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• Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial

  ABACUS is a single arm phase 2 study that investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in 95 patients with muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint.

  Study EGAS00001004445

• Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets

  Untreated prostate cancers rely on androgen receptor (AR) signaling for growth and survival, forming the basis for the initial efficacy of androgen deprivation therapy (ADT). Yet, the disease can relapse and progress to a lethal stage termed castration-resistant prostate cancer (CRPC). Reactivation of AR signaling represents the most common driver of CRPC growth and next generation AR signaling inhibitors (ARSIs) are now used in combination with ADT as a first line therapy. However, ARSIs can result in selective pressure generating AR-independent tumors. The transition from AR-dependence frequently accompanies a change in phenotype resembling developmental trans-differentiation or ‘lineage plasticity’. Neuroendocrine prostate cancer, which lacks a defined pathologic classification, is the most studied type of lineage plasticity. However, most AR-null tumors do not exhibit neuroendocrine features and are classified as ‘double-negative prostate cancer’, the drivers of which are poorly defined. Lineage plasticity studies in CRPC are limited by the lack of genetically defined patient-derived models that recapitulate the disease spectrum. To address this, we developed a biobank of organoids generated from patient biopsies to study the landscape of metastatic CRPC and allow for functional validation assays. Proteins called transcription factors (TFs) are drivers of tumor lineage plasticity. To identify the key TFs that drive the growth of AR-independent tumors, we integrated epigenetic and transcriptomic data generated from CRPC models. By presenting a map of the chromatin accessibility and transcriptomic landscape of CRPC using a diverse biobank of organoids, PDXs and cell lines that recapitulate the heterogeneity of metastatic prostate cancer, we validate CRPC-AR and CRPC-NE subtypes and reveal two subtypes of AR-negative/low samples as well as their respective masterTFs. Additional analysis revealed a model in which YAP, TAZ, TEAD and AP-1 function together and drive oncogenic growth in CRPC-SCL samples. Overall, we show here how an approach to stratify CRPC patients into four subtypes using their transcriptomic signatures can potentially inform upon appropriate clinical decisions.

  Study EGAS00001006059

• CRISPR-Mediated ASD Gene Knockout Reduces Neuronal Activity

  Autism Spectrum Disorder is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of 10 ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNAseq revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory post-synaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2- and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.

  Study phs001816

• Recapitulation of genetic predisposition to medulloblastoma in human neuroepithelial stem cells

  Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome, patients predisposed to medulloblastoma due to germline mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

  Study EGAS00001003620

• TONIC-Trial-cfDNA-Project

  Cell-free DNA (cfDNA) is an emerging technology to predict and monitor response to cancer treatment, including immune checkpoint blockade (ICB). However, data on cfDNA dynamics during ICB in metastatic triple negative breast cancer (mTNBC) are limited. While most applications of cfDNA involve assays that focus on mutation detection, mTNBC and multiple other cancer types are driven by copy number alterations (CNAs). We evaluate cfDNA-based copy number profile abnormality (CPA) score as a potential biomarker for monitoring ICB response in mTNBC, analyzing data from 87 patients enrolled in stage 1 and stage 2 of the TONIC-trial. We find significant concordance between cfDNA-based and tissue-based CNA profiles. Additionally, responders show a decrease in CPA scores upon ICB at week 6 (3 cycles of nivolumab). These findings underscore the potential of cfDNA-based CNA dynamics as a non-invasive biomarker for ICB early response assessment in patients with mTNBC.

  Study EGAS50000001308

• Cell-free DNA sequencing data of healthy control, atrophic gastritis, and gastric cancer patients’ blood

  Sample cohort (n=48) is consisted of healthy, atrophic gastritis and gastric cancer patients. Some of the gastric cancer patients samples are collected at the separate time points: -1 before the operation; -2 after the operation; -3 during the control visit. For the hybridisation capture of the genes unique 15 gastric cancer-related gene panel was developed and very deep sequencing using TruSight Oncology Unique Molecular Identifier (UMI) Reagents (Illumina) was used.

  Dataset EGAD00001011153

• Evaluation of protocols for rRNA depletion-based RNA sequencing of nanogram inputs of mammalian total RNA

  Next generation RNA-Sequencing (RNA-seq) is a flexible approach that can be applied to e.g. global quantification of transcript expression, the characterization of RNA structure such as splicing patterns and profiling of expressed mutations. Many RNA-seq protocols require up to microgram levels of total RNA input amounts to generate high quality data, and thus remain impractical for the limited starting material amounts typically obtained from rare cell populations, such as those from early developmental stages or from laser micro-dissected clinical samples. Here, we present an assessment of the contemporary ribosomal RNA depletion-based protocols, and identify those that are suitable for inputs as low as 1-10 ng of intact total RNA and 100-500 ng of partially degraded RNA from formalin-fixed paraffin-embedded tissues.

  Dataset EGAD00001005316

• The Role of CTCF in the Organization of the Centromeric 11p15 Imprinted Domain Interactome

  Beckwith-Wiedemann Syndrome (BWS) is the most common human imprinting disorder and comprises a spectrum of overgrowth phenotypes. While approximately 35% of BWS cases are caused by isolated loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15, only around 5% of patients develop BWS due to structural alterations to the IC2 domain. In this study, we identify a BWS-causing 7.6 kB familial deletion within the IC2 domain by performing Whole Genome Sequencing (WGS) on patient-derived human fibroblasts. Using a chromatin conformation capture technique, Capture C, on 3 control fibroblast samples, 3 BWS LOM fibroblast samples, and the single familial deletion sample, we investigate how the domain interactome changes in BWS patients. We find that high-strength interactions occur within the IC2 domain between the 5’ end of KCNQ1, KCNQ1 intron 2, and the 5’ end of CDKN1C in the control profile that are largely abrogated in the BWS samples, but some lower frequency contacts between the imprinting control region (ICR), KCNQ1 intron 2, and the 5’ end of CDKN1C are unaffected. We conclude that the strong KCNQ1-CDKN1C interactions are important in maintaining the domain imprint.

  Study phs002408

• Analysis of genes associated with autistic spectrum disorder, schizophrenia, and bipolar disorder.

  Autism spectrum disorders (ASD) represent a heterogeneous group of neurodevelopmental disorders with strong genetic predispositions. Although an increasing number of genetic variants have been implicated in the pathogenesis of ASD, little is known about the relationship between ASD-associated genetic variants and individual ASD traits. We performed case-control association study of 32 Japanese children with ASD (mainly with high-functioning autism) and 36 with typical development.

  Study JGAS000731

• Whole genome sequencing of AML with FUS-ERG

  FUS-ERG is a chimeric gene with a poor prognosis, found in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We investigated whether azacitidine (Aza) are effective in AML with FUS-ERG and how FUS-ERG induces chemoresistance. In a clinical case of AML with FUS-ERG, we compared whole-genome alterations between the initial diagnosis of MDS and the recurrence of AML after Aza treatment.

  Study JGAS000587

• Analysis of tumor periphery and center-specific mutations in renal cell carcinoma

  Renal cell carcinoma (RCC) is a genomically heterogeneous tumor. In the present project, the question whether intratumoral heterogeneity follows a zonal pattern indicating spatial niches was addressed. Whole exome sequencing of 16 paired samples from tumor periphery and center revealed a number of region-specific functional SNVs and Indels. Therefore, RCCs are not composed of evenly admixed tumor cells but show topological differences in their clonal composition.

  Study EGAS00001001784

• A GWAS meta-analysis on severe acne on a European population of 26,722 individuals

  Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin. We performed a genome-wide association study of 3,823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identified 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease.

  Study EGAS00001003278

• Somatic L1 retrotranspositions in normal human cells

  Genomic mutations accumulate in normal cells during lifetime; however, somatic mosaicism generated by mobilization of transposable elements is not well understood. Here, we explored whole-genome sequences of single-cell expanded clones to illustrate the mutational landscape produced by L1. In addition, we analyzed promoter DNA methylation status of retrotransposition-competent L1 and read-through RNA expression profiles to investigate the epigenetic regulation of L1 activity.

  Study EGAS00001006213

• Strand-seq of hematopoietic stem and progenitor cells along human aging

  Somatic mosaicism (SM), referring to the presence of somatic mutations in sub-populations of cells within healthy individuals, is associated with an increased risk of a variety of diseases, including cancer. Blood is at particularly high risk of SM, given its rapid turnover and functionally- heterogeneous cell-type composition. While the roles of point mutations and large-scale rearrangements in blood SM have been scrutinised in recent years, the functional impact of mosaic structural variants (mSVs) remains poorly understood. Using haplotype-resolved single-cell multi-omics based on Strand-seq technology, we explored the mSV landscape of human hematopoietic stem and progenitor cells (HSPCs).

  Dataset EGAD00001009402

• Nicotine Addiction Genetics and Correlates

  Ascertainment: Families were ascertained through panels of adult Australian twins, and a sample of spouses of Australian twins. Families with at least one offspring who was identified as a current or former smoker in an earlier survey. Screening telephone interviews were conducted with index cases to provide confirmation of a history of heavy cigarette smoking, to obtain confirmation of a history of heavy cigarette smoking, and to obtain additional information on the history of cigarette use and the survival status of other family members, and their full siblings and parents. Index cases were the affected spouse of a twin, or the affected twin from pairs discordant for a history of heavy smoking, or a randomly chosen twin from pairs where both have a history of regular smoking (i.e., has smoked at least 100 cigarettes lifetime), and at least one live biological parent to identify sibships with at least one affected sib pair (ASP) concordant for heavy smoking, and at least one living parent. If permission was granted by the index case, eligible family members were contacted and invited to provide a blood sample and to complete a telephone diagnostic interview. In families with just one available biological parent, and additional unaffected sibling who had never smoked on a regular basis (i.e., has smoked fewer than 100 cigarette lifetime, but has experimented with cigarettes once or twice) was included (when available) to help compensate for the loss of information due to missing parental phenotypes. (Target N=400 Australian families with approximately 600 ASPs; and 600 TDT trios comprised of a nicotine dependent index case and both biological parents). Diagnostic Assessment: The telephone diagnostic interview assessed DSM-IV and modified DSM-IIIR diagnoses (i.e., without time clustering) for nicotine dependence, alcohol and other drug dependence and abuse, major depression, and childhood conduct disorder. Most diagnostic assessments were based on the SSAGA/SSAGA-II, developed for the multi-site gene-mapping alcoholism study (the Collaborative Study on the Genetics of Alcohol. An exception was the tobacco section, which was developed directly from the CIDI and DIS (as the original SSAGA did not include a diagnostic section on nicotine dependence). In version 2 of this study, a text file containing 7704 SNPs with large allele frequency discrepancy as compared to 1000 Genomes is included. Users have the option to exlude these 7704 SNPs.

  Study phs001299

• Molecular characteristics in Burkitt lymphoma over age groups

  Treatment optimization has improved the overall survival in Burkitt lymphoma (BL) patients but there are still relevant outcome differences between pediatric and adult patients. In both age groups survival remains poor for patients who suffer relapse. Therefore, new treatment approaches are warranted to improve survival. Thus, we conducted a comparative study in the largest pediatric cohort to date including 191 cases and 97 samples from adult patients and analyzed the mutational landscape. We detected overlapping molecular profiles but also significant differences in the mutational pattern. Samples from pediatric patients show a higher frequency of mutations in ID3, DDX3X and BAF-complex components ARID1A and SMARCA4, while YY1AP1 and BCL2 are more frequently mutated in cases from adult BL patients. Correlation of the mutational profile with clinical data was available for the pediatric cohort and identified TP53 mutations to be highly significantly associated with the incidence of relapse thus identifying the first molecular marker to be associated with the incidence of relapse in pediatric BL. As the hotspot analysis of TP53 mutations showed mostly gain of function mutations, it is tempting to speculate that drugs decreasing the amount of malignant TP53 or increase the abundance of wildtype TP53 could be a promising approach for future treatment regimens to further improve prognosis.

  Study EGAS00001005270

• Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis thymoma

  Myasthenia gravis (MG) is known to be epidemiologically associated with abnormalities of the thymus, an organ that maintains central tolerance. However, due to the complexity of the thymus, specific characteristics related to the pathogenesis of MG remain elusive. In our study, we attempted to narrow down the features associated with MG using spatial transcriptome analysis of thymoma and thymic hyperplasia samples. We found that the majority of thymomas were constituted by the cortical region, whereas the medullary region was localized in comparatively restricted areas. Moreover, the medullary region contained polygenic enrichment, MG-specific germinal center structures, and a supporting immune microenvironment. Additionally, neuromuscular medullary thymic epithelial cells (nmTECs), previously identified as MG-specific autoantigen-producing cells, were situated at the cortico-medullary junction. The immune microenvironment in the medulla was characterized by a specific chemokine pattern and specific immune cells, such as CCR7+ migratory dendritic cells (migDCs) and effector regulatory T (Treg) cells. Furthermore, similar germinal center structures and immune microenvironments were observed in the medulla during thymic hyperplasia. This study indicates that the medulla and junction areas are related to the pathology of MG, suggesting that these areas should be the focus of future studies on MG pathogenesis and drug targeting.

  Study JGAS000672

• Developmental Mechanisms of Human Congenital Heart Disease in Subjects with 22q11.2 Deletion Syndrome (DiGeorge Syndrome/Velocardiofacial Syndrome)

  The study is designed to identify genetic modifiers of cardiovascular defects in subjects with 22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome or velo-cardio-facial syndrome. Affymetrix 6.0 arrays were processed on 1,480 subjects with known cardiovascular anomalies or with normal structures, all with 22q11.2DS. One sample is a duplicate so it was removed. There are 1,472 samples total of unrelated, de-identified, probands. Over 90% have the same sized 3 million base pair deletion flanked by low copy repeats (LCR22) A and D, while approximately 6% have nested A to B deletions. The rest have other nested deletions, that include a deletion in the vicinity of TBX1 (between LCR22 A and B). A subset of the data was used to identify copy number variations serving as modifiers. Some data were previously published by Dr. Emanuel's team at Children's Hospital of Philadelphia in PA, USA (PMID:26742502; PMID:4896312; PMID:25892112; PMID:4570279). The de-identified DNA data from unrelated subjects come from multiple research sites in the US and Europe as part of the International 22q11.2 Consortium and the International 22q11.2 Brain and Behavior Consortium.

  Study phs001339

• Exome Sequencing of Alcohol-Associated Hepatitis

  Alcoholic hepatitis (AH) is a clinically severe, acute disease that only afflicts a fraction of patients with alcohol use disorder (AUD). Although recent genomic studies of alcoholic cirrhosis (AC) and steatosis have revealed that several genes of large effect are shared between these disorders, the genetic and environmental sources of variation that lead to AH, AC or alcohol fatty liver disease (AFLD) in some AUD patients remain largely unknown. In order to investigate the genetic determinants of AH, we sequenced a 58 Mb exome target to high genotype accuracy (0.996) and completeness (0.941) in 1,735 patients with AH (N=784) and heavy drinking controls without alcohol-associated liver disease (ALD) (N=951), detecting 1,085,982 unique single nucleotide variants (SNVs). Analysis of common SNPs that comprised 17.5% of those SNVs, we observed exome-wide significant association of PNPLA3 (rs738409-G allele: odds ratio [OR]=1.73, 95% confidence interval [CI]: 1.44-2.08, p =3.75e-9), as had previously been seen for AH in candidate gene contexts, and as previously observed for PNPLA3 to AC and nonalcohol steatohepatitis in GWAS. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B, also a known liver disease gene. However, SNPs at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant and of large effect-size (ICOSLG rs13052840-C allele: OR=1.67, 95% CI: 1.39-2.02, p = 4.59e-8; TOX4/RAB2B rs17516362-C allele: OR = 0.61, 95% CI: 0.50-0.74, p=1.25e-7). ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation, and thus could be tied to the inflammatory component of AH. TOX4 was previously implicated in diabetes and immune system and its linked SNP is a cis eQTL for TOX4 and RAB2B. A polygenic signal was visible on the exome-wide quantile-quantile graph, where there was modest p value inflation (lambda = 1.040). Ranking p values of all 18,705 genes evaluated versus a list of 227 genes objectively precompiled for relationship to liver diseases (via GWAS), we observed a strong (pThe data generated here also represents a resource that can be used cumulatively or meta-analytically with future datasets.

  Study phs003659

• Phenotyping and Therapeutic Approaches for Patients with Sellar/Suprasellar Disorders

  The goal of the study is to phenotype and genotype patients with rare hypothalamic and pituitary disorders and identify biomarkers of disease diagnosis, presentation, and progression. We are investigating genetic mechanisms of pituitary tumorigenesis as well as genomic/transcriptomic markers of disease presentation and severity. Patients with suspected or confirmed hypothalamic and/or pituitary disorders and their family members are recruited. Biospecimens including peripheral blood, urine, tumor tissue (as available), and/or stool are collected. Genetic analysis may include a variety of techniques including peripheral blood or tumor tissue targeted Sanger sequencing of one or few genes, peripheral blood or tumor tissue whole exome sequencing, and other as applicable.

  Study phs003245

• Quick Guide for data submission

  Quick Guide This is a quick guide to submit data to the EGA. Please select data type to display the right detailed instructions. Sequence data Array-based data Get your submission account You first need to create your EGA user. Then, once your account has been verified by the Help Desk team, request your submission account and provide details of the data type and platform(s) in your submission. Register Study/DAC Use Submitter Portal to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the and upload it to your inbox using SFTP. Register experiments and runs Associate each data file to a registered sample and study by Linking files to samples. Details of the experimental procedure you followed must be provided. Finalise your submission Group your runs/analysis into datasets and link them to your new or existing DAC and policy using DAC Portal. Data request are done at a dataset level, thus files within a datasets must share release conditions. Release and admin When finalising the submission, set a released date to instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released. Get your submission account Fill the submission form and provide details of the data type and platform(s) in your submission. Register Study/DAC Use EGA Programmatic submission to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the EgaCryptor and upload it using default FTP clients or Aspera. Complete the Array-Format (AF) spreadsheet Download the AF spreadsheet and complete all four sections. Return the spreadsheet to the EGA helpdesk. Release and admin Instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released.

  Documentation submission/quickguide

• Genetic and Phenotypic Analysis of Multiple Sclerosis in Hispanics

  We sought to identify MS susceptibility variants specific to the Major Histocompatibility Complex and to assess the effect of ancestral risk modification within 2652 Latinx and Hispanic individuals, as well as 2435 Black and African American individuals ascertained in collaboration with the Alliance for Research in Hispanic MS (ARHMS). All DNA samples were obtained through whole blood extraction and were genotyped on the MS Chip, an Illumina Infinium custom genotyping array that contains targeted and dense coverage of the extended MHC, specifically designed for imputation. Classical HLA alleles, SNPs, and amino acid residues were imputed simultaneously from genotyped SNPs using HLA-TAPAS and a multi-ethnic reference panel of 2504 samples from the 1000 Genomes Project. We have identified several novel susceptibility alleles which are rare in European populations including HLA-B*53:01, and we have identified an independent role for HLA-DRB1*15:01 and HLA-DQB1*06:02 on MS risk. We found a decrease in Native American ancestry in MS cases vs controls across the MHC, peaking near the previously identified MICB locus; and we have identified several susceptibility variants for which MS risk is modified by global or local ancestry. We are making data on all genotyped and imputed SNPs, classical HLA alleles, and amino acid residues available through dbGaP for the Hispanic and African American samples utilized in these analyses.

  Study phs003105

• A spatiotemporal organ-wide gene expression and cell atlas of the developing human heart

  The process of cardiac morphogenesis in humans is incompletely understood. Its full characterization requires a deep exploration of the organ-wide orchestration of gene expression with a single-cell spatial resolution. Here, we present a molecular approach that reveals the comprehensive transcriptional landscape of cell types populating the embryonic heart at three developmental stages, and which maps cell type-specific gene expression to specific anatomical domains. Spatial Transcriptomics identified unique gene profiles corresponding to distinct anatomical regions in each developmental stage. Human embryonic cardiac cell types identified by single-cell RNA-sequencing confirmed and enriched the spatial annotation of embryonic cardiac gene expression. In situ sequencing was then used to refine these results and create spatial subcellular map for the three developmental phases. Finally, we generated a publicly available web resource of the human developing heart to facilitate future studies on human cardiogenesis.

  Study EGAS00001003996

• Genome-Wide Association Study of Sporadic and Familial Testicular Germ Cell Tumors

  Case-Control Study:Testicular germ cell cancer has been increasing among men during most of the 20th century. Despite this increase, the etiology of testicular cancer is poorly understood. To better understand the molecular epidemiology of testicular cancer, the National Cancer Institute and the Department of Defense are conducting a case-control study of testicular cancer among military servicemen. The project includes obtaining biosamples and questionnaire data from all participants. Pre-diagnostic serum samples are available from the approximately 1,000 cases and 1,000 controls enrolled in the study. Multiple-Case Family Study:In a parallel project, we are also studying families in which 2 or more testicular cancers have occurred. Among those men diagnosed with testicular cancer, about 1-3 percent report a family history of the disease (FTGCT). Brothers of affected individuals are 8 to 10 times more likely to develop testicular cancer, and men whose fathers had testicular cancer are four times more likely to develop testicular cancer, when compared with the relatives of men who have never had testicular cancer. Large-scale genetic linkage studies have failed to identify one or more rare, highly-penetrant testicular susceptibility genes. Rather, it appears that these familial clusters are due to the combined effects of multiple more common genes with low penetrance (so-called "polygenic inheritance"). Our cohort of FTGCT families was assembled to characterize this syndrome's clinical phenotype, and to discover the full range of cancer susceptibility loci that influence TGCT pathogenesis.

  Study phs001303

• NHLBI GO-ESP: Family Studies (Familial Atrial Fibrillation)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. Large epidemiological studies have demonstrated a significant heritable component in atrial fibrillation (AF), especially the Lone forms, suggesting a monogenic syndrome. Although substantial genetic contribution has been made to the etiology of AF, the specific genes have not yet been identified. The familial form of this disease remains poorly characterized and largely undetermined. Here we seek to identify, characterize and determine the natural course of AF in our clinical practice. We identified four large multi-generation families (FAF 1-4). In FAF 1-2, most family members have symptomatic paroxysmal Atrial Fibrillation (AF) and were adequately treated with a combination of rate and rhythm therapies. By contrast, the AF substrate in FAF 3 and 4 was resistant to anti-arrhythmic drugs and ablation therapies.

  Study phs000362