AIM: To utilize three-dimensional (3D) geometric morphometry for visualization of the level of facial asymmetry in patients with the oculo-auriculo-vertebral spectrum (OAVS). MATERIALS AND METHODS: Three-dimensional facial scans of 25 Czech patients with OAVS were processed. The patients were divided into subgroups according to Pruzansky classification. For 13 of them, second 3D facial scans were obtained. The 3D facial scans were processed using geometric morphometry. Soft tissue facial asymmetry in the sagittal plane and its changes in two time spots were visualized using colour-coded maps with a thermometre-like scale. RESULTS: Individual facial asymmetry was visualized in all patients as well as the mean facial asymmetry for every Pruzansky subgroup. The mean colour-coded maps of type I and type IIA subgroups showed no differences in facial asymmetry, more pronounced asymmetry in the middle and the lower facial third was found between type IIA and type IIB (maximum 1.5 mm) and between type IIB and type III (maximum 2 mm). The degree of intensity facial asymmetry in affected middle and lower facial thirds did not change distinctly during the two time spots in all subgroups. CONCLUSIONS: The 3D geometric morphometry in OAVS patients could be a useful tool for objective facial asymmetry assessment in patients with OAVS. The calculated colour-coded maps are illustrative and useful for clinical evaluation.

• Keywords
• facial soft tissue asymmetry, geometric morphometry, oculo‐auriculo‐vertebral spectrum, three‐dimensional scanning,
• MeSH
• Facial Asymmetry * diagnostic imaging   pathology   MeSH
• Child MeSH
• Goldenhar Syndrome * diagnostic imaging   pathology   MeSH
• Cephalometry methods   MeSH
• Humans MeSH
• Adolescent MeSH
• Face anatomy & histology   diagnostic imaging   pathology   MeSH
• Imaging, Three-Dimensional * methods   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Cluster analyzes of facial models of autistic patients aim to clarify whether it is possible to diagnose autism on the basis of facial features and further to stratify the autism spectrum disorder. We performed a cluster analysis of sets of 3D scans of ASD patients (116) and controls (157) using Euclidean and geodesic distances in order to recapitulate the published results on the Czech population. In the presented work, we show that the major factor determining the clustering structure and consequently also the correlation of resulting clusters with autism severity degree is body mass index corrected for age (BMIFA). After removing the BMIFA effect from the data in two independent ways, both the cluster structure and autism severity correlations disappeared. Despite the fact that the influence of body mass index (BMI) on facial dimensions was studied many times, this is the first time to our knowledge when BMI was incorporated into the faces clustering study and it thereby casts doubt on previous results. We also performed correlation analysis which showed that the only correction used in the existing clustering studies-dividing the facial distance by the average value within the face-is not eliminating correlation between facial distances and BMIFA within the facial cohort.

• Keywords
• 3D morphometry, Autism spectrum disorders, Cluster analysis, Facial landmarks,
• MeSH
• Child MeSH
• Body Mass Index * MeSH
• Humans MeSH
• Adolescent MeSH
• Face * diagnostic imaging   MeSH
• Autism Spectrum Disorder * diagnostic imaging   MeSH
• Child, Preschool MeSH
• Cluster Analysis MeSH
• Imaging, Three-Dimensional * methods   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

• MeSH
• Algorithms MeSH
• Biological Ontologies * MeSH
• Phenotype MeSH
• Genomics MeSH
• Humans MeSH
• Rare Diseases MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Congenital myasthenic syndromes (CMSs) are characterized by hypotonia, episodic apnea, muscle weakness, ptosis and generalized fatigability. CMS type 20 (CMS20) is a rare disorder caused by variants in SLC5A7. In contrast to most other CMSs, CMS20 is also associated with neurodevelopmental disorders (NDDs). Only 19 patients from 14 families have been reported so far. METHODS: We studied a 12-year-old boy with symptoms manifested at six weeks of age. Later, he also showed speech delay, moderate intellectual disability and autism. Analysis of CMS genes known at the time of clinical diagnosis yielded no results. Trio exome sequencing (ES) was performed. RESULTS: ES revealed compound heterozygosity for two SLC5A7 variants, p.(Asn431Lys) and p.(Ile291Thr). While the first variant was absent from all databases, the second variant has already been described in one patient. In silico analysis of known pathogenic SLC5A7 variants showed that variants with a higher predicted deleteriousness may be associated with earlier onset and increased severity of neuromuscular manifestations. CONCLUSION: Our patient confirms that CMS20 can be associated with NDDs. The study illustrates the strength of ES in deciphering the genetic basis of rare diseases, contributes to characterization of CMS20 and suggests trends in genotype-phenotype correlation in CMS20.

• Keywords
• SLC5A7, congenital myasthenic syndrome type 20, exome sequencing, neurodevelopmental disorders,
• MeSH
• Genetic Association Studies MeSH
• Heterozygote MeSH
• Myasthenic Syndromes, Congenital * genetics   diagnosis   MeSH
• Humans MeSH
• Intellectual Disability * complications   MeSH
• Mutation, Missense MeSH
• Symporters * genetics   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• SLC5A7 protein, human MeSH Browser
• Symporters * MeSH

Zimmermann-Laband syndrome is a rare, heterogeneous disorder characterized by gingival hypertrophy or fibromatosis, aplastic/hypoplastic nails, hypoplasia of the distal phalanges, hypertrichosis, various degrees of intellectual disability, and distinctive facial features. Three genes are considered causative for ZLS: KCNH1, KCNN3, and ATP6V1B2. We report on a pair of female concordant monozygotic twins, both carrying a novel pathogenic variant in the KCNN3 gene, identified using exome sequencing. Only six ZLS patients with the KCNN3 pathogenic variant have been reported so far. The twins show facial dysmorphism, hypoplastic distal phalanges, aplasia or hypoplasia of nails, and hypertrichosis. During infancy, they showed mild developmental delays, mainly speech. They successfully completed secondary school education and are socio-economically independent. Gingival overgrowth is absent in both individuals. Our patients exhibited an unusually mild phenotype compared to published cases, which is an important diagnostic finding for proper genetic counseling for Zimmermann-Laband syndrome patients and their families.

• Keywords
• KCNN3, Zimmermann-Laband syndrome, channelopathy, gingival fibromatosis, monozygotic twins,
• MeSH
• Twins, Monozygotic genetics   MeSH
• Phenotype MeSH
• Fibromatosis, Gingival * diagnosis   genetics   MeSH
• Hyperplasia MeSH
• Hypertrichosis * genetics   MeSH
• Craniofacial Abnormalities MeSH
• Humans MeSH
• Nails, Malformed congenital   MeSH
• Abnormalities, Multiple MeSH
• Small-Conductance Calcium-Activated Potassium Channels genetics   MeSH
• Hand Deformities, Congenital MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• KCNN3 protein, human MeSH Browser
• Small-Conductance Calcium-Activated Potassium Channels MeSH

The clinical utility of computational phenotyping for both genetic and rare diseases is increasingly appreciated; however, its true potential is yet to be fully realized. Alongside the growing clinical and research availability of sequencing technologies, precise deep and scalable phenotyping is required to serve unmet need in genetic and rare diseases. To improve the lives of individuals affected with rare diseases through deep phenotyping, global big data interrogation is necessary to aid our understanding of disease biology, assist diagnosis, and develop targeted treatment strategies. This includes the application of cutting-edge machine learning methods to image data. As with most digital tools employed in health care, there are ethical and data governance challenges associated with using identifiable personal image data. There are also risks with failing to deliver on the patient benefits of these new technologies, the biggest of which is posed by data siloing. The Minerva Initiative has been designed to enable the public good of deep phenotyping while mitigating these ethical risks. Its open structure, enabling collaboration and data sharing between individuals, clinicians, researchers and private enterprise, is key for delivering precision public health.

• Keywords
• Faces, data protection, data sharing, patient information, phenotyping, rare disease,
• Publication type
• Journal Article MeSH

Three-dimensional (3D) virtual facial models facilitate genotype-phenotype correlations and diagnostics in clinical dysmorphology. Within cross-sectional analysis of both genders we evaluated facial features in representative cohorts of Czech patients with Williams-Beuren-(WBS; 12 cases), Noonan-(NS; 14), and 22q11.2 deletion syndromes (22q11.2DS; 20) and compared their age-related developmental trajectories to 21 age, sex and ethnically matched controls in 3-18 years of age. Using geometric morphometry statistically significant differences in facial morphology were found in all cases compared to controls. The dysmorphic features observed in WBS were specific and manifested in majority of cases. During ontogenesis, dysmorphic features associated with increased facial convexity become more pronounced whereas other typical features remained relatively stable. Dysmorphic features observed in NS cases were mostly apparent during childhood and gradually diminished with age. Facial development had a similar progress as in controls, while there has been increased growth of patients' nose and chin in adulthood. Facial characteristics observed in 22q11.2DS, except for hypoplastic alae nasi, did not correspond with the standard description of its facial phenotype because of marked facial heterogeneity of this clinical entity. Because of the sensitivity of 3D facial morphometry we were able to reach statistical significance even in smaller retrospective patient cohorts, which proves its clinical utility within the routine setting.

• Keywords
• 22q11.2 deletion syndrome, 3D facial gestalt analysis, 3D imaging, Noonan syndrome, Williams-Beuren syndrome, dysmorphology, facial shape and size, geometric morphometry, ontogenetic trajectory,
• MeSH
• DiGeorge Syndrome diagnosis   genetics   MeSH
• Child MeSH
• Facies * MeSH
• Humans MeSH
• Adolescent MeSH
• Models, Anatomic * MeSH
• Noonan Syndrome diagnosis   genetics   MeSH
• Child, Preschool MeSH
• Cross-Sectional Studies MeSH
• Williams Syndrome diagnosis   genetics   MeSH
• Imaging, Three-Dimensional * MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

Kabuki syndrome is mainly caused by dominant de-novo pathogenic variants in the KMT2D and KDM6A genes. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult, even for experienced clinical geneticists. Herein we present molecular genetic findings of causal genetic variation using array comparative genome hybridization and a Mendeliome analysis, utilizing targeted exome analysis focusing on regions harboring rare disease-causing variants in Kabuki-like patients which remained KMT2D/KDM6A-negative. The aCGH analysis revealed a pathogenic CNV in the 14q11.2 region, while targeted exome sequencing revealed pathogenic variants in genes associated with intellectual disability (HUWE1, GRIN1), including a gene coding for mandibulofacial dysostosis with microcephaly (EFTUD2). Lower values of the MLL2-Kabuki phenotypic score are indicative of Kabuki-like phenotype (rather than true Kabuki syndrome), where aCGH and Mendeliome analyses have high diagnostic yield. Based on our findings we conclude that for new patients with Kabuki-like phenotypes it is possible to choose a specific molecular testing approach that has the highest detection rate for a given MLL2-Kabuki score, thus fostering more precise patient diagnosis and improved management in these genetically- and phenotypically heterogeneous clinical entities.

• Keywords
• EFTUD2, GRIN1, HUWE1, Intellectual disability, KMT2D, Kabuki syndrome,
• MeSH
• Child MeSH
• DNA-Binding Proteins genetics   MeSH
• Peptide Elongation Factors genetics   MeSH
• Exome MeSH
• Phenotype * MeSH
• Genetic Heterogeneity * MeSH
• Genotype * MeSH
• Histone Demethylases genetics   MeSH
• Nuclear Proteins genetics   MeSH
• Hematologic Diseases diagnosis   genetics   physiopathology   MeSH
• Humans MeSH
• Chromosomes, Human, Pair 14 MeSH
• Ribonucleoprotein, U5 Small Nuclear genetics   MeSH
• Mandibulofacial Dysostosis genetics   MeSH
• Intellectual Disability genetics   MeSH
• Microcephaly genetics   MeSH
• Abnormalities, Multiple diagnosis   genetics   physiopathology   MeSH
• Neoplasm Proteins genetics   MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Face abnormalities   physiopathology   MeSH
• Child, Preschool MeSH
• Nerve Tissue Proteins genetics   MeSH
• Receptors, N-Methyl-D-Aspartate genetics   MeSH
• Comparative Genomic Hybridization MeSH
• Ubiquitin-Protein Ligases genetics   MeSH
• Vestibular Diseases diagnosis   genetics   physiopathology   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• DNA-Binding Proteins MeSH
• EFTUD2 protein, human MeSH Browser
• Peptide Elongation Factors MeSH
• GRIN1 protein, human MeSH Browser
• Histone Demethylases MeSH
• HUWE1 protein, human MeSH Browser
• Nuclear Proteins MeSH
• KDM6A protein, human MeSH Browser
• KMT2D protein, human MeSH Browser
• Ribonucleoprotein, U5 Small Nuclear MeSH
• Neoplasm Proteins MeSH
• Tumor Suppressor Proteins MeSH
• Nerve Tissue Proteins MeSH
• Receptors, N-Methyl-D-Aspartate MeSH
• Ubiquitin-Protein Ligases MeSH

BACKGROUND: With only 11 patients reported, 5p tetrasomy belongs to rare postnatal findings. Most cases are due to small supernumerary marker chromosomes (sSMCs) or isochromosomes. The patients share common but unspecific symptoms such as developmental delay, seizures, ventriculomegaly, hypotonia, and fifth finger clinodactyly. Simple interstitial duplications leading to trisomies of parts of 5p are much more frequent and better described. Duplications encompassing 5p13.2 cause a defined syndrome with macrocephaly, distinct facial phenotype, heart defects, talipes equinovarus, feeding difficulties, respiratory distress and anomalies of the central nervous system, developmental delay and hypotonia. CASE PRESENTATION: We present a boy with dysmorphic features, developmental delay, intellectual disability and congenital anomalies, and a mosaic sSMC inv dup(5)(p15.33p15.1). He is the fourth and the oldest reported patient with distal 5p tetrasomy. His level of mosaicism was significantly different in lymphocytes (13.2%) and buccal cells (64.7%). The amplification in our patient is smaller than that in the three previously published patients but the only phenotype difference is the absence of seizures in our patient. CONCLUSIONS: Our observations indicate that for the assessment of prognosis, especially with respect to intellectual functioning, the level of mosaicism could be more important than the extent of amplification and the number of extra copies. Evaluation of the phenotypical effect of rare chromosomal aberrations is challenging and each additional case is valuable for refinement of the genotype-phenotype correlation. Moreover, our patient demonstrates that if the phenotype is severe and if the level of sSMC mosaicism is low in lymphocytes, other tissues should be tested.

• Keywords
• 5p tetrasomy, Intellectual disability, Marker chromosome, Mosaicism,
• Publication type
• Journal Article MeSH
• Case Reports MeSH

OBJECTIVES: To evaluate facial asymmetry changes in pre-school patients with orofacial clefts after neonatal cheiloplasty and to compare facial asymmetry with age-matched healthy controls. METHODS AND MATERIALS: The sample consisted of patients with unilateral cleft lip (UCL), unilateral cleft lip and palate (UCLP), and bilateral cleft lip and palate (BCLP). The patients were divided in two age groups with a mean age of 3 years (n = 51) and 4.5 years (n = 45), respectively, and 78 age-matched individuals as controls. Three-dimensional (3D) facial scans were analyzed using geometric morphometry and multivariate statistics. RESULTS: Geometric morphometry showed positive deviations from perfect symmetry on the right side of the forehead in the intervention groups and the controls. The UCL groups showed the greatest asymmetric nasolabial area on the cleft-side labia and the contralateral nasal tip. The UCLP group showed, moreover, asymmetry in buccal region due to typical maxillar hypoplasia, which was accentuated in the older group. The BCLP groups showed slightly similar but greater asymmetry than the control groups, except for the philtrum region. CONCLUSIONS: Asymmetry of each of the cleft groups significantly differed from the controls. Except for the buccal region in the UCLP and BCLP groups, asymmetry did not significantly increase with age.

• Keywords
• 3D scanning, Asymmetry, Cleft, Geometric morphometry, Neonatal cheiloplasty,
• MeSH
• Facial Asymmetry diagnosis   epidemiology   etiology   MeSH
• Child MeSH
• Infant MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Face abnormalities   surgery   MeSH
• Child, Preschool MeSH
• Lip abnormalities   surgery   MeSH
• Cleft Palate complications   surgery   MeSH
• Cleft Lip complications   surgery   MeSH
• Plastic Surgery Procedures adverse effects   methods   MeSH
• Imaging, Three-Dimensional methods   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH