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

Les leucémies aigües lymphoblastiques type Early T-cell Precursor de l'enfant (données et pronostic des patients pris en charge dans le protocole européen EORTC - CLG essai 58951)

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Invasive Fungal Infections in Immunocompromised Children: Novel Insight Following a National Study

International audienceTo obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT).Study design: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units.Results: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10-4) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents.Conclusions: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children

Clinical spectrum and long-term follow-up of 14 cases with G6PC3 mutations from the French severe congenital neutropenia registry

International audienceBackground : The purpose of this study was to describe the natural history of severe congenital neutropenia (SCN) in 14 patients with G6PC3 mutations and enrolled in the French SCN registry.Methods : Among 605 patients included in the French SCN registry, we identified 8 pedigrees that included 14 patients with autosomal recessive G6PC3 mutations.Results : Median age at the last visit was 22.4 years. All patients had developed various comordibities, including prominent veins (n = 12), cardiac malformations (n = 12), intellectual disability (n = 7), and myopathic syndrome with recurrent painful cramps (n = 1). Three patients developed Crohn’s disease, and five had chronic diarrhea with steatorrhea. Neutropenia was profound ( A /p.Trp83*) was detected in one pedigree.Conclusions : Severe congenital neutropenia with autosomal recessive G6PC3 mutations is associated with considerable clinical heterogeneity. This series includes the first described case of malignancy in this neutropenia