Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first... Show moreAgammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondria! numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1(-/-) animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of I immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity. Show less
Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal... Show moreAmplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) was spiked into each sample as a library-specific quality control and calibrator. NGS identified 259 (average 5.2/sample, range 0-14) clonal sequences vs. Sanger-sequencing 248 (average 5.0/sample, range 0-14). NGS primers covered possible IG/TR rearrangement types more completely compared with local multiplex PCR sets and enabled sequencing of bi-allelic rearrangements and weak PCR products. The cPT-QC showed high reproducibility across all laboratories. These validated and reproducible quality-controlled EuroClonality-NGS assays can be used for standardized NGS-based identification of IG/TR markers in lymphoid malignancies. Show less
Bruggemann, M.; Knecht, H.; Kotrova, M.; Bartram, J.; Bystry, V.; Darzentas, N.; ... ; Langerak, A.W. 2017
The Spitzer Extended Deep Survey (SEDS) is a very deep infrared survey within five well-known extragalactic science fields: the UKIDSS Ultra-Deep Survey, the Extended Chandra Deep Field South,... Show moreThe Spitzer Extended Deep Survey (SEDS) is a very deep infrared survey within five well-known extragalactic science fields: the UKIDSS Ultra-Deep Survey, the Extended Chandra Deep Field South, COSMOS, the Hubble Deep Field North, and the Extended Groth Strip. SEDS covers a total area of 1.46 deg$^{2}$ to a depth of 26 AB mag (3{$σ$}) in both of the warm Infrared Array Camera (IRAC) bands at 3.6 and 4.5 {$μ$}m. Because of its uniform depth of coverage in so many widely-separated fields, SEDS is subject to roughly 25% smaller errors due to cosmic variance than a single-field survey of the same size. SEDS was designed to detect and characterize galaxies from intermediate to high redshifts (z = 2-7) with a built-in means of assessing the impact of cosmic variance on the individual fields. Because the full SEDS depth was accumulated in at least three separate visits to each field, typically with six-month intervals between visits, SEDS also furnishes an opportunity to assess the infrared variability of faint objects. This paper describes the SEDS survey design, processing, and publicly-available data products. Deep IRAC counts for the more than 300,000 galaxies detected by SEDS are consistent with models based on known galaxy populations. Discrete IRAC sources contribute 5.6 {plusmn} 1.0 and 4.4 {plusmn} 0.8 nW m$^{-2}$ sr$^{-1}$ at 3.6 and 4.5 {$μ$}m to the diffuse cosmic infrared background (CIB). IRAC sources cannot contribute more than half of the total CIB flux estimated from DIRBE data. Barring an unexpected error in the DIRBE flux estimates, half the CIB flux must therefore come from a diffuse component. Show less
