Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_297

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation

Swift-BAT GUANO follow-up of gravitational-wave triggers in the third LIGO-Virgo-KAGRA observing run

International audienceWe present results from a search for X-ray/gamma-ray counterparts of gravitational-wave (GW) candidates from the third observing run (O3) of the LIGO-Virgo-KAGRA (LVK) network using the Swift Burst Alert Telescope (Swift-BAT). The search includes 636 GW candidates received in low latency, 86 of which have been confirmed by the offline analysis and included in the third cumulative Gravitational-Wave Transient Catalogs (GWTC-3). Targeted searches were carried out on the entire GW sample using the maximum--likelihood NITRATES pipeline on the BAT data made available via the GUANO infrastructure. We do not detect any significant electromagnetic emission that is temporally and spatially coincident with any of the GW candidates. We report flux upper limits in the 15-350 keV band as a function of sky position for all the catalog candidates. For GW candidates where the Swift-BAT false alarm rate is less than 10$^{-3}$ Hz, we compute the GW--BAT joint false alarm rate. Finally, the derived Swift-BAT upper limits are used to infer constraints on the putative electromagnetic emission associated with binary black hole mergers

Swift-BAT GUANO follow-up of gravitational-wave triggers in the third LIGO-Virgo-KAGRA observing run

International audienceWe present results from a search for X-ray/gamma-ray counterparts of gravitational-wave (GW) candidates from the third observing run (O3) of the LIGO-Virgo-KAGRA (LVK) network using the Swift Burst Alert Telescope (Swift-BAT). The search includes 636 GW candidates received in low latency, 86 of which have been confirmed by the offline analysis and included in the third cumulative Gravitational-Wave Transient Catalogs (GWTC-3). Targeted searches were carried out on the entire GW sample using the maximum--likelihood NITRATES pipeline on the BAT data made available via the GUANO infrastructure. We do not detect any significant electromagnetic emission that is temporally and spatially coincident with any of the GW candidates. We report flux upper limits in the 15-350 keV band as a function of sky position for all the catalog candidates. For GW candidates where the Swift-BAT false alarm rate is less than 10$^{-3}$ Hz, we compute the GW--BAT joint false alarm rate. Finally, the derived Swift-BAT upper limits are used to infer constraints on the putative electromagnetic emission associated with binary black hole mergers

Swift-BAT GUANO follow-up of gravitational-wave triggers in the third LIGO-Virgo-KAGRA observing run

International audienceWe present results from a search for X-ray/gamma-ray counterparts of gravitational-wave (GW) candidates from the third observing run (O3) of the LIGO-Virgo-KAGRA (LVK) network using the Swift Burst Alert Telescope (Swift-BAT). The search includes 636 GW candidates received in low latency, 86 of which have been confirmed by the offline analysis and included in the third cumulative Gravitational-Wave Transient Catalogs (GWTC-3). Targeted searches were carried out on the entire GW sample using the maximum--likelihood NITRATES pipeline on the BAT data made available via the GUANO infrastructure. We do not detect any significant electromagnetic emission that is temporally and spatially coincident with any of the GW candidates. We report flux upper limits in the 15-350 keV band as a function of sky position for all the catalog candidates. For GW candidates where the Swift-BAT false alarm rate is less than 10$^{-3}$ Hz, we compute the GW--BAT joint false alarm rate. Finally, the derived Swift-BAT upper limits are used to infer constraints on the putative electromagnetic emission associated with binary black hole mergers

Swift-BAT GUANO follow-up of gravitational-wave triggers in the third LIGO-Virgo-KAGRA observing run

International audienceWe present results from a search for X-ray/gamma-ray counterparts of gravitational-wave (GW) candidates from the third observing run (O3) of the LIGO-Virgo-KAGRA (LVK) network using the Swift Burst Alert Telescope (Swift-BAT). The search includes 636 GW candidates received in low latency, 86 of which have been confirmed by the offline analysis and included in the third cumulative Gravitational-Wave Transient Catalogs (GWTC-3). Targeted searches were carried out on the entire GW sample using the maximum--likelihood NITRATES pipeline on the BAT data made available via the GUANO infrastructure. We do not detect any significant electromagnetic emission that is temporally and spatially coincident with any of the GW candidates. We report flux upper limits in the 15-350 keV band as a function of sky position for all the catalog candidates. For GW candidates where the Swift-BAT false alarm rate is less than 10$^{-3}$ Hz, we compute the GW--BAT joint false alarm rate. Finally, the derived Swift-BAT upper limits are used to infer constraints on the putative electromagnetic emission associated with binary black hole mergers

Swift-BAT GUANO follow-up of gravitational-wave triggers in the third LIGO-Virgo-KAGRA observing run

International audienceWe present results from a search for X-ray/gamma-ray counterparts of gravitational-wave (GW) candidates from the third observing run (O3) of the LIGO-Virgo-KAGRA (LVK) network using the Swift Burst Alert Telescope (Swift-BAT). The search includes 636 GW candidates received in low latency, 86 of which have been confirmed by the offline analysis and included in the third cumulative Gravitational-Wave Transient Catalogs (GWTC-3). Targeted searches were carried out on the entire GW sample using the maximum--likelihood NITRATES pipeline on the BAT data made available via the GUANO infrastructure. We do not detect any significant electromagnetic emission that is temporally and spatially coincident with any of the GW candidates. We report flux upper limits in the 15-350 keV band as a function of sky position for all the catalog candidates. For GW candidates where the Swift-BAT false alarm rate is less than 10$^{-3}$ Hz, we compute the GW--BAT joint false alarm rate. Finally, the derived Swift-BAT upper limits are used to infer constraints on the putative electromagnetic emission associated with binary black hole mergers

Swift-BAT GUANO follow-up of gravitational-wave triggers in the third LIGO-Virgo-KAGRA observing run

International audienceWe present results from a search for X-ray/gamma-ray counterparts of gravitational-wave (GW) candidates from the third observing run (O3) of the LIGO-Virgo-KAGRA (LVK) network using the Swift Burst Alert Telescope (Swift-BAT). The search includes 636 GW candidates received in low latency, 86 of which have been confirmed by the offline analysis and included in the third cumulative Gravitational-Wave Transient Catalogs (GWTC-3). Targeted searches were carried out on the entire GW sample using the maximum--likelihood NITRATES pipeline on the BAT data made available via the GUANO infrastructure. We do not detect any significant electromagnetic emission that is temporally and spatially coincident with any of the GW candidates. We report flux upper limits in the 15-350 keV band as a function of sky position for all the catalog candidates. For GW candidates where the Swift-BAT false alarm rate is less than 10$^{-3}$ Hz, we compute the GW--BAT joint false alarm rate. Finally, the derived Swift-BAT upper limits are used to infer constraints on the putative electromagnetic emission associated with binary black hole mergers