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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., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders.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 This includes previously unpublished reports for more than 40% of the African patients.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.

Infantile hypercalcemia (IH) is a rare genetic disorder characterized by hypercalcemia, hypercalciuria, low parathyroid hormone, and nephrocalcinosis during the first months of life. Biallelic variants in the genes CYP24A1 and SCL34A1 cause IH1 and 2, respectively. We present the case of a newborn with an antenatal diagnosis of IH2 due to the identification of echogenic, yet normal-sized kidneys at 23 weeks gestation. Trio whole-exome sequencing initially identified only a heterozygous pathogenic variant in SLC34A1. Re-analysis of the exome data because of the clinical suspicion of IH2 revealed a 21-basepair deletion in trans that had initially been filtered out because of its high allele frequency. The diagnosis of IH2 enabled postnatal screening for hypercalcemia, present already at week 1, resulting in early treatment with phosphate supplementation and vitamin D avoidance. In the subsequent course, biochemical parameters were normalized, and the patient showed no obvious clinical complications of IH2, apart from the nephrocalcinosis., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype., Methods: We collected patients with duplications encompassing ARID1A and ARID1B duplications., Results: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1-1.2 Mb(1-44 genes) for ARID1A and 0.9-10.3 Mb(2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation re-analysis, resulting in the reclassification of two ARID1A and two ARID1B duplications as pathogenic., Conclusion: Our findings reveal that ARID1B duplications manifest a clinical phenotype and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole gene duplication rather than haploinsufficiency., (Copyright © 2024. Published by Elsevier Inc.)

Here we report the case of a young boy with developmental delay, thin sparse hair, early closure of the anterior fontanel, bilateral choanal atresia, brachyturicephaly; and dysmorphic features closely resembling those seen in trichorhinophalangeal syndrome (TRPS). These features include sparse hair, sparse lateral eyebrows, a bulbous pear shaped nose, a long philtrum, thin lips, small/hypoplastic nails, pes planovalgus; bilateral cone-shaped epiphyses at the proximal 5th phalanx, slender long bones, coxa valga, mild scoliosis, and delayed bone age. Given that TRPS had been excluded by a thorough genetic analysis, whole exome sequencing was performed and a heterozygous likely pathogenic variant was identified in the FBXO11 gene (NM_001190274.2: c.1781A > G; p. His594Arg), confirming the diagnosis of the newly individualized IDDFBA syndrome: Intellectual Developmental Disorder, dysmorphic Facies, and Behavioral Abnormalities (OMIM# 618,089). Our findings further delineate the clinical spectrum linked to FBXO11 and highlight the importance of investigating further cases with mutations in this gene to establish a potential genotype-phenotype correlation., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

46,XY gonadal dysgenesis (GD) is a disorder of sex development due to incomplete gonadal differentiation into testes, resulting in female to ambiguous external genitalia. Duplications at the Xp21.2 locus involving the NR0B1 (DAX1) gene have previously been associated with 46,XY GD. More recently, a complex structural variant not directly involving NR0B1 has been reported in 46,XY GD illustrating that the mechanism of how copy number variants (CNVs) at Xp21.2 may cause 46,XY gonadal dysgenesis is not yet fully understood. Here, we report on three families in which a duplication involving the NR0B1 gene was detected in the context of prenatal screening. This is the first report of duplications involving NR0B1 in three phenotypically normal males in two families. Fertility problems were present in one adult male carrier. The data reported here from an unbiased screening population broaden the phenotype associated with CNVs involving NR0B1, and this may aid clinicians in counseling and decision making in the prenatal context., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Introduction: Around 1 in 1000-2000 pregnancies are affected by a cancer diagnosis. Previous studies have shown that chemotherapy during pregnancy has reassuring cognitive and cardiac neonatal outcomes, and hence has been proposed as standard of care. However, although these children perform within normal ranges for their age, subtle differences have been identified. Given that chemotherapeutic compounds can cross the placenta, the possibility that prenatal chemotherapy exposure mutates the offspring's genome and/or epigenome, with potential deleterious effects later in life, urges to be investigated., Methods and Analyses: This multicentric observational study aims to collect cord blood, meconium and neonatal buccal cells at birth, as well as peripheral blood, buccal cells and urine from infants when 6, 18 and/or 36 months of age. Using bulk and single-cell approaches, we will compare samples from chemotherapy-treated pregnant patients with cancer, pregnant patients with cancer not treated with chemotherapy and healthy pregnant women. Potential chemotherapy-related newborn genomic and/or epigenomic alterations, such as single nucleotide variants, copy number variants and DNA-methylation alterations, will be identified in mononuclear and epithelial cells, isolated from blood, buccal swabs and urine. DNA from maternal peripheral blood and paternal buccal cells will be used to determine de novo somatic mutations in the neonatal blood and epithelial cells. Additionally, the accumulated exposure of the fetus, and biological effective dose of alkylating agents, will be assessed in meconium and cord blood via mass spectrometry approaches., Ethics and Dissemination: The Ethics Committee Research of UZ/KU Leuven (EC Research) and the Medical Ethical Review Committee of University Medical Center Amsterdam have approved the study. Results of this study will be disseminated via presentations at (inter)national conferences, through peer-reviewed, open-access publications, via social media platforms aimed to inform patients and healthcare workers, and through the website of the International Network on Cancer, Infertility and Pregnancy (www.cancerinpregnancy.org)., Competing Interests: Competing interests: TV is co-inventor on licensed patents WO/2011/157846 (Methods for haplotyping single cells), WO/2014/053664 (High-throughput genotyping by sequencing low amounts of genetic material) and WO/2015/028576 (Haplotyping and copy number typing using polymorphic variant allelic frequencies)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis., Objective: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome., Study Design: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site., Results: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019)., Conclusion: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Maternally inherited 15q11-q13 duplications are generally found to cause more severe neurodevelopmental anomalies compared to paternally inherited duplications. However, this assessment is mainly inferred from the study of patient populations, causing an ascertainment bias towards patients at the more severe end of the phenotypic spectrum. Here, we analyze the low coverage genome-wide cell-free DNA sequencing data obtained from pregnant women during non-invasive prenatal screening (NIPS). We detect 23 15q11-q13 duplications in 333,187 pregnant women (0.0069%), with an approximately equal distribution between maternal and paternal duplications. Maternally inherited duplications are always associated with a clinical phenotype (ranging from learning difficulties to intellectual impairment, epilepsy and psychiatric disorders), while paternal duplications are normal or associated with milder phenotypes (mild learning difficulties and dyslexia). This data corroborates the difference in impact between paternally and maternally inherited 15q11-q13 duplications, contributing to the improvement of genetic counselling. We recommend reporting 15q11-q13 duplications identified during genome-wide NIPS with appropriate genetic counselling for these pregnant women in the interest of both mothers and future children., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background: Sickle Cell Anemia (SCA) is the most common genetic disease worldwide caused by a single mutation in the gene HBB . The disease severity is very variable and depends on many factors. We evaluated the clinical and biological profile of sickle cell anemia children in rural Central Africa., Methods: This cross-sectional study was conducted in the Hôpital Saint Luc de Kisantu, located 120 km away from Kinshasa-DR Congo in an area of 35 km around Kisantu with a population of roughly 80 000 individuals. We included SCA patients aged 6 months to 18 years. We collected clinical and hematological data. The SCA scoring system proposed by Adegoke et al. in 2013 was applied to determine the disease severity. We searched for factors associated to the disease severity., Results: This study included 136 patients, 66 males and 70 females (sex-ratio M/F 0.94). The mean severity score was 8.21 ± 5.30 (ranges 0-23). Fifty-nine (43.4%) children had mild disease, 62 (45.6%) moderate and 15 (11%) severe disease. Girls had higher levels of HbF than boys ( p  = 0.003). An inverse correlation was observed between fetal hemoglobin and the disease severity ( p  = 0.005, r -0.239, IC 95% -6.139; -1.469). Some factors such age influence the occurrence of certain chronic complications such as avascular bone necrosis., Conclusion: In conclusion, the disease severity of SCA depends on multiple factors. In this study, fetal hemoglobin was the main modulator of the disease severity. These data may also serve as a baseline to initiate HU treatment in this setting.

Background: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined., Methods: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature., Results: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones., Conclusion: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To assess maternal characteristics and comorbidities in patients with persistent uninterpretable non-invasive prenatal testing (NIPT) and to evaluate the association with adverse pregnancy outcome in a general risk population., Methods: A retrospective cohort study (July 2017-December 2020) was conducted of patients with persistent uninterpretable NIPT samples. Maternal characteristics and pregnancy outcomes were compared with the general Belgian obstetric population., Results: Of the 148 patients with persistent uninterpretable NIPT, 37 cases were due to a low fetal fraction (LFF) and 111 due to a low quality score (LQS). Both groups (LFF, LQS) showed more obesity (60.6%, 42.4%), multiple pregnancies (18.9%, 4.5%) and more obstetrical complications. In the LQS group, a high rate of maternal auto-immune disorders (30.6%) was seen and hypertensive complications (17.6%), preterm birth (17.6%) and neonatal intensive care unit (NICU) admission (22%) were significantly increased. In the LFF group hypertensive complications (21.6%), gestational diabetes (20.6%), preterm birth (27%), SGA (25.6%), major congenital malformations (11.4%), c-section rate (51.4%) and NICU admission (34.9%) were significantly increased. Chromosomal abnormalities were not increased in both groups., Conclusions: Patients with persistent uninterpretable NIPT have significantly more maternal obesity, comorbidities and adverse pregnancy outcome than the general population and should receive high-risk pregnancy care. Distinguishing between LFF and LQS optimizes counseling because maternal characteristics and pregnancy outcome differ between these groups., (© 2023 John Wiley & Sons Ltd.)

Background: Computer-aided software such as the facial image diagnostic aid (FIDA) and Face2Gene has been developed to perform pattern recognition of facial features with promising clinical results. The aim of this pilot study was to test Face2Gene's recognition performance on Bantu Congolese subjects with Fragile X syndrome (FXS) as compared to Congolese subjects with intellectual disability but without FXS (non-FXS)., Method: Frontal facial photograph from 156 participants (14 patients with FXS and 142 controls) predominantly young-adults to adults, median age 18.9 age range 4-39yo, were uploaded. Automated face analysis was conducted by using the technology used in proprietary software tools called Face2Gene CLINIC and Face2Gene RESEARCH (version 17.6.2). To estimate the statistical power of the Face2Gene technology in distinguishing affected individuals from controls, a cross validation scheme was used., Results: The similarity seen in the upper facial region (of males and females) is greater than the similarity seen in other parts of the face. Binary comparison of subjects with FXS versus non-FXS and subjects with FXS versus subjects with Down syndrome reveal an area under the curve values of 0.955 (p = 0.002) and 0.986 (p = 0.003)., Conclusion: The Face2Gene algorithm is separating well between FXS and Non-FXS subjects., Competing Interests: Declaration of competing interest The authors declare no potential conflict of interest., (Copyright © 2023. Published by Elsevier Masson SAS.)

Preeclampsia (PE) is a leading cause for peripartal morbidity, especially if developing early in gestation. To enable prophylaxis in the prevention of PE, pregnancies at risk of PE must be identified early-in the first trimester. To identify at-risk pregnancies we profiled methylomes of plasma-derived, cell-free DNA from 498 pregnant women, of whom about one-third developed early-onset PE. We detected DNA methylation differences between control and PE pregnancies that enabled risk stratification at PE diagnosis but also presymptomatically, at around 12 weeks of gestation (range 9-14 weeks). The first-trimester risk prediction model was validated in an external cohort collected from two centers (area under the curve (AUC) = 0.75) and integrated with routinely available maternal risk factors (AUC = 0.85). The combined risk score correctly predicted 72% of patients with early-onset PE at 80% specificity. These preliminary results suggest that cell-free DNA methylation profiling is a promising tool for presymptomatic PE risk assessment, and has the potential to improve treatment and follow-up in the obstetric clinic., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Alexander disease is a leukodystrophy caused by mutations in the GFAP gene, primarily affecting the astrocytes. This report describes the prenatal and post-mortem neuroimaging findings in a case of genetically confirmed, fetal-onset Alexander disease with pathological correlation after termination of pregnancy. The additional value of fetal brain magnetic resonance imaging in the third trimester as a complementary evaluation tool to neurosonography is shown for suspected cases of fetal-onset Alexander disease. Diffuse signal abnormalities of the periventricular white matter in association with thickening of the fornix and optic chiasm can point towards the diagnosis. Furthermore, the presence of atypical imaging findings such as microcephaly and cortical folding abnormalities in this case broadens our understanding of the phenotypic variability of Alexander disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background : Despite a high incidence of sickle cell anemia, hydroxyurea (HU) treatment is rarely used in the DR Congo. This study aims to assess the efficacy of HU, the incidence of side effects that may limit its use in adults and to determine the dose needed for clinical improvement in patients. Methods : In a prospective study, patients received an initial dose of 15 mg/kg/day which was increased by 5 mg/kg every 6 months, up to a maximum of 30 mg/kg/day. The response and side effects to HU were evaluated biologically and clinically every 3 months during a 2-year period. Results : Seventy adult patients with a moderate or severe clinical phenotype initiated treatment. Only minor side effects were reported. At the end of the 2-year treatment phase, 45 (64.3%) had dropped out, of whom 33 were without a clear reason. Clinical and biological improvement was more marked during the first year. There was a reduction in severe vaso-occlusive crises ( p  < 0.001), need for transfusion ( p  < 0.001), and hospitalization days ( p  = 0.038). Fetal hemoglobin (HbF) levels increased on average 2.9 times after 12 months ( p  < 0.001). The increase in mean corpuscular volume was greater in the first year ( p  < 0.001) than in the second year ( p  = 0.041). The decrease in leukocytes ( p  < 0.001) was significant during the first year. In 70% of patients, the 20 mg/kg/day dose was needed to reach the 20% HbF threshold. Conclusion : HU is effective and well tolerated. The magnitude of the response varies from one patient to another. Improvement of clinical manifestations is achieved in most patients with a relatively low dose. Effective implementation of HU treatment will require improved adherence to treatment., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS, OMIM 615722) is a rare autosomal dominant disorder characterized by intellectual disability, optic atrophy, cortical visual impairment, mild facial dysmorphism, hypotonia, hearing problems, attention deficit and a thin corpus callosum. The gene underlying this disorder is NR2F1 located on chromosome 5q15 which encodes for a nuclear receptor protein. Mutations and deletions have been identified in patients. Here we report on a brother and a sister carrying a pathogenic nonsense NR2F1 variant. The patients have a mild phenotype showing optic atrophy, mild intellectual disability, dysmorphic features and thin corpus callosum. This correlates with previously described milder phenotypes in patients with mutations in this domain. The variant was not identified in the parental genome indicating most likely a gonadal mosaicism. Gonadal mosaicism has not yet been reported in Bosch-Boonstra-Schaaf Optic Atrophy Syndrome., Competing Interests: Declaration of competing interest We declare no conflicts of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: The Netherlands and Belgium have been among the first countries to offer non-invasive prenatal testing (NIPT) as a first-tier screening test. Despite similarities, differences exist in counseling modalities and test uptake. This study explored decision-making and perspectives of pregnant women who opted for NIPT in both countries., Methods: A questionnaire study was performed among pregnant women in the Netherlands (NL) (n = 587) and Belgium (BE) (n = 444) opting for NIPT, including measures on informed choice, personal and societal perspectives on trisomy 21, 18 and 13 and pregnancy termination., Results: Differences between Dutch and Belgian women were shown in the level of informed choice (NL: 83% vs. BE: 59%, p < 0.001), intention to terminate the pregnancy in case of confirmed trisomy 21 (NL: 51% vs. BE: 62%, p = 0.003) and trisomy 13/18 (NL: 80% vs. BE: 73%, p = 0.020). More Belgian women considered trisomy 21 a severe condition (NL: 64% vs. BE: 81%, p < 0.001). Belgian women more frequently indicated that they believed parents are judged for having a child with trisomy 21 (BE: 42% vs. NL: 16%, p < 0.001) and were less positive about quality of care and support for children with trisomy 21 (BE: 23% vs. NL: 62%, p < 0.001)., Conclusion: Differences in women's decision-making regarding NIPT and the conditions screened for may be influenced by counseling aspects and country-specific societal and cultural contexts., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

An intensely debated topic is whether political polarization on social media is on the rise. We can investigate this question only if we can quantify polarization, by taking into account how extreme the opinions of the people are, how much they organize into echo chambers, and how these echo chambers organize in the network. Current polarization estimates are insensitive to at least one of these factors: They cannot conclusively clarify the opening question. Here, we propose a measure of ideological polarization that can capture the factors we listed. The measure is based on the generalized Euclidean distance, which estimates the distance between two vectors on a network, e.g., representing people's opinion. This measure can fill the methodological gap left by the state of the art and leads to useful insights when applied to real-world debates happening on social media and to data from the U.S. Congress.

Background: Sickle cell anemia (SCA) is a monogenic hemoglobinopathy associated with severe acute and chronic complications, with the highest incidence worldwide in Sub-Saharan Africa. The wide variability in clinical manifestations suggest that a uniform response to hydroxurea may not be attained. In view of a potential treatment with hydroxyurea (HU), we assessed the variability of clinical and hematological manifestations in a cohort of adults with SCA in Kinshasa, capital of the DR Congo in Central Africa., Methods: A cross-sectional study was conducted in a hospital dedicated to SCA management in Kinshasa. Clinical history of patients was recorded, a complete physical examination performed. The diagnosis was confirmed by means of DNA analysis. A full blood count and hemolysis markers were measured. The severity of the disease was evaluated by means of a previously reported score., Results: The study group consisted of 166 genetically confirmed SCA patients. The SCA severity was mild in 28.9%, moderate in 64.5% and severe in 6.6%. The disease severity score increased with patient's age (p ≤ 0.001). The severity was higher in males compared to females (p = 0.012). In males, the severity score was correlated with the presence of priapism (p = 0.045), a manifestation not previously incorporated in the severity score. The severity score was inversely correlated with the fetal hemoglobin (HbF) rate (p = 0.005). Malnutrition (BMI <18.5 kg/m2) was present in 47% of patients and was related to the male sex, hip disease (aOR 3.11; p = 0.019) and severe phenotype (aOR 3.53; p = 0.012). Leg ulcers were more frequent in males than in females (p = 0.001; OR 24.3) and were correlated with the number of days of hospitalization (p = 0.029). Hip disease was related to the increasing age (p = 0.008)., Conclusion: In this selected, hospital-based populations of adults with SCA, severe disease was rare, which may be due to survival bias. However, two thirds had moderate severity of the disease, mostly with a low HbF, and they may benefit from HU treatment. In the Central-African setting the separation between vaso-occlusive and hyperhemolytic sub-phenotypes was not applicable., Competing Interests: No, The authors have declared that no competing interests exist., (Copyright: © 2022 Lumbala et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Non-invasive prenatal testing has been introduced for the detection of Trisomy 13, 18, and 21. Using genome-wide screening also other "rare" autosomal trisomies (RATs) can be detected with a frequency about half the frequency of the common trisomies in the large population-based studies. Large prospective studies and clear clinical guidelines are lacking to provide adequate counseling and management to those who are confronted with a RAT as a healthcare professional or patient. In this review we reviewed the current knowledge of the most common RATs. We compiled clinical relevant parameters such as incidence, meiotic or mitotic origin, the risk of fetal (mosaic) aneuploidy, clinical manifestations of fetal mosaicism for a RAT, the effect of confined placental mosaicism on placental function and the risk of uniparental disomy (UPD). Finally, we identified gaps in the knowledge on RATs and highlight areas of future research. This overview may serve as a first guide for prenatal management for each of these RATs., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

Purpose: We aimed to investigate the molecular basis of a novel recognizable neurodevelopmental syndrome with scalp and enamel anomalies caused by truncating variants in the last exon of the gene FOSL2, encoding a subunit of the AP-1 complex., Methods: Exome sequencing was used to identify genetic variants in all cases, recruited through Matchmaker exchange. Gene expression in blood was analyzed using reverse transcription polymerase chain reaction. In vitro coimmunoprecipitation and proteasome inhibition assays in transfected HEK293 cells were performed to explore protein and AP-1 complex stability., Results: We identified 11 individuals from 10 families with mostly de novo truncating FOSL2 variants sharing a strikingly similar phenotype characterized by prenatal growth retardation, localized cutis scalp aplasia with or without skull defects, neurodevelopmental delay with autism spectrum disorder, enamel hypoplasia, and congenital cataracts. Mutant FOSL2 messenger RNAs escaped nonsense-mediated messenger RNA decay. Truncated FOSL2 interacts with c-JUN, thus mutated AP-1 complexes could be formed., Conclusion: Truncating variants in the last exon of FOSL2 associate a distinct clinical phenotype by altering the regulatory degradation of the AP-1 complex. These findings reveal a new role for FOSL2 in human pathology., Competing Interests: Conflict of Interest L.A.P.-J. is founding partner and scientific advisor of qGenomics Laboratories. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)

Background: Oculocutaneous albinism (OCA) is an autosomal recessive genetic disorder associated with reduced or absent pigmentation in the skin, hair and eyes. OCA type 2 (OCA2) is the most common type in Sub-Saharan Africa, related to a recurrent 2.7 kb intragenic deletion. Genomic data from Congolese patients are lacking. We aimed to describe genetic causes of OCA2 in a cohort of Congolese persons with OCA, and explore possible genotype-phenotype correlations., Methods: A cross sectional study was conducted from January 2015 to December 2017 in Kinshasa, Democratic Republic of Congo (DRC). 165 Congolese unrelated families with non-syndromic OCA, identified through patients' associations, consented to participate to this study. All index cases were tested for the known 2.7 kb deletion involving the exon 7 of the OCA2 gene. Patients heterozygous for the deletion underwent Sanger sequencing of all exons and flanking sequences in the OCA2 gene. Family segregation was performed for candidate pathogenic variants., Results: The 2.7 kb deletion in the OCA2 gene was identified in 136/165 (82.4%) index cases, including 113 (68.5%) homozygotes and 23 (13.9%) heterozygotes. Sanger sequencing identified a pathogenic or likely pathogenic variant in the OCA2 gene in 12 out of 23 heterozygotes investigated (52.1%). Segregation analysis allowed us to locate the point mutation on the trans allele in the three patients from whom parental DNA was available., Conclusion: The OCA2 2.7 kb deletion is the major cause of non-syndromic OCA in Congolese patients recruited in this study, confirming results from other Sub-Saharan African populations. Several additional mutations were detected in OCA patient's heterozygote for the deletion, with to date no evidence for a second frequent founder mutation. The confirmation of a single mutation as the major cause will facilitate genetic counselling in this country., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations., Competing Interests: Declaration of interests H.T.B. is a consultant for Mahzi therapeutics., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The evaluation of dysmorphism is often subjective because many continuous traits are not easily measured or lack normal values. Because many common morphologic profiles vary between populations, population-specific reference ranges of relevant traits are needed. We aim to evaluate the objective assessment of facial dysmorphism in 553 Congolese newborns based on facial measurements. Measurements taken with a ruler were on average larger compared to those with a caliper, but the bias did not depend on the size of the measurement. We therefore introduced a correction factor that allows to use both techniques for facial measurements interchangeably in future studies. The outer canthal distance, palpebral fissure length, and mouth width were significantly larger in Congolese newborns (respectively mean 6.59 [SD 0.48]; mean 2.20 [SD 0.24]; mean 2.78 [SD 0.26]) when compared to references based on European newborns (respectively mean 3.59 [SD 1.76]; mean 4.20 [SD 2.26]; mean 0.47 [SD 1.21]), while the rest of measurements were significantly smaller. The interpupillary distance (IPD) calculated from inner canthal distance and outer canthal distance was not significantly different. We observed a poor agreement between clinical evaluation and measured features (kappa of 0.432). Clinicians were more likely to recognize a face as having wide-spaced eyes when it had been recognized as such during the clinical examination, more than if the child had a high interpupillary distance. This suggests that the measured IPD is not precisely reflecting what is clinically evaluated as wide-spaced eyes., (© 2022 Wiley Periodicals LLC.)

The early detection of tissue and organ damage associated with autoimmune diseases (AID) has been identified as key to improve long-term survival, but non-invasive biomarkers are lacking. Elevated cell-free DNA (cfDNA) levels have been observed in AID and inflammatory bowel disease (IBD), prompting interest to use cfDNA as a potential non-invasive diagnostic and prognostic biomarker. Despite these known disease-related changes in concentration, it remains impossible to identify AID and IBD patients through cfDNA analysis alone. By using unsupervised clustering on large sets of shallow whole-genome sequencing (sWGS) cfDNA data, we uncover AID- and IBD-specific genome-wide patterns in plasma cfDNA in both the obstetric and general AID and IBD populations. We demonstrate that pregnant women with AID and IBD have higher odds of receiving inconclusive non-invasive prenatal screening (NIPS) results. Supervised learning of the genome-wide patterns allows AID prediction with 50% sensitivity at 95% specificity. Importantly, the method has the potential to identify pregnant women with AID during routine NIPS. Since AID pregnancies have an increased risk of severe complications, early recognition or detection of new-onset AID can redirect pregnancy management and limit potential adverse events. This method opens up new avenues for screening, diagnosis and monitoring of AID and IBD., (© 2022. The Author(s).)

Centrality measures quantify the importance of a node in a network based on different geometric or diffusive properties, and focus on different scales. Here, we adopt a geometrical viewpoint to define a multiscale centrality in networks. Given a metric distance between the nodes, we measure the centrality of a node by its tendency to be close to geodesics between nodes in its neighborhood, via the concept of triangle inequality excess. Depending on the size of the neighborhood, the resulting Gromov centrality defines the importance of a node at different scales in the graph, and it recovers as limits well-known concepts such as the clustering coefficient and closeness centrality. We argue that Gromov centrality is affected by the geometric and boundary constraints of the network, and illustrate how it can help distinguish different types of nodes in random geometric graphs and empirical transportation networks.

Background: Sickle-cell anemia (SCA) is the most common genetic disease worldwide caused by a single mutation in the gene HBB. DNA testing can help to clarify the diagnosis when Hb electrophoresis is inconclusive. We evaluated the usefulness and feasibility of DNA-based diagnosis of SCA in rural Central Africa., Methods: This is a cross-sectional study conducted from November 2016 to end October 2017 in the Hôpital Saint Luc de Kisantu, located 120 km from Kinshasa. This hospital offers the management of SCA patients, mainly identified using the Sickling test (Emmel test) combined with clinical features. We included patients aged 6 months to 18 years locally diagnosed as SCA, and we collected clinical and hematological data. All patients were offered Hb electrophoresis and DNA testing at the Center for Human Genetics of the University of Kinshasa., Results: This study included 160 patients. Hemoglobin capillary electrophoresis suggested that 136 (85%) were homozygote SS, 13 (8.1%) were heterozygote (AS), and 11 (6.9%) were homozygote normal (AA). DNA testing confirmed these electrophoresis findings, with the exception of four patients, two AS in electrophoresis were found SS due to recent transfusion, and two SS in electrophoresis were found AS because they have compound heterozygous form S/β°-thalassemia. The diagnosis of SCA was therefore wrongly ascertained with Emmel test in 15% of patients., Conclusion: This study reveals a high proportion of false-positive SCA diagnoses in a rural environment in Central Africa. This underlines the importance of DNA testing in conjunction with Hb electrophoresis., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Purpose: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease., Methods: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher., Results: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present., Conclusion: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease., Competing Interests: Conflict of Interest This work was carried out within the framework of Nantes University Medical Center activity without additional funding. One patient was diagnosed in the context of work in a private company (AiLife Diagnostics, Pearland, Texas). The other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

The rich and diverse genomics of African populations is significantly underrepresented in reference and in disease-associated databases. This renders interpreting the Next Generation Sequencing (NGS) data and reaching a diagnostic more difficult in Africa and for the African diaspora. It increases chances for false positives with variants being misclassified as pathogenic due to their novelty or rarity. We can increase African genomic data by (1) making consent for sharing aggregate frequency data an essential component of research toolkit; (2) encouraging investigators with African data to share available data through public resources such as gnomAD, AVGD, ClinVar, DECIPHER and to use MatchMaker Exchange; (3) educating African research participants on the meaning and value of sharing aggregate frequency data; and (4) increasing funding to scale-up the production of African genomic data that will be more representative of the geographical and ethno-linguistic variation on the continent. The RDWG of H3Africa is hereby calling to action because this underrepresentation accentuates the health disparities. Applying the NGS to shorten the diagnostic odyssey or to guide therapeutic options for rare diseases will fully work for Africans only when public repositories include sufficient data from African subjects., (© 2022. The Author(s).)

Background: Hemoglobin-based tests form the reference diagnostic test for SCA. In limited resource countries, these tests face limitations including cost, low sensitivity due to recurrent transfusions in endemic malaria region, and interference from fetal hemoglobin in neonatal diagnostic. This study aimed at adapting DNA-based SCA tests to limited resource countries and evaluating the economic benefit., Methods: 338 participants were recruited in the Democratic Republic of Congo, sorted in 3 cohorts based on venous blood, umbilical cord blood (UCB) and buccal swab sampling. RFLP was performed to identify mutated allele. The feasibility and technical validity of this RFLP was evaluated for specimens collected on DBS cards and on EDTA tubes. RFLP on DBS stored at room temperature was regularly repeated to assess sample conservation. Finally, the cost analysis was performed., Results: DBS cards yielded identical results to extracted DNA. Repeated testing returned the same result after four years. The DBS-based test performed on UCB or on buccal swab had a sensitivity and a precision of 100%. Cost comparison indicated that our approach costs half price of the widely used isoelectrofocussing of hemoglobin., Conclusion: The implemented DNA-based test approach overcomes the limitations faced by hemoglobin-based tests, while being more affordable. We propose to implement the RFLP test as a first line diagnostic test after transfusion and as second tiers for newborn screening. However, users should be aware that this test is unable to differentiate HbC from HbS or identify other point mutation of gene deletion of HBB gene., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Congenital diaphragmatic hernia (CDH) is characterized by a defect in the muscle dividing the thoracic and abdominal cavities. This leads to herniation of the abdominal organs into the thorax and a disturbance of lung development. Two-thirds of cases are identified by prenatal ultrasound in the second trimester, which should prompt referral to a tertiary center for prognosis assessment and counseling by a multidisciplinary team familiar with this condition. In this review, we summarize evidence on prenatal diagnosis and postnatal management of CDH. There is a focus on information that should be provided to expecting parents during prenatal counseling., (© 2020 John Wiley & Sons Ltd.)

We describe a four-year-old girl with bilateral severe iris hypoplasia and secondary ocular hypertension. Genetic testing revealed a de novo deletion in the FOXC1 gene, establishing the diagnosis of Axenfeld-Rieger syndrome (ARS). The girl developed a gradually increasing exotropia, up to 95 prism diopters by the age of 3 years wherefore strabismus surgery was performed. Intra-operatively, only very rudimentary developed medial and lateral rectus muscles were found. This is the first observation of pronounced hypoplasia of both medial and lateral rectus muscles associated with ARS.