception, or very rarely, as in our case, distortion restricted to the central area of the face. Furthermore, there could be topographical correspondences between facial structures and the fusiform face area.
PMCID: PMC3540293  PMID: 23323142
prosopometamorphopsia; fusiform face area; face perception
13.  Epilepsy and the New Cytogenetics 
Epilepsia  2011;52(3):423-432.
We set out to review the extent to which molecular karyotyping has overtaken conventional cytogenetics in applications related to epilepsy. Multiplex ligase-dependent probe amplification (MLPA) targeted to predetermined regions such as SCN1A and KCNQ2 has been effectively applied over the past half a decade and oligonucleotide array comparative genome hybridization (array CGH) is now well established for genome wide exploration of microchromosomal variation. Array CGH is applicable to the characterization of lesions present in both sporadic and familial epilepsy, especially where clinical features of affected cases depart from established syndromes. Copy number variants (CNVs) associated with epilepsy and a range of other syndromes and conditions can be recurrent due to non-allelic homologous recombination in regions of segmental duplication. The most common of the recurrent microdeletions associated with generalized epilepsy are typically seen at a frequency of around 1% at 15q13.3, 16p13.11 and 15q11.2, sites that also confer susceptibility for intellectual disability, autism and schizophrenia. Incomplete penetrance and variable expressivity confound the established rules of cytogenetics for determining the pathogenicity for novel CNVs; however, as knowledge is gained for each of the recurrent CNVs, this is translated to genetic counselling. CNVs play a significant role in the susceptibility profile for epilepsies with complex genetics and their comorbidities both from the “hotspots” defined by segmental duplication and elsewhere in the genome where their location and size are often novel.
PMCID: PMC3079368  PMID: 21269290
14.  A face feature space in the macaque temporal lobe 
Nature neuroscience  2009;12(9):1187-1196.
The ability of primates to effortlessly recognize faces has been attributed to the existence of specialized face areas. One such area, the macaque middle face patch, consists almost entirely of cells that are selective for faces, but the principles by which these cells analyze faces are unknown. We found that middle face patch neurons detect and differentiate faces using a strategy that is both part based and holistic. Cells detected distinct constellations of face parts. Furthermore, cells were tuned to the geometry of facial features. Tuning was most often ramp-shaped, with a one-to-one mapping of feature magnitude to firing rate. Tuning amplitude depended on the presence of a whole, upright face and features were interpreted according to their position in a whole, upright face. Thus, cells in the middle face patch encode axes of a face space specialized for whole, upright faces.
PMCID: PMC2819705  PMID: 19668199
15.  Processes and factors involved in decisions regarding return of incidental genomic findings in research 
Studies have begun exploring whether researchers should return incidental findings in genomic studies, and if so, which findings should be returned; however, how researchers make these decisions— the processes and factors involved—has remained largely unexplored.
We interviewed 28 genomics researchers in-depth about their experiences and views concerning the return of incidental findings.
Researchers often struggle with questions concerning which incidental findings to return and how to make those decisions. Multiple factors shape their views, including information about the gene variant (e.g., pathogenicity and disease characteristics), concerns about participants’ well-being and researcher responsibility, and input from external entities. Researchers weigh the evidence, yet they face conflicting pressures, with relevant data frequently being unavailable. Researchers vary in who they believe should decide: participants, principal investigators, institutional review boards, and/or professional organizations. Contextual factors can influence these decisions, including policies governing return of results by institutions and biobanks and the study design. Researchers vary in desires for: guidance from institutions and professional organizations, changes to current institutional processes, and community- wide genetics education.
These data, the first to examine the processes by which researchers make decisions regarding the return of genetic incidental findings, highlight several complexities involved and have important implications for future genetics research, policy, and examinations of these issues.
PMCID: PMC3966970  PMID: 24071801
benefits and risks; decision making; genome sequencing; incidental findings; return of results
16.  Evaluation of magnetic resonance imaging-negative drug-resistant epilepsy 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S80-S88.
A structural brain lesion in patients with drug-resistant epilepsy (DRE) greatly increases the likelihood of identification of the seizure focus and ultimately seizure-free outcome following resective epilepsy surgery. In contrast, surgical outcomes of true non-lesional DRE are less favorable. Therefore, discovery of an underlying lesion is paramount in the pre-surgical work-up of patients with DRE. Over the years, the surgical treatment of pharmacoresistant epilepsy has evolved from straightforward lesional cases to include cases with hippocampal sclerosis. With the advent of magnetic resonance imaging (MRI), most cases of mesial temporal sclerosis became more easily identifiable on pre-operative neuroimaging. With the widespread use of high-resolution MRI with epilepsy protocols over the last two decades, our ability to visualize subtle structural changes has been greatly enhanced. However, there are some cases of lesional epilepsy, which remain unidentified on these routine MRIs. In such “non-lesional” refractory epilepsies, further investigation with advanced neuroimaging techniques, including metabolic imaging, as well as electrophysiological studies may help to identify the previously non-visualized focal brain abnormalities. In this review, we outline the current status for evaluation of MRI-negative DRE.
PMCID: PMC4001223  PMID: 24791094
Epilepsy surgery; investigations; medically refractory epilepsy; non-lesional epilepsy; pharmacoresistant seizures
17.  Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study 
Brain  2010;133(7):2136-2147.
Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.
PMCID: PMC2892941  PMID: 20522523
partial epilepsy; genome-wide association; genetics; common variants
18.  Bidirectional communication between amygdala and fusiform gyrus during facial recognition 
NeuroImage  2011;56(4):2348-2355.
Decades of research have documented the specialization of fusiform gyrus (FG) for facial information processes. Recent theories indicate that FG activity is shaped by input from amygdala, but effective connectivity from amygdala to FG remains undocumented. In this fMRI study, 39 participants completed a face recognition task. 11 participants underwent the same experiment approximately four months later. Robust face-selective activation of FG, amygdala, and lateral occipital cortex were observed. Dynamic causal modeling and Bayesian Model Selection (BMS) were used to test the intrinsic connections between these structures, and their modulation by face perception. BMS results strongly favored a dynamic causal model with bidirectional, face-modulated amygdala-FG connections. However, the right hemisphere connections diminished at time 2, with the face modulation parameter no longer surviving Bonferroni correction. These findings suggest that amygdala strongly influences FG function during face perception, and that this influence is shaped by experience and stimulus salience.
PMCID: PMC3137553  PMID: 21497657
Functional MRI; Face processing; Amygdala; Effective connectivity; Dynamic causal modeling
19.  Factors contributing to the adaptation aftereffects of facial expression 
Brain research  2007;1191:116-126.
Previous studies have demonstrated the existence of adaptation aftereffects for facial expressions. Here we investigated which aspects of facial stimuli contribute to these aftereffects. In Experiment 1 we examined the role of local adaptation to image elements such as curvature, shape and orientation, independent of expression, by using hybrid faces constructed from either the same or opposing expressions. While hybrid faces made with consistent expressions generated aftereffects as large as that with normal faces, there were no aftereffects from hybrid faces made from different expressions, despite the fact that these contained the same local image elements. In Experiment 2 we examined the role of facial features independent of the normal face configuration, by contrasting adaptation with whole faces to adaptation with scrambled faces. We found that scrambled faces also generated significant aftereffects, indicating that expressive features without a normal facial configuration could generate expression aftereffects. In Experiment 3 we examined the role of facial configuration by using schematic faces made from line elements that in isolation do not carry expression-related information (e.g. curved segments and straight lines), but that convey an expression when arranged in a normal facial configuration. We obtained a significant aftereffect for facial configurations but not scrambled configurations of these line elements. We conclude that face expression aftereffects are not due to local adaptation to image elements but due to high-level adaptation of neural representations that involve both facial features and facial configuration.
PMCID: PMC2538428  PMID: 18096142
Adaptation; aftereffects; facial expression; face perception; features
20.  Ethanol-Induced Face-Brain Dysmorphology Patterns Are Correlative and Exposure-Stage Dependent 
PLoS ONE  2012;7(8):e43067.
Prenatal ethanol exposure is the leading preventable cause of congenital mental disability. Whereas a diagnosis of fetal alcohol syndrome (FAS) requires identification of a specific pattern of craniofacial dysmorphology, most individuals with behavioral and neurological sequelae of heavy prenatal ethanol exposure do not exhibit these defining facial characteristics. Here, a novel integration of MRI and dense surface modeling-based shape analysis was applied to characterize concurrent face-brain phenotypes in C57Bl/6J fetuses exposed to ethanol on gestational day (GD)7 or GD8.5. The facial phenotype resulting from ethanol exposure depended upon stage of insult and was predictive of unique patterns of corresponding brain abnormalities. Ethanol exposure on GD7 produced a constellation of dysmorphic facial features characteristic of human FAS, including severe midfacial hypoplasia, shortening of the palpebral fissures, an elongated upper lip, and deficient philtrum. In contrast, ethanol exposure on GD8.5 caused mild midfacial hypoplasia and palpebral fissure shortening, a shortened upper lip, and a preserved philtrum. These distinct, stage-specific facial phenotypes were associated with unique volumetric and shape abnormalities of the septal region, pituitary, and olfactory bulbs. By demonstrating that early prenatal ethanol exposure can cause more than one temporally-specific pattern of defects, these findings illustrate the need for an expansion of current diagnostic criteria to better capture the full range of facial and brain dysmorphology in fetal alcohol spectrum disorders.
PMCID: PMC3425589  PMID: 22937012
21.  High resolution magnetic resonance imaging in adults with partial or secondary generalised epilepsy attending a tertiary referral unit. 
In the past the underlying structural abnormalities leading to the development of chronic seizure disorders have usually only been disclosed by histological examination of surgical or postmortem material, due to their often subtle nature that was beyond the resolution of CT or early MRI. The MRI findings in 341 patients with chronic, refractory epilepsy attending The National Hospital for Neurology and Neurosurgery and Chalfont Centre for Epilepsy are reported. Studies were performed on a 1.5 Tesla scanner with a specific volumetric protocol, allowing the reconstruction of 1.5 mm contiguous slices throughout the whole brain. Direct visual inspection of the two dimensional images without the use of additional quantitative measures showed that 254/341 (74%) were abnormal. Twenty four (7%) patients had more than one lesion. The principal MRI diagnoses were hippocampal asymmetry (32%), cortical dysgenesis (12%), tumour (12%), and vascular malformation (8%). Pathological confirmation was available from surgical specimens in 70 patients and showed a very high degree of sensitivity and specificity for the different entities. The advent of more widely available high resolution MRI should make it possible to identify the underlying pathological substrate in most patients with chronic partial epilepsy. This will allow a fundamental reclassification of the epilepsies for both medical and surgical management, with increasing precision as new methods (both of acquisition and postprocessing) are added to the neuroimaging battery used in clinical practice.
PMCID: PMC486074  PMID: 7561917
22.  Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies 
Most of our social interactions involve perception of emotional information from the faces of other people. Furthermore, such emotional processes are thought to be aberrant in a range of clinical disorders, including psychosis and depression. However, the exact neurofunctional maps underlying emotional facial processing are not well defined.
Two independent researchers conducted separate comprehensive PubMed (1990 to May 2008) searches to find all functional magnetic resonance imaging (fMRI) studies using a variant of the emotional faces paradigm in healthy participants. The search terms were: “fMRI AND happy faces,” “fMRI AND sad faces,” “fMRI AND fearful faces,” “fMRI AND angry faces,” “fMRI AND disgusted faces” and “fMRI AND neutral faces.” We extracted spatial coordinates and inserted them in an electronic database. We performed activation likelihood estimation analysis for voxel-based meta-analyses.
Of the originally identified studies, 105 met our inclusion criteria. The overall database consisted of 1785 brain coordinates that yielded an overall sample of 1600 healthy participants. Quantitative voxel-based meta-analysis of brain activation provided neurofunctional maps for 1) main effect of human faces; 2) main effect of emotional valence; and 3) modulatory effect of age, sex, explicit versus implicit processing and magnetic field strength. Processing of emotional faces was associated with increased activation in a number of visual, limbic, temporoparietal and prefrontal areas; the putamen; and the cerebellum. Happy, fearful and sad faces specifically activated the amygdala, whereas angry or disgusted faces had no effect on this brain region. Furthermore, amygdala sensitivity was greater for fearful than for happy or sad faces. Insular activation was selectively reported during processing of disgusted and angry faces. However, insular sensitivity was greater for disgusted than for angry faces. Conversely, neural response in the visual cortex and cerebellum was observable across all emotional conditions.
Although the activation likelihood estimation approach is currently one of the most powerful and reliable meta-analytical methods in neuroimaging research, it is insensitive to effect sizes.
Our study has detailed neurofunctional maps to use as normative references in future fMRI studies of emotional facial processing in psychiatric populations. We found selective differences between neural networks underlying the basic emotions in limbic and insular brain regions.
PMCID: PMC2783433  PMID: 19949718
23.  Epilepsy Genetics—Past, Present, and Future 
Human epilepsy is a common and heterogeneous condition in which genetics play an important etiological role. We begin by reviewing the past history of epilepsy genetics, a field that has traditionally included studies of pedigrees with epilepsy caused by defects in ion channels and neurotransmitters. We highlight important recent discoveries that have expanded the field beyond the realm of channels and neurotransmitters and that have challenged the notion that single genes produce single disorders. Finally, we project toward an exciting future for epilepsy genetics as large-scale collaborative phenotyping studies come face to face with new technologies in genomic medicine.
PMCID: PMC4074083  PMID: 21277190
24.  Genome-Wide Copy Number Variation in Epilepsy: Novel Susceptibility Loci in Idiopathic Generalized and Focal Epilepsies 
PLoS Genetics  2010;6(5):e1000962.
Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy.
Author Summary
Epilepsy, a common neurological disorder characterized by recurrent seizures, affects up to 3% of the population. In some cases, the epilepsy has a clear cause such as an abnormality in the brain or a head injury. However, in many cases there is no obvious cause. Numerous studies have shown that genetic factors are important in these types of epilepsy, but although several epilepsy genes are known, we can still only identify the genetic cause in a very small fraction of cases. In order to identify new genes that contribute to the genetic causes of epilepsy, we searched the human genome for deletions (missing copies) and duplications (extra copies) of genes in ∼500 patients with epilepsy that are not found in control individuals. Using this approach, we identified several large deletions that are important in at least 3% of epilepsy cases. Furthermore, we found new candidate genes, some of which are also thought to play a role in other related disorders such as autism and intellectual disability. These genes are candidates for further studies in patients with epilepsy.
PMCID: PMC2873910  PMID: 20502679
25.  Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability 
Journal of Applied Genetics  2013;55:125-144.
We used whole-genome exon-targeted oligonucleotide array comparative genomic hybridization (array CGH) in a cohort of 256 patients with developmental delay (DD)/intellectual disability (ID) with or without dysmorphic features, additional neurodevelopmental abnormalities, and/or congenital malformations. In 69 patients, we identified 84 non-polymorphic copy-number variants, among which 41 are known to be clinically relevant, including two recently described deletions, 4q21.21q21.22 and 17q24.2. Chromosomal microarray analysis revealed also 15 potentially pathogenic changes, including three rare deletions, 5q35.3, 10q21.3, and 13q12.11. Additionally, we found 28 copy-number variants of unknown clinical significance. Our results further support the notion that copy-number variants significantly contribute to the genetic etiology of DD/ID and emphasize the efficacy of the detection of novel candidate genes for neurodevelopmental disorders by whole-genome array CGH.
Electronic supplementary material
The online version of this article (doi:10.1007/s13353-013-0181-x) contains supplementary material, which is available to authorized users.
PMCID: PMC3909616  PMID: 24297458
Copy-number variation; Microdeletion; Microduplication; Chromosomal microarray analysis

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