Facial Phenotype Research Articles

The relationship between facial directional asymmetry, handedness, chewing side preference, and eyedness

We aimed to describe facial directional asymmetry (DA) in individuals with different manifestations of laterality. Due to the overlap between brain and face development, a relationship between the manifestation of brain laterality and DA is hypothesised. These findings could clarify the relationship between the brain and facial phenotype and help to plan facial or oral motor rehabilitation. The DA of 163 healthy individuals was assessed by two complementary 3D methods: landmark and polygonal surface analysis using colour-coded maps. Handedness was assessed using the Edinburgh Handedness Inventory, while chewing side and eye preferences were self-reported. The results showed a similar DA pattern regardless of sex and laterality (the right-sided protrusion of the forehead, nose, lips, and chin) and a slightly curved C-shape of the midline in landmark analysis. A relationship between lateralized behaviours and DA was found only in males, in females the DA pattern was more homogenous. Right-handed individuals and right-side chewers showed a protrusion of the right hemiface. Males, left-handed and left-side chewers, manifested a protrusion of the left lateral hemiface. We suggest that these specific differences in males may be due to their typically higher level of brain asymmetry. No apparent relationship was found between eyedness and DA.

Diagnosis and Screening of Velocardiofacial Syndrome by Evaluating Facial Photographs Using a Deep Learning-Based Algorithm.

Early detection of rare genetic diseases, including velocardiofacial syndrome (VCFS), is essential for patient well-being. However, their rarity and limited clinical experience of physicians make diagnosis challenging. Deep learning algorithms have emerged as promising tools for efficient and accurate diagnosis. This study investigates the use of a deep learning algorithm to develop a face recognition model for diagnosing VCFS. The study employed publicly available labeled face datasets to train the multitask cascaded convolutional neural networks (MTCNN) model. Subsequently, we examined the binary classification performance for diagnosing VCFS using the most efficient face recognition model. A total of 98 VCFS patients (920 facial photographs) and 91 non-VCFS controls (463 facial photographs) were randomly divided into training and test sets. Additionally, we analyzed whether the classification results matched the known facial phenotype of VCFS. The face recognition model demonstrated high accuracy, ranging from 94% to 99%, depending on the training dataset. The accuracy of the binary classification diagnostic model varied from 81% to 88% when evaluating with photographs taken at various angles, but reached 95% evaluating with frontal photographs only. Gradient-weighted class activation mapping heatmap revealed the high importance level of perinasal and periorbital areas, exhibiting consistency with the conventional facial phenotypes of VCFS. This study shows the feasibility and effectiveness of MTCNN-based model for detecting VCFS solely from facial photographs. The high accuracy underscores the potential of deep learning in aiding early diagnosis of rare genetic diseases, facilitating timely interventions for patient care.

Treacher Collins Syndrome 2 caused by a novel pathogenic variant in PLOR1D: clinical report and literature review

Objective: To investigate the clinical features, molecular etiology, and treatment of a family with Treacher Collins Syndrome 2 (TCS2). Methods: Information of the proband (female, 8 years old) including medical history and family history was collected. Physical examination and examinations concerning laboratory, audiology, and radiology were performed on the proband. Physical examination was also performed on the family members. Genomic DNA of proband was extracted for whole exome sequencing, and then the genomic DNA of family members was extracted for Sanger sequencing. POLR1D and TCS2 related literatures published before August 31,2023 were searched and sifted in PubMed and CKNI databases. The clinical characteristics of TCS2 were summarized. Results: The proband had poor hearing since childhood, with pure tone audiometry indicating conductive hearing loss. She had a smaller jaw, bilateral preauricular fistulas and cup-shaped ear deformities. Temporal bone CT scan revealed deformities in the left external ear canal, bilateral middle ear and inner ear. A bone-conduction hearing aid device was surgically implanted, resulting in restoration of almost normal hearing levels. The proband's mother also had a slightly smaller jaw. Genetic analysis revealed a novel heterozygous variant NM_015972.4:c.38_47del in the POLR1D gene in the proband, which was inherited from her mother. A review of the literature revealed no clear evidence of genotype-phenotype correlation in TCS2. Conclusions: Molecular diagnosis plays a vital role in the diagnosis of TCS2. Patients with normal facial phenotype may be carriers of pathogenic variants in the POLR1D gene and have the risk of passing it to the offsprings with complete penetrance. Proper bone conductive hearing devices can improve the quality of life of TCS2 patients.

Parenti–Migno neurodevelopmental disorder: a case associated with a new variant in the <i>CHD5</i> gene

Parenti–Migno neurodevelopmental disorder is a rare syndromal form of intellectual disability in children, associated with the CHD5 gene, the prevalence of which is not established. Currently, 16 patients with this pathology have been described. CHD5 belongs to the conservative family of chromatin remodeler proteins, is part of the histone deacetylase NuRD complex, and is crucial for the early differentiation of neurons in the central nervous system and acts as a tumor suppressor. Recently, thanks to the application of whole-exome sequencing, the association of this gene with Parenti–Migno neurodevelopmental disorder was first described in patients with developmental delay, psycho-neurological disturbances, facial phenotype features, and skull pathology. We present a unique case of the disease associated with a new variant p.Arg1521Thr in the CHD5 gene, in a girl with intellectual and neurological impairments, craniofacial dysmorphism, as well as previously undescribed symptoms such as cleft lip and palate, hydrocephalus, and renal pathology. The cause of the disease was determined through whole-genome sequencing, which highlights the value of this method in the diagnosis of undifferentiated forms of intellectual disabilities.

The face of Non-photosensitive trichothiodystrophy phenotypic spectrum: A subsequent study on paediatric population.

Non-photosensitive trichothiodystrophies (TTDs) are a diverse group of genodermatoses within the subset of conditions known as "sulphur-deficient brittle hair" syndromes. A part of them has only recently been identified, revealing novel causative genes and very rare phenotypes of these genetic skin disorders. At the same time, the molecular basis of previously published and unresolved cases has been revealed through the introduction of innovative genetic techniques. We have previously described the facial phenotype of patients with the Photosensitive form of TTD during childhood. This study marks the beginning of an effort to expand the analysis to include individuals of the same age who do not have photosensitivity. A total of 26 facial portraits of TTD paediatric patients with Non-photosensitivity from the literature were analysed using computer-aided technologies, and their facial features were examined through a detailed clinical review. Distinct facial features were identified in both Photosensitive and Non-photosensitive TTDs. The present study has comprehensively elucidated the facial features in TTDs, encompassing the Non-photosensitive clinical spectrum.

Impact of Alcohol-Induced Facial Flushing Phenotype on Alcohol Consumption Among Korean Adults: 2-Year Cross-Sectional Study.

The alcohol-induced facial flushing phenotype (flushing) is common among East Asians. Despite a small intake of alcohol, they experience heightened levels of acetaldehyde, a group-1 carcinogen, which, in turn, causes unpleasant symptoms such as redness, acting as a robust protective mechanism against consuming alcohol. However, some individuals with this genetic trait exhibit weakened alcohol restraint, which increases the risk of developing alcohol-related cancers, such as esophageal and head or neck cancer, by several times. Although this flushing phenomenon is crucial for public health, there is a paucity of studies that have comprehensively investigated the effect of flushing or its genotype on alcohol consumption in a large group of East Asians while controlling for various sociodemographic and health-related variables at a country level. This 2-year cross-sectional study aims to explore the effect of flushing on drinking behavior in Koreans and to examine whether the effect varies across sociodemographic and health-related factors. We used data from the Korea National Health and Nutrition Examination Survey (KNHANES) for 2019 and 2020 conducted by the Korea Disease Control and Prevention Agency. Our sample comprised 10,660 Korean adults. The study investigated the association of 26 variables, including flushing, with drinking frequency and amount. The effect of flushing was examined with and without adjusting for the other 25 variables using multinomial logistic regression analysis. In addition, we tested the interaction effect with flushing and conducted a simple effect analysis. We used complex sample design elements, including strata, clusters, and weights, to obtain unbiased results for the Rao-Scott χ2 test, 2-tailed t test, and multinomial logistic regression analysis. The suppressive effect of flushing was significant (P<.001) across all pronounced categories of alcohol consumption in 2019. The ranges of standardized regression slopes and odds ratios (ORs) were -6.70≥β≥-11.25 and 0.78≥OR≥0.50 for frequency and -5.37≥β≥-17.64 and 0.73≥OR≥0.36 for amount, respectively. The effect became somewhat stronger when adjusted for confounders. The effect also exhibited an overall stronger trend as the severity of alcohol consumption increased. The β values and ORs were consistently smaller in 2020 compared to the previous year. A simple effect analysis revealed a diminished alcohol-suppressive effect of flushing on alcohol consumption for specific groups (eg, those with low levels of education, limited family support, physical labor, or health-related issues). Our findings suggest that flushing suppresses drinking in Koreans overall but has little or no effect in certain susceptible populations. Therefore, health authorities should conduct targeted epidemiological studies to assess drinking patterns and disease profiles, particularly regarding alcohol-related cancers, and establish effective preventive measures tailored to this population.

Facial recognition models for identifying genetic syndromes associated with pulmonary stenosis in children.

Williams-Beuren syndrome, Noonan syndrome, and Alagille syndrome are common types of genetic syndromes (GSs) characterized by distinct facial features, pulmonary stenosis, and delayed growth. In clinical practice, differentiating these three GSs remains a challenge. Facial gestalts serve as a diagnostic tool for recognizing Williams-Beuren syndrome, Noonan syndrome, and Alagille syndrome. Pretrained foundation models (PFMs) can be considered the foundation for small-scale tasks. By pretraining with a foundation model, we propose facial recognition models for identifying these syndromes. A total of 3297 (n = 1666) facial photos were obtained from children diagnosed with Williams-Beuren syndrome (n = 174), Noonan syndrome (n = 235), and Alagille syndrome (n = 51), and from children without GSs (n = 1206). The photos were randomly divided into five subsets, with each syndrome and non-GS equally and randomly distributed in each subset. The proportion of the training set and the test set was 4:1. The ResNet-100 architecture was employed as the backbone model. By pretraining with a foundation model, we constructed two face recognition models: one utilizing the ArcFace loss function, and the other employing the CosFace loss function. Additionally, we developed two models using the same architecture and loss function but without pretraining. The accuracy, precision, recall, and F1 score of each model were evaluated. Finally, we compared the performance of the facial recognition models to that of five pediatricians. Among the four models, ResNet-100 with a PFM and CosFace loss function achieved the best accuracy (84.8%). Of the same loss function, the performance of the PFMs significantly improved (from 78.5% to 84.5% for the ArcFace loss function, and from 79.8% to 84.8% for the CosFace loss function). With and without the PFM, the performance of the CosFace loss function models was similar to that of the ArcFace loss function models (79.8% vs 78.5% without PFM; 84.8% vs 84.5% with PFM). Among the five pediatricians, the highest accuracy (0.700) was achieved by the senior-most pediatrician with genetics training. The accuracy and F1 scores of the pediatricians were generally lower than those of the models. A facial recognition-based model has the potential to improve the identification of three common GSs with pulmonary stenosis. PFMs might be valuable for building screening models for facial recognition. Key messages What is already known on this topic: Early identification of genetic syndromes (GSs) is crucial for the management and prognosis of children with pulmonary stenosis (PS). Facial phenotyping with convolutional neural networks (CNNs) often requires large-scale training data, limiting its usefulness for GSs. What this study adds: We successfully built multi-classification models based on face recognition using a CNN to accurately identify three common PS-associated GSs. ResNet-100 with a pretrained foundation model (PFM) and CosFace loss function achieved the best accuracy (84.8%). Pretrained with the foundation model, the performance of the models significantly improved, although the impact of the type of loss function appeared to be minimal. How this study might affect research, practice, or policy: A facial recognition-based model has the potential to improve the identification of GSs in children with PS. The PFM might be valuable for building identification models for facial detection.

Toward 3D facial analysis for recognizing Mendelian causes of autism spectrum disorder.

Recognizing Mendelian causes is crucial in molecular diagnostics and counseling for patients with autism spectrum disorder (ASD). We explored facial dysmorphism and facial asymmetry in relation to genetic causes in ASD patients and studied the potential of objective facial phenotyping in discriminating between Mendelian and multifactorial ASD. In a cohort of 152 ASD patients, 3D facial images were used to calculate three metrics: a computational dysmorphism score, a computational asymmetry score, and an expert dysmorphism score. High scores for each of the three metrics were associated with Mendelian causes of ASD. The computational dysmorphism score showed a significant correlation with the average expert dysmorphism score. However, in some patients, different dysmorphism aspects were captured making the metrics potentially complementary. The computational dysmorphism and asymmetry scores both enhanced the individual expert dysmorphism scores in differentiating Mendelian from non-Mendelian cases. Furthermore, the computational asymmetry score enhanced the average expert opinion in predicting a Mendelian cause. By design, our study does not allow to draw conclusions on the actual point-of-care use of 3D facial analysis. Nevertheless, 3D morphometric analysis is promising for developing clinical dysmorphology applications in diagnostics and training.

A novel ABCC9 variant in a Greek family with Cantu syndrome affecting multiple generations highlights the functional role of the SUR2B NBD1.

Cantu syndrome (CS) (OMIM #239850) is an autosomal dominant multiorgan system condition, associated with a characteristic facial phenotype, hypertrichosis, and multiple cardiovascular complications. CS is caused by gain-of-function (GOF) variants in KCNJ8 or ABCC9 that encode pore-forming Kir6.1 and regulatory SUR2 subunits of ATP-sensitive potassium (KATP) channels. A novel heterozygous ABCC9 variant, c.2440G>T; p.Gly814Trp, was identified in three individuals from a four generation Greek family. The membrane potential in cells stably expressing hKir6.1 and hSUR2B with p.Gly814Trp was hyperpolarized compared to cells expressing WT channels, and inside-out patch-clamp assays of KATP channels formed with hSUR2B p.Gly814Trp demonstrated a decreased sensitivity to ATP inhibition, confirming a relatively mild GOF effect of this variant. The specific location of the variant reveals an unrecognized functional role of the first glycine in the signature motif of the nucleotide binding domains in ATP-binding cassette (ABC) protein ion channels.

Mapping genes for human face shape: exploration of univariate phenotyping strategies.

Advancements linking variation in the human genome to phenotypes have rapidly evolved in recent decades and have revealed that most human traits are influenced by genetic variants to at least some degree. While many traits, such as stature, are straightforward to acquire and investigate, the multivariate and multipartite nature of facial shape makes quantification more challenging. In this study, we compared the impact of different facial phenotyping approaches on gene mapping outcomes. Our findings suggest that the choice of facial phenotyping method has an impact on apparent trait heritability and the ability to detect genetic association signals. These results offer valuable insights into the importance of phenotyping in genetic investigations, especially when dealing with highly complex morphological traits.

Novel SETBP1 D874V adjacent to the degron causes canonical schinzel–giedion syndrome: a case report and review of the literature

Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.

Anthropometric Analysis of Indian Faces: A Systematic Review.

Facial anthropometric data vary significantly within the Indian population due to the racial, ethnic and geographic diversity. The anthropometric data of a given ethnic community may not match the other due to diverse ethnic variations, and hence, this study is intended to review the facial anthropometric data pertaining to the diverse Indian populace through a systematic literature survey. An electronic search done on Medline, Embase and Central databases was utilized to conduct a systematic review of literature. The available data were analyzed based on the various esthetic subunits of the face. The following inclusion criteria were considered: (1) studies depicting the anthropometric data of any ethnic group identified as belonging to India, (2) studies originating from Indian subcontinent, (3) studies which included data of male and female subjects separately and (4) articles in English language only. The following exclusion criteria were considered: (1) atudies conducted on participants with severe malocclusion, developmental craniofacial anomalies, post-traumatic facial deformities or with a history of previous craniofacial or cosmetic surgery, (2) studies which did not specify the anthropometric landmarks used to obtain the measurements, (3) studies in which the statistical analysis was not provided, or if data were grouped across genders and (4) editorials, commentaries, case reports, systematic reviews, meta-analyses and articles not available in English language. Twenty-one articles met the inclusion criteria. Majority of the Indians, particularly men, seem to have a mesoproscopic facial phenotype. The vertical and horizontal facial dimensions of the Indian male are comparably larger than the Indian female. There is sexual dimorphism among the Indian population with regard to the upper and lower thirds of the face, with little or no gender difference as regards the middle third of the face. It was observed that the nasal dimensions of the Indian race were not compatible with that of the occidental, oriental or the western race. The overall facial structure and the upper half of the face were critical in determining facial attractiveness in Indian males while the lower half of the face and the mandibular contour were critical in determining facial attractiveness in females. It is observed that there is a paucity of facial anthropometric data for the Indian population considering the ethnic, racial and geographic diversity. Since the prevalence of craniofacial anomalies and dentofacial deformities in India is high and thus the scope for corrective surgery, it is important to compile baseline facial anthropometric data based on the ethnic diversity of the Indian population.

Phenotypic mismatch between suspects and fillers but not phenotypic bias increases eyewitness identifications of Black suspects.

Despite converging evidence that people more closely associate the construct of criminality with Black people who exhibit a more African facial phenotype than Black people who express a more European phenotype, eyewitness researchers have largely ignored phenotypic bias as a potential contributor to the racial disparities in the criminal legal system. If this form of phenotypic bias extends to eyewitness identification tasks, eyewitnesses may be more likely to identify Black suspects with an African rather than European phenotype, regardless of their guilt status. Further, in cases where the witness's description of the perpetrator does not contain phenotypic information, phenotypic mismatch between the suspect and the other lineup members may bias identification decisions toward or against the suspect. If witnesses can use elements of the lineup construction to guide their identification decisions rather than relying on their recognition memory, then the lineup should be deemed unfair due to suspect bias. The current study also investigated lineup presentation method as a procedural safeguard, predicting that that when lineups were presented simultaneously, there would be a significant two-way interaction of phenotypic bias and lineup composition, with a larger simple main effect of phenotypic bias when lineups were suspect-biased (i.e., the fillers were a phenotypic mismatch to the suspect) than when all lineup members shared the same phenotype. We expected that this interaction would be significantly smaller or non-significant for sequential lineups. Participants watched a mock crime video that contained a Black culprit with either a more African phenotype or a less African phenotype before attempting identifications from a photo array that contained a suspect whose phenotype always matched the culprit viewed in the video, but varied in culprit-presence, phenotypic match of the suspect and fillers, and presentation method. Participants did not identify Black suspects with Afrocentric features more often than Black suspects with Eurocentric features. However, witnesses made more identifications of suspects when the fillers did not match the suspect's phenotype compared to when all lineup members possessed similar phenotypic features. In sum, phenotypic bias did not influence our participant-witnesses' identification decisions, nor interact with lineup composition and lineup presentation type to affect identifications of suspects, suggesting that phenotypic bias may be less influential in match-to-memory tasks than other types of legal decision-making (e.g., determining guilt and sentencing). However, the suggestiveness created by failing to match fillers' phenotypes to the suspect's phenotype can be avoided with proper attention to fair lineup construction.

Simulated multimodal deep facial diagnosis

Facial phenotypes are extensively studied in medical and biological research, serving as critical markers that potentially indicate underlying genetic traits or medical conditions. With the recent advancements in big data, algorithms, and hardware, deep facial diagnosis, which employs deep learning techniques to systematically examine facial phenotypes and identify signs of certain diseases or medical conditions, has attracted significant attention and research, gradually emerging as a promising tool in precision medicine. Primarily limited by the scarcity of data for training facial diagnosis models, the accuracy of facial diagnosis for various conditions remains low up to now. In the past decade, RGB-D cameras, measuring depth information along with standard RGB capabilities, have proven superior in processing spatial details with more stability and accuracy. Motivated by the facts mentioned above, in this paper, we propose a Simulated Multimodal Framework, which effectively improves the computer-aided facial diagnosis performance of state-of-the-art models in experiments under different conditions. The underlying principle is to leverage the simulated depth by generative models to improve the performance of RGB image recognition. Furthermore, as a rapid and non-invasive tool for disease screening and detection, our proposal demonstrated an average accuracy improvement of over 20% compared to practicing physicians in the study.

Zebrafish raptor mutation inhibits the activity of mTORC1, inducing craniofacial defects due to autophagy-induced neural crest cell death.

The mechanistic target of rapamycin (mTOR) coordinates metabolism and cell growth with environmental inputs. mTOR forms two functional complexes: mTORC1 and mTORC2. Proper development requires both complexes but mTORC1 has unique roles in numerous cellular processes, including cell growth, survival and autophagy. Here, we investigate the function of mTORC1 in craniofacial development. We created a zebrafish raptor mutant via CRISPR/Cas9, to specifically disrupt mTORC1. The entire craniofacial skeleton and eyes were reduced in size in mutants; however, overall body length and developmental timing were not affected. The craniofacial phenotype associates with decreased chondrocyte size and increased neural crest cell death. We found that autophagy is elevated in raptor mutants. Chemical inhibition of autophagy reduced cell death and improved craniofacial phenotypes in raptor mutants. Genetic inhibition of autophagy, via mutation of the autophagy gene atg7, improved facial phenotypes in atg7;raptor double mutants, relative to raptor single mutants. We conclude that finely regulated levels of autophagy, via mTORC1, are crucial for craniofacial development.

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis.

Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC - a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, we demonstrate that the rs6740960 SNP is sufficient to confer chondrocyte-specific differences in PKDCC expression. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in the maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.

Validation of 3 Computer-Aided Facial Phenotyping Tools (DeepGestalt, GestaltMatcher, and D-Score): Comparative Diagnostic Accuracy Study.

While characteristic facial features provide important clues for finding the correct diagnosis in genetic syndromes, valid assessment can be challenging. The next-generation phenotyping algorithm DeepGestalt analyzes patient images and provides syndrome suggestions. GestaltMatcher matches patient images with similar facial features. The new D-Score provides a score for the degree of facial dysmorphism. We aimed to test state-of-the-art facial phenotyping tools by benchmarking GestaltMatcher and D-Score and comparing them to DeepGestalt. Using a retrospective sample of 4796 images of patients with 486 different genetic syndromes (London Medical Database, GestaltMatcher Database, and literature images) and 323 inconspicuous control images, we determined the clinical use of D-Score, GestaltMatcher, and DeepGestalt, evaluating sensitivity; specificity; accuracy; the number of supported diagnoses; and potential biases such as age, sex, and ethnicity. DeepGestalt suggested 340 distinct syndromes and GestaltMatcher suggested 1128 syndromes. The top-30 sensitivity was higher for DeepGestalt (88%, SD 18%) than for GestaltMatcher (76%, SD 26%). DeepGestalt generally assigned lower scores but provided higher scores for patient images than for inconspicuous control images, thus allowing the 2 cohorts to be separated with an area under the receiver operating characteristic curve (AUROC) of 0.73. GestaltMatcher could not separate the 2 classes (AUROC 0.55). Trained for this purpose, D-Score achieved the highest discriminatory power (AUROC 0.86). D-Score's levels increased with the age of the depicted individuals. Male individuals yielded higher D-scores than female individuals. Ethnicity did not appear to influence D-scores. If used with caution, algorithms such as D-score could help clinicians with constrained resources or limited experience in syndromology to decide whether a patient needs further genetic evaluation. Algorithms such as DeepGestalt could support diagnosing rather common genetic syndromes with facial abnormalities, whereas algorithms such as GestaltMatcher could suggest rare diagnoses that are unknown to the clinician in patients with a characteristic, dysmorphic face.

Evaluating the relationship between the proportion of X-chromosome deletions and clinical manifestations in children with turner syndrome.

Analyze the relationship between changes in the proportion of X-chromosome deletions and clinical manifestations in children with Turner syndrome (TS). X-chromosome number abnormalities in 8,635 children with growth retardation were identified using fluorescence in situ hybridization (FISH). Meanwhile, the relationship between the proportion of X-chromosome deletions and the clinical manifestations of TS, such as face and body phenotype, cardiovascular, renal, and other comorbidities in children with TS was analyzed. A total of 389 children had X-chromosome number abnormalities, with an average age at diagnosis of 9.2 years. There was a significant increase in diagnoses around the ages of 3 and 7 years and highest number of diagnoses at 10 years of age. 130 with XO (complete loss of an X-chromosome), 205 with XO/XX, 8 with XO/XXX, 23 with XO/XX/XXX, 19 with XO/XY, and 4 with XO/XY/XYY. Body and facial phenotypes increased with higher mosaicism proportions, with a relatively high correlation shown with Pearson correlation analysis (r = 0.26, p = 1.7e-06). The incidence of congenital heart malformations was 25.56%, mainly involving a bicuspid aortic valve, and were more common in patients who had complete loss of an X-chromosome. However, this relationship was not present for renal disease (p = 0.26), central nervous system, thyroid, or liver disease. The mosaicism (XO/XX) is the most common karyotype of TS in screened cases. The phenotypes in children with TS may increase with the proportion of X-chromosome deletions, but the renal disease and comorbidities did not show the same characteristics.

Dosage-dependent effects of FGFR2W290R mutation on craniofacial shape and cellular dynamics of the basicranial synchondroses.

Craniosynostosis 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.

Identification of the DNA methylation signature of Mowat-Wilson syndrome

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis.