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• Germline DNMT3A mutation in mother-son pair with AML

  A mother/son pair with adult onset diploid AML were evaluated and found to have a dominant negative germline mutation in DNMT3A that is associated with global hypomethylation

  Study EGAS00001002940

• Procardis study on novel susceptibility genes for coronary artery disease (CAD)

  An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS: We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS: Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS: We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.

  Study EGAS00000000055

• Genome-wide copy number analysis of neuroblastoma

  Neuroblastoma is the most common extracranial solid tumor in childhood. Despite the improvement of risk-stratified therapies, overall survival rate of high-risk group is still as low as 40-50%. To investigate genome-wide copy number profiles of neuroblastoma, we performed SNP array analysis and PCR-based amplicon deep sequencing of neuroblastoma-related genes in 522 neuroblastoma samples.

  Study JGAS000046

• Recursive splicing in long vertebrate genes

  Recent studies have shown that expression of many genes with exceptionally long introns in the mammalian brain can be perturbed by regulatory factors linked to neurodevelopmental or neurodegenerative disorders1-3, suggesting unique regulatory mechanisms. Here we identify functional recursive splice sites (RSS) in long introns of genes expressed in the brain. These RSS are highly conserved in genes with extreme length across diverse vertebrate species and permit step-wise removal of long introns via recursive splicing. Recursive splicing requires initial definition of a “recursive exon” that is located downstream of RSS, and most often contains premature stop codons. Moreover, we show that RSS create a splicing switch driven by splice site competition in order to distinguish primary mRNA isoforms from alternative isoforms that are prevalent in long genes. The recursive exon is not detectable in the dominant mRNA isoform due to recursive splicing, but is completely included when cryptic promoters or other cryptic exons are used. Thus, by coupling inclusion of recursive exons with the use of cryptic elements, RSS act to distinguish new mRNA isoforms emerging from long genes.

  Study EGAS00001001170

• Risk Factors for Asymptomatic Diverticulosis

  Data for this analysis came from a prospective study of colonic diverticulosis at the University of North Carolina Hospital in Chapel Hill, North Carolina (NIH R01DK094738). This is a case-control genetic and transcriptomic study to identify the genetic and cellular determinants underlying colonic diverticulosis and the relationship with other gastrointestinal disorders. The study inclusion and exclusion are described below. DNA and RNA sequencing were performed on colonic tissue from 404 patients with (N=172) and without (N=232) diverticulosis. We assessed variation in the transcriptome associated with diverticulosis and integrated this variation with human intestine single-cell RNA-seq data. We integrated our expression quantitative trait loci with GWAS using Mendelian Randomization. A polygenic risk score analysis examined associations between severity of diverticulosis and other gastrointestinal disorders. We identified 38 genes with differential expression and 17 genes with varied transcript usage linked to diverticulosis. Our results suggest tissue remodeling as a primary mechanism for diverticula formation. The presence of diverticulosis was linked to stromal and epithelial cells in the colon including endothelial cells, myofibroblasts, fibroblasts, goblet, tuft, enterocytes, neurons, and glia. MR highlighted five genes including CCN3, CRISPLD2, ENTPD7, PHGR1, and TNFSF13. In diverticulosis cases, ENTPD7 upregulation was confirmed. A greater burden of diverticula was positively correlated with genetic predisposition to diverticulitis. The data related to the study including total RNA-Seq, SNP array and imputed genotypes will be available through dbGaP.

  Study phs003556

• Host Genetic Determinants of the Outcome of Staphylococcus Aureus Bacteremia by Whole Exome Sequencing

  In this case-control study, Complicated Staphylococcus aureus (case) is defined as bacteremia plus endocarditis or bone/joint infection, and Uncomplicated Staphylococcus aureus (control) has no such complications and was cured at follow-up. We used whole exome sequencing to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 Complicated SAB and 84 Uncomplicated SAB, frequency matched by age, sex and bacterial clonal complex). Then we evaluated the 334 most significantly associated genes and 8 biological candidate genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched by age, sex and bacterial clonal complex). All participants were white, non-Hispanic of European descent. In the discovery sample, gene-based analysis using SKAT-O identified 334 genes associated with complicated SAB at p<3.5 x 10-3;. Gene-based analysis of the 342 genes in the replication sample using SKATO identified one gene, GLS2 (GeneID: 27165), significantly associated with complicated SAB (p=1.2 x10-4;) after Bonferroni correction. GLS2 is an interesting candidate gene for complicated SAB due to its role in regulating glutamine metabolism, a key factor in white blood cell proliferation and activation.

  Study phs001505

• Variant calling dataset from the whole-exome study of familial pulmonary fibrosis in the Canary Islands-VCF files

  Sequence reads were obtained from a set of 13 families with familial pulmonary fibrosis in the Canary Islands, Spain, using Illumina paired-end reads, respectively, at the Institute of Technology and Renewable Energy (ITER). Briefly, we used bcl2fastq v2.18 to perform sample demultiplexing and BWA-MEM v0.7.15 (https://github.com/lh3/bwa) to align reads to GRCh37/hg19 reference. Resulting BAM files were assessed with SAMtools v1.3 (http://www.htslib.org) and Picard v2.10.10 (https://broadinstitute.github.io/picard/) for quality control steps. Small insertions/deletions (< 50 bp) and single nucleotide variants (SNVs) were identified using an in-house bioinformatics pipeline based on GATK HaplotypeCaller v3.8 (https://gatk.broadinstitute.org/hc/en-us/articles/360037225632-HaplotypeCaller). This pipeline follows the Best Practices recommendations for germline variant calling and its description is publicly available (https://github.com/genomicsITER/benchmarking/tree/master/WES).

  Dataset EGAD50000001152

• Surgery in combination with immune checkpoint therapy as an effective treatment for patients with metastatic cancer.

  Abstract Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial (N=104) using three different ICT-containing strategies plus cytoreductive or “debulking” surgery to remove the primary tumor-bearing kidney or a metastatic lesion as a treatment for patients (N=43) with metastatic clear cell renal cell carcinoma (mccRCC). For those patients (N=61) who were not candidates for cytoreductive surgery, a biopsy was obtained instead for correlative biological studies. Our data demonstrated that the combination of ICT with cytoreductive surgery was safe and feasible in patients with mccRCC. The 2-year overall survival was 84% with a median OS of 54.7 months for patients who received ICT containing regimens plus surgery. Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.

  Study EGAS00001005667

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - WGS

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015430

• Selection of somatic escape variants in SERPINA1 in liver tissue of patients with alpha-1 anti-trypsin deficiency - Exome

  Somatic variants accumulate in non-malignant tissues with age. Functional variants leading to clonal advantage of hepatocytes accumulate in the liver from patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing aetiologies is unknown. We analysed liver somatic variants in patients with genetic CLD from alpha-1 anti-trypsin (A1AT) deficiency or haemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered leading to truncation or coding change at the C-terminus of A1AT. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

  Dataset EGAD00001015431