GestaltMatcher Database - A global reference for facial phenotypic variability in rare human diseases.

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

GestaltMatcher Database - A global reference for the facial phenotypic variability of rare human diseases.

Dysmorphologists sometimes encounter challenges in recognizing disorders due to phenotypic variability influenced by factors such as age and ethnicity. Moreover, the performance of Next Generation Phenotyping Tools such as GestaltMatcher is dependent on the diversity of the training set. Therefore, we developed GestaltMatcher Database (GMDB) - a global reference for the phenotypic variability of rare diseases that complies with the FAIR-principles. We curated dysmorphic patient images and metadata from 2,224 publications, transforming GMDB into an online dynamic case report journal. To encourage clinicians worldwide to contribute, each case can receive a Digital Object Identifier (DOI), making it a citable micro-publication. This resulted in a collection of 2,312 unpublished images, partly with longitudinal data. We have compiled a collection of 10,189 frontal images from 7,695 patients representing 683 disorders. The web interface enables gene- and phenotype-centered queries for registered users (https://db.gestaltmatcher.org/). Despite the predominant European ancestry of most patients (59%), our global collaborations have facilitated the inclusion of data from frequently underrepresented ethnicities, with 17% Asian, 4% African, and 6% with other ethnic backgrounds. The analysis has revealed a significant enhancement in GestaltMatcher performance across all ethnic groups, incorporating non-European ethnicities, showcasing a remarkable increase in Top-1-Accuracy by 31.56% and Top-5-Accuracy by 12.64%. Importantly, this improvement was achieved without altering the performance metrics for European patients. GMDB addresses dysmorphology challenges by representing phenotypic variability and including underrepresented groups, enhancing global diagnostic rates and serving as a vital clinician reference database.

Oral-genital HPV infection transmission, concordance of HPV genotypes and genital lesions among spouses/ partners of patients diagnosed with HPV-related head and neck squamous cell carcinoma (HNSCC): a scoping review.

BACKGROUND: There is an increase in number of Human Papillomavirus related head and neck squamous cell carcinoma (HPV-related HNSCC) High risk HPV(HR-HPV) types can be cleared by an infected person, however, some can persist and develop HN cancer. There is a broad knowledge gap regarding HPV and related cancers. MAIN TEXT: The aim of this review is to assess existing published knowledge on oral-genital HPV transmission, concordance of HPV genotypes and risk of oral or/and genital lesions among spouses/partners of patients diagnosed with HPV-related HNSCC, identify gaps in the current research and highlight areas that requires further inquiry. METHOD: Database like Pub med, Google Scholar, Scopus, Puplon, Wiley online library were used for search strategy. Published papers on transmission, concordance of HPV genotypes and genital lesions among spouses/partners of patients diagnosed with HPV-related HNSCC were included. Papers published from January1,2000 to October 31, 2022 were included. The published papers included are 8 Case reports, 2 cross-sectional studies, 3 Cohort studies and 2 systematic reviews. RESULTS: A total of 2125 citations were retrieved from the five sources. 15papers were included. Case reports reported concurrent HPV-related oropharyngeal, tonsillar, unspecified HNSCC, laryngeal and nasopharyngeal carcinoma among couples. The two cross-sectional studies were done. Almost all the tumors taken from patients with HPV-related oropharyngeal carcinoma (HPV-related OPC) and their spouses were positive for identical HPV 16 type. The three cohort studies showed an increase risk of upper aero-digestive tract cancer among male spouses of females with cervical cancer. Two systematic reviews reviewed literature studies which evaluated concurrent cases of HPV-related Oropharyngeal cancers. Examination of these papers showed that the majority of the studies suggested that there is HPV transmission, concordance and risk of HNSCC cancer among spouses with HPV-related oral-genital cancer. No studies evaluated the risk of developing genital cancer in spouses of patients with HNSCC. CONCLUSION: The findings of this review highlighted big need of further research on oral-genital HPV infection among spouses of patients diagnosed with HPV-related HNSCC. Studies are needed to evaluate the risk of getting genital and upper aero-digestive tract HPV-related cancer among spouses with HPV-related HNC.

A Mendelian randomization study of genetic liability to post-traumatic stress disorder and risk of ischemic stroke.

Observational studies have shown an association between post-traumatic stress disorder (PTSD) and ischemic stroke (IS) but given the susceptibility to confounding it is unclear if these associations represent causal effects. Mendelian randomization (MR) facilitates causal inference that is robust to the influence of confounding. Using two sample MR, we investigated the causal effect of genetic liability to PTSD on IS risk. Ancestry-specific genetic instruments of PTSD and four quantitative sub-phenotypes of PTSD, including hyperarousal, avoidance, re-experiencing, and total symptom severity score (PCL-Total) were obtained from the Million Veteran Programme (MVP) using a threshold P value (P) of <5 × 10-7, clumping distance of 1000 kilobase (Mb) and r2 < 0.01. Genetic association estimates for IS were obtained from the MEGASTROKE consortium (Ncases = 34,217, Ncontrols = 406,111) for European ancestry individuals and from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) (Ncases = 3734, Ncontrols = 18,317) for African ancestry individuals. We used the inverse-variance weighted (IVW) approach as the main analysis and performed MR-Egger and the weighted median methods as pleiotropy-robust sensitivity analyses. In European ancestry individuals, we found evidence of an association between genetic liability to PTSD avoidance, and PCL-Total and increased IS risk (odds ratio (OR)1.04, 95% Confidence Interval (CI) 1.007-1.077, P = 0.017 for avoidance and (OR 1.02, 95% CI 1.010-1.040, P = 7.6 × 10-4 for PCL total). In African ancestry individuals, we found evidence of an association between genetically liability to PCL-Total and reduced IS risk (OR 0.95 (95% CI 0.923-0.991, P = 0.01) and hyperarousal (OR 0.83 (95% CI 0.691-0.991, P = 0.039) but no association was observed for PTSD case-control, avoidance, or re-experiencing. Similar estimates were obtained with MR sensitivity analyses. Our findings suggest that specific sub-phenotypes of PTSD, such as hyperarousal, avoidance, PCL total, may have a causal effect on people of European and African ancestry's risk of IS. This shows that the molecular mechanisms behind the relationship between IS and PTSD may be connected to symptoms of hyperarousal and avoidance. To clarify the precise biological mechanisms involved and how they may vary between populations, more research is required.

Clinicopathological Characteristics and Mutational Landscape of APC, HOXB13, and KRAS among Rwandan Patients with Colorectal Cancer.

Cancer research in Rwanda is estimated to be less than 1% of the total African cancer research output with limited research on colorectal cancer (CRC). Rwandan patients with CRC are young, with more females being affected than males, and most patients present with advanced disease. Considering the paucity of oncological genetic studies in this population, we investigated the mutational status of CRC tissues, focusing on the Adenomatous polyposis coli (APC), Kirsten rat sarcoma (KRAS), and Homeobox B13 (HOXB13) genes. Our aim was to determine whether there were any differences between Rwandan patients and other populations. To do so, we performed Sanger sequencing of the DNA extracted from formalin-fixed paraffin-embedded adenocarcinoma samples from 54 patients (mean age: 60 years). Most tumors were located in the rectum (83.3%), and 92.6% of the tumors were low-grade. Most patients (70.4%) reported never smoking, and 61.1% of patients had consumed alcohol. We identified 27 variants of APC, including 3 novel mutations (c.4310_4319delAAACACCTCC, c.4463_4470delinsA, and c.4506_4507delT). All three novel mutations are classified as deleterious by MutationTaster2021. We found four synonymous variants (c.330C>A, c.366C>T, c.513T>C, and c.735G>A) of HOXB13. For KRAS, we found six variants (Asp173, Gly13Asp, Gly12Ala, Gly12Asp, Gly12Val, and Gln61His), the last four of which are pathogenic. In conclusion, here we contribute new genetic variation data and provide clinicopathological information pertinent to CRC in Rwanda.

Community engagement in epigenomic and neurocognitive research on post-traumatic stress disorder in Rwandans exposed to the 1994 genocide against the Tutsi: lessons learned.

Epigenomic and neurocognitive studies have provided new perspectives on post-traumatic stress disorder and its intergenerational transmission. This article outlines the lessons learned from community engagement (CE) in such research on Rwandan genocide survivors. A strong trauma-related response was observed within the research project-targeted community (genocide survivors) during explanation of the project. CE also revealed privacy concerns, as community members worried that any leakage of genetic/(epi)genomic data could affect not only themselves but also their close relatives. Adopting a culture of CE in the process of research implementation enables the prioritization of targeted community needs and interests. Furthermore, CE has stimulated the development of mental healthcare interventions, which married couples can apply to protect their offspring and thus truly break the cycle of inherited vulnerability.

Studies of how human genes are affected by the environment (epigenomic studies) have provided new perspectives on post-traumatic stress disorder and its intergenerational transmission. This article describes the lessons learned from community engagement (CE) in this type of research in a Rwandan genocide-exposed population. A strong trauma-related response was observed within the community while explaining the project. CE also revealed the participants' privacy concerns related to leakage of genetic/(epi)genomic data that could also affect their close relatives. Adopting a culture of CE in the process of research implementation enables the prioritization of community needs and interests. CE has furthermore stimulated the development of preventive interventions for married couples to protect their offspring and thus truly break the cycle of inherited vulnerability.

Leveraging artificial intelligence and data science techniques in harmonizing, sharing, accessing and analyzing SARS-COV-2/COVID-19 data in Rwanda (LAISDAR Project): study design and rationale.

BACKGROUND: Since the outbreak of COVID-19 pandemic in Rwanda, a vast amount of SARS-COV-2/COVID-19-related data have been collected including COVID-19 testing and hospital routine care data. Unfortunately, those data are fragmented in silos with different data structures or formats and cannot be used to improve understanding of the disease, monitor its progress, and generate evidence to guide prevention measures. The objective of this project is to leverage the artificial intelligence (AI) and data science techniques in harmonizing datasets to support Rwandan government needs in monitoring and predicting the COVID-19 burden, including the hospital admissions and overall infection rates. METHODS: The project will gather the existing data including hospital electronic health records (EHRs), the COVID-19 testing data and will link with longitudinal data from community surveys. The open-source tools from Observational Health Data Sciences and Informatics (OHDSI) will be used to harmonize hospital EHRs through the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). The project will also leverage other OHDSI tools for data analytics and network integration, as well as R Studio and Python. The network will include up to 15 health facilities in Rwanda, whose EHR data will be harmonized to OMOP CDM. EXPECTED RESULTS: This study will yield a technical infrastructure where the 15 participating hospitals and health centres will have EHR data in OMOP CDM format on a local Mac Mini ("data node"), together with a set of OHDSI open-source tools. A central server, or portal, will contain a data catalogue of participating sites, as well as the OHDSI tools that are used to define and manage distributed studies. The central server will also integrate the information from the national Covid-19 registry, as well as the results of the community surveys. The ultimate project outcome is the dynamic prediction modelling for COVID-19 pandemic in Rwanda. DISCUSSION: The project is the first on the African continent leveraging AI and implementation of an OMOP CDM based federated data network for data harmonization. Such infrastructure is scalable for other pandemics monitoring, outcomes predictions, and tailored response planning.

Leukocyte methylomic imprints of exposure to the genocide against the Tutsi in Rwanda: a pilot epigenome-wide analysis.

Aim & methods: We conducted a pilot epigenome-wide association study of women from Tutsi ethnicity exposed to the genocide while pregnant and their resulting offspring, and a comparison group of women who were pregnant at the time of the genocide but living outside of Rwanda.Results: Fifty-nine leukocyte-derived DNA samples survived quality control: 33 mothers (20 exposed, 13 unexposed) and 26 offspring (16 exposed, 10 unexposed). Twenty-four significant differentially methylated regions (DMRs) were identified in mothers and 16 in children. Conclusions:In utero genocide exposure was associated with CpGs in three of the 24 DMRs: BCOR, PRDM8 and VWDE, with higher DNA methylation in exposed versus unexposed offspring. Of note, BCOR and VWDE show significant correlation between brain and blood DNA methylation within individuals, suggesting these peripherally derived signals of genocide exposure may have relevance to the brain.

Lay abstract The 1994 Rwandan genocide against ethnic Tutsi has been associated with adverse mental health outcomes in survivors decades later, but the molecular mechanisms that contribute to this association remain poorly characterized. Epigenetic mechanisms such as DNA methylation regulate gene function and change in response to life experiences. We identified differentially methylated regions (DMRs) in genocide-exposed versus unexposed mothers and children. In utero genocide exposure was linked with methylation differences in three maternal DMRs, with higher methylation in exposed offspring. Two of three DMRs show correlation between brain and blood methylation within individuals, suggesting that peripherally derived signals of genocide exposure may be relevant to the brain.

Exploring Perceptions and Acceptance of Minimally Invasive Tissue Sampling among Bereaved Relatives and Health-Care Professionals in Rwanda.

PURPOSE: In most low- and lower middle-income countries (LMICs), minimally invasive tissue sampling (MITS) is a relatively new procedure for identifying the cause of death (CoD). This study aimed to explore perceptions and acceptance of bereaved families and health-care professionals regarding MITS in the context of MITS initiation in Rwanda as an alternative to clinical autopsy. METHODS: This was a qualitative phenomenological study with thematic analysis. Participants were bereaved relatives (individual interviews) and health-care professionals (focus-group discussions) involved in MITS implementation. It was conducted in the largest referral and teaching hospital in Rwanda. RESULTS: Motivators of MITS acceptance included eagerness to know the CoD, noninvasiveness of MITS, trust in medics, and the fact that it was free. Barriers to consent to MITS included inadequate explanations from health-care professionals, high socioeconomic status, lack of power to make decisions, and lack of trust in medics. Health-care professionals perceived both conventional autopsy and MITS as gold-standard procedures in CoD determination. They recommended including MITS among hospital services and commended the post-MITS multidisciplinary discussion panel in CoD determination. They pointed out that there might be reticence in approaching bereaved relatives to obtain consent for MITS. Both groups of participants highlighted the issue of delay in releasing MITS results. CONCLUSION: Both health-care professionals and bereaved relatives appreciate that MITS is an acceptable procedure to include in routine hospital services. Dealing with barriers met by either group is to be considered in the eventual next phases of MITS implementation in Rwanda and similar sociocultural contexts.

Development of a Mobile App to Improve Numeracy Skills of Children With Autism Spectrum Disorder: Participatory Design and Usability Study.

BACKGROUND: The use of information and communication technologies is transforming the lives of millions of people including children with autism spectrum disorder (ASD). However, the process of developing a user-friendly and effective mobile app needs to follow a complex standard protocol and culture-sensitive customization, and involves multiple sectors. This complex work becomes even more challenging when considering children with ASD in low- and middle-income countries as the users. OBJECTIVE: This study aimed to design and develop a more intuitive mobile app to improve numeracy skills of children with ASD in Rwanda and evaluate the usability of the app. METHODS: A participatory design approach was utilized in this study in which 40 children with ASD, 5 teachers, and 10 parents of children with ASD participated in focus group discussions (FGDs) and usability testing. A narrative literature review was performed to explore existing mobile apps and compare previous studies to design the questions for FGD and facilitate a framework for designing the app. The agile methodology was used to develop the mobile app, and the heuristics evaluation method was used to test and evaluate the usability of the initial version of the app to improve its functionalities. The interviews were recorded, transcribed, and analyzed following the guidelines of the qualitative narrative analysis (QNA) method. RESULTS: During the FGDs the respondents shared their need for a mobile app in teaching and learning numeracy for children with ASD and pointed to possibilities of integrating the mobile app into existing curriculum. Ten themes emerged from the FGDs and exercise of developing the mobile app. The themes were related to (1) teaching and learning numeracy for children with ASD, (2) planning and development of a mobile app for a person with ASD, (3) testing a mobile app, (4) strength of the developed app against the existing ones, (5) behavioral maintenance and relapse prevention, (6) possibilities to integrate the mobile app into the existing curriculum, (7) data protection for users, (8) social implications, (9) challenges in Rwanda, and (10) focus on future. CONCLUSIONS: The community plays an important role in the planning, development, and evaluation of a mobile app for children with ASD. In this study, inputs from teachers and parents resulted in an optimally designed mobile app that can improve numeracy skills in children diagnosed with ASD to support the implementation of competency-based curriculum in Rwanda.

A pooled testing strategy for identifying SARS-CoV-2 at low prevalence.

Suppressing infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will probably require the rapid identification and isolation of individuals infected with the virus on an ongoing basis. Reverse-transcription polymerase chain reaction (RT-PCR) tests are accurate but costly, which makes the regular testing of every individual expensive. These costs are a challenge for all countries around the world, but particularly for low-to-middle-income countries. Cost reductions can be achieved by pooling (or combining) subsamples and testing them in groups1-7. A balance must be struck between increasing the group size and retaining test sensitivity, as sample dilution increases the likelihood of false-negative test results for individuals with a low viral load in the sampled region at the time of the test8. Similarly, minimizing the number of tests to reduce costs must be balanced against minimizing the time that testing takes, to reduce the spread of the infection. Here we propose an algorithm for pooling subsamples based on the geometry of a hypercube that, at low prevalence, accurately identifies individuals infected with SARS-CoV-2 in a small number of tests and few rounds of testing. We discuss the optimal group size and explain why, given the highly infectious nature of the disease, largely parallel searches are preferred. We report proof-of-concept experiments in which a positive subsample was detected even when diluted 100-fold with negative subsamples (compared with 30-48-fold dilutions described in previous studies9-11). We quantify the loss of sensitivity due to dilution and discuss how it may be mitigated by the frequent re-testing of groups, for example. With the use of these methods, the cost of mass testing could be reduced by a large factor. At low prevalence, the costs decrease in rough proportion to the prevalence. Field trials of our approach are under way in Rwanda and South Africa. The use of group testing on a massive scale to monitor infection rates closely and continually in a population, along with the rapid and effective isolation of people with SARS-CoV-2 infections, provides a promising pathway towards the long-term control of coronavirus disease 2019 (COVID-19).

The Sickle Cell Disease Ontology: Enabling Collaborative Research and Co-Designing of New Planetary Health Applications.

Sickle cell disease (SCD) is one of the most common blood disorders impacting planetary health. Over 300,000 newborns are diagnosed with SCD each year globally, with an increasing trend. The sickle cell disease ontology (SCDO) is the most comprehensive multidisciplinary SCD knowledge portal. The SCDO was collaboratively developed by the SCDO working group, which includes experts in SCD and data standards from across the globe. This expert review presents highlights and lessons learned from the fourth SCDO workshop that marked the beginning of applications toward planetary health impact, and with an eye to empower and cultivate multisite SCD collaborative research. The workshop was organized by the Sickle Africa Data Coordinating Center (SADaCC) and attended by 44 participants from 14 countries, with 2 participants connecting remotely. Notably, from the standpoint of democratizing and innovating scientific meeting design, an SCD patient advocate also presented at the workshop, giving a broader real-life perspective on patients' aspirations, needs, and challenges. A major component of the workshop was new approaches to harness SCDO to harmonize data elements used by different studies. This was facilitated by a web-based platform onto which participants uploaded data elements from previous or ongoing SCD-relevant research studies before the workshop, making multisite collaborative research studies based on existing SCD data possible, including multisite cohort, SCD global clinical trials, and SCD community engagement approaches. Trainees presented proposals for systematic literature reviews in key SCD research areas. This expert review emphasizes potential and prospects of SCDO-enabled data standards and harmonization to facilitate large-scale global SCD collaborative initiatives. As the fields of public and global health continue to broaden toward planetary health, the SCDO is well poised to play a prominent role to decipher SCD pathophysiology further, and co-design diagnostics and therapeutics innovation in the field.

Rubinstein-Taybi syndrome in diverse populations.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.

Burden of post-traumatic stress disorder in postgenocide Rwandan population following exposure to 1994 genocide against the Tutsi: A meta-analysis.

BACKGROUND: The 1994 genocide against Tutsi resulted in a massive death toll that reached one million people. Despite the tremendous efforts made to mitigate the adverse effects of the genocide, a substantial burden of mental health disorders still exists including the notably high prevalence of post-traumatic stress disorder (PTSD) among genocide survivors. However, a synthesized model of PTSD vulnerability in this population is currently lacking. METHODS: A meta-analysis of 19 original research studies that reported PTSD prevalence (n = 12,610). Medline-PubMed and Science.gov were key search engines. Random-Effects Model (k = 19; tau^2 estimator: DL) was applied. Data extraction, synthesis, and meta-analysis were carried out using R. RESULTS: The total of 2957 out of 11,746 individuals suffered from PTSD. The summary proportion is 25% (95% CI=0.16,0.36). The tau^2 is 0.06 (95% CI=0.03,0.14) in the absence of subgroups, and the Q-statistic is 2827.65 (p<0.0001), all of which suggests high heterogeneity in the effect sizes. Year of data collection and Year of publication were significant moderators. PTSD pooled prevalence in the genocide survivor category was estimated at 37% (95% CI=0.21,0.56). CONCLUSION: The PTSD prevalence among genocide survivors is considerably higher compared to the general Rwandan population. The burden of PTSD in the general Rwandan population declined significantly over time, likely due to treatment of symptoms through strong national mental health programs, peace building and resolution of symptoms over time. To the best of our knowledge little evidence has reported the burden of PTSD prevalence in African post conflict zones particularly in Rwanda. LIMITATION: Limitations of our review include the use of retrospective studies and studies with very small sample sizes, as well as language criterion.

Turner syndrome in diverse populations.

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p < .001) was found for TS versus general population controls and 0.925 (p < .001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome.

VPS51 biallelic variants cause microcephaly with brain malformations: A confirmatory report.

Whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, with brain malformations consisting of cerebellar atrophy in the eldest affected and hypoplastic corpus callosum in the younger sister; revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sorting-associated protein, one the four subunits of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a single child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.

Cornelia de Lange syndrome in diverse populations.

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.