The detection of a strong episignature for Chung–Jansen syndrome, partially overlapping with Börjeson–Forssman–Lehmann and White–Kernohan syndromes

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung–Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung–Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White–Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson–Forssman–Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung–Jansen, Börjeson–Forssman–Lehmann and White–Kernohan syndromes.</p

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

La personnalité des individus atteints de RASopathies

Les RASopathies sont des maladies mendéliennes monogéniques résultant d’anomalies au niveau de gènes intervenant dans la voie de signalisation Ras/MAPK. En se basant sur le modèle à cinq facteurs de la personnalité (agréabilité, extraversion, conscienciosité, ouverture et névrosisme), et en y ajoutant un questionnaire évaluant le sens de l’humour, la personnalité de 80 individus atteints de RASopathies est comparée à celle d’un groupe contrôle constitué de 55 frères et soeurs non atteints, à l’aide d’analyses de variances multivariée et d’analyses en composantes principales.Les résultats de l’étude mettent en évidence un profil de personnalité spécifique aux individus atteints de RASopathies, et les observations faites sur chacun des traits observés permettent une première approche synthétique de ce profil

The role of three-dimensional printing in coronavirus disease-19 medical management: A French nationwide survey

OBJECTIVES Coronavirus disease-19 (COVID-19) has spread worldwide and poses various challenges to healthcare services. The limited supply of medical and personal-protective equipment has affected the ability of many countries to respond to the crisis. Three-dimensional printing (3DP) is well suited to addressing these shortages. We assessed the medical role of 3DP during the COVID-19 outbreak in hospitals in France. DESIGN Retrospective survey. SETTING AND INTERVENTION We included and questioned all French level-1 and -2 COVID-certified centers. PARTICIPANTS One hundred and thirty-eight COVID-certified centers were contacted across France: 38 (27.5 %) level 1 and 100 (72.5 %) level 2 centers. The analysis focused on 133 centers (96.37 %), among which 98 (73.68 %) used 3DP. MAIN OUTCOMES MEASURES The primary endpoint was the number of pieces printed in 3D. The secondary endpoints were the mode, type, and benefits of 3DP. RESULTS The total number of pieces printed in 3D nationwide was 84,886: 76,000 pieces of individual protective equipment (IPE) (89.53 %), 6335 pieces of biomedical equipment (7.47 %), and 2551 prototypes (3.01 %). In 91 cases (92.85 %), 3DP was performed using external printers. The pieces 3D-printed by the various centers helped around 6109 patients and protected around 41,091 caregivers. CONCLUSIONS 3DP produced more than 84,000 pieces at 98 centers, helped more than 6000 patients, and protected more than 41,000 caregivers. Therefore, 3DP played a major role in medical aid during the COVID-19 outbreak in France

RASopathies are associated with a distinct personality profile

Personality is a complex, yet partially heritable, trait. Although some Mendelian diseases like Williams-Beuren syndrome are associated with a particular personality profile, studies have failed to assign the personality features to a single gene or pathway. As a family of monogenic disorders caused by mutations in the Ras/MAPK pathway known to influence social behavior, RASopathies are likely to provide insight into the genetic basis of personality. Eighty subjects diagnosed with cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, and Noonan syndrome were assessed using a parent-report BFQ-C (Big Five Questionnaire for Children) evaluating agreeableness, extraversion, conscientiousness, intellect/openness, and neuroticism, along with 55 unaffected sibling controls. A short questionnaire was added to assess sense of humor. RASopathy subjects and sibling controls were compared for individual components of personality, multidimensional personality profiles, and individual questions using Student tests, analysis of variance, and principal component analysis. RASopathy subjects were given lower scores on average compared to sibling controls in agreeableness, extraversion, conscientiousness, openness, and sense of humor, and similar scores in neuroticism. When comparing the multidimensional personality profile between groups, RASopathies showed a distinct profile from unaffected siblings, but no difference in this global profile was found within RASopathies, revealing a common profile for the Ras/MAPK-related disorders. In addition, several syndrome-specific strengths or weaknesses were observed in individual domains. We describe for the first time an association between a single pathway and a specific personality profile, providing a better understanding of the genetics underlying personality, and new tools for tailoring educational and behavioral approaches for individuals with RASopathies

Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review

Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual disability, with congenital anomalies and dysmorphic features. They are often inherited from unaffected parents and the pathogenicity is difficult to assess. We describe the phenotypic and genotypic data for 34 probands carrying CNVs in the 1q21.1 chromosome region (24 duplications, 8 deletions and 2 triplications). We also reviewed 89 duplications, 114 deletions and 5 triplications described in the literature, at variable 1q21.1 locations. We aimed to identify the most highly associated clinical features to determine the phenotypic expression in affected individuals. Developmental delay or learning disabilities and neuropsychiatric disorders were common in patients with deletions, duplications and triplications of 1q21.1. Mild dysmorphic features common in these CNVs include a prominent forehead, widely spaced eyes and a broad nose. The CNVs were mostly inherited from apparently unaffected parents. Almost half of the CNVs were distal, overlapping with a common minimal region of 1.2 Mb. We delineated the clinical implications of 1q21.1 CNVs and confirmed that these CNVs are likely pathogenic, although subject to incomplete penetrance and variable expressivity. Long‐term follow‐up should be performed to each newly diagnosed case, and prenatal genetic counseling cautiously discussed, as it remains difficult to predict the phenotype in the event of an antenatal diagnosis

Caractérisation phénotypique et génotypique des réarrangements chromosomiques en 1q21.1: description d'une nouvelle cohorte de 34 patients et revue de la littérature

International audienc

Syndrome Tricho-rhino-phalangien de type I: description clinique et moléculaire chez 15 cas non apparentés

International audienceDécrire une cohorte de patients atteints de TRPS de type I sur le plan phénotypique et moléculaire. Patients & Méthodes : Il s'agit d'une cohorte française multicentrique rétrospective de 15 patients. L'étude moléculaire a été réalisée par séquençage haut débit (Ion Personal Genome Machine, ThermoFisher Scientific) et recherche de réarrangements par Multiplex Ligation-dependent Probe Amplification (MLPA kit P228-B1, MRC-Holland)

Pycnodysostosis: Natural history and management guidelines from 27 French cases and a literature review

International audiencePycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis, facial features and an increased risk of fractures. The clinical heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow-up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = -3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non-invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow-up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow-up