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• Nature and Contribution of Noncoding, Regulatory Mutations in Neurodevelopmental Disorders

  This dbGaP study contains variant call files generated from whole-genome sequencing data of families with autism. The variant callers include FreeBayes, GATK, Platypus, and Strelka2. A family-level VCF file, from each caller, is provided for each family in the study. The families included in this study are from the Simons Simplex Collection (SSC), the Study of Autism Genetics Exploration (SAGE), and The Autism Simplex Collection (TASC); sequencing was performed at the New York Genome Center, as part of the Centers for Common Disease Genomics (CCDG) Consortium. The analysis to generate the variant callsets was supported by a K99 Pathway to Independence grant to Dr. Tychele Turner (1K99MH117165-01). *Access to phenotype data at the individual level for Simons Simplex Collection (SSC) subjects can be requested from SFARI Base: https://www.sfari.org/resource/sfari-base/.

  Study phs001874

• NHLBI TOPMed: African American Sarcoidosis Genetics Resource

  This study aims to comprehensively interrogate the genomes of African American sarcoidosis families. Sarcoidosis is characterized by a hyperimmune response resulting in granuloma formation in multiple organs. It affects African Americans (AAs) more frequently and more severely than whites. While previous linkage, admixture, candidate gene and genome-wide association (GWA) studies show statistically compelling effects, causal variants are still unknown and much of sarcoidosis heritability is yet to be explained. This "missing" heritability likely includes effects of both common (minor allele frequency (MAF)>5%) and rare variants (MAF

  Study phs001207

• H3Africa - An integrated approach to the identification of genetic determinants of susceptibility to trypanosomiasis

  The over-arching aim of this network is to improve the health of people living in some of the poorest countries in the world that carry a disproportionate burden of infectious diseases. Despite their importance, the study of many tropical diseases has lagged behind that of diseases of developed countries. This network will redress the balance by performing high quality research into two neglected tropical diseases, human African Trypanosomiasis (HAT) and schistosomiasis. Our aim is to investigate the genetic determinants of the human reservoirs of HAT and schistosomiasis, filling an important knowledge gap, while extending and strengthening the underpinning infrastructure to deliver these scientific objectives in particular by developing the next generation of African geneticists.

  Study EGAS00001007173

• Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies

  To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). Laser capture microdissection of tumour islets was performed on samples prior to chemotherapy, after three cycles of chemotherapy and at recurrence. Long frament read whole genome sequencing was performed and mutations were identified. To our knowledge, this is the first longitudinal study that attempts to investigate spatial and temporal micro-heterogeneity in cancer.

  Study EGAS00001001909

• Oxidative DNA damage and ubiquitin proteasome system dysfunction underpins neurodegeneration in young adults with a DNA repair disorder

  Xeroderma pigmentosum (XP) is caused by defective nucleotide excision-repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We have identified substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find endoplasmic reticulum stress is upregulated, and, critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity improves phenotypes, albeit inadequately, implying that early detection/prevention strategies are necessary to produce clinically impactful outcomes. Thus, we develop an early detection assay predicting neurodegeneration in at-risk patients.

  Study EGAS50000000158

• Oxidative DNA damage and ubiquitin proteasome system dysfunction underpins neurodegeneration in young adults with a DNA repair disorder

  Xeroderma pigmentosum (XP) is caused by defective nucleotide excision-repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We have identified substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find endoplasmic reticulum stress is upregulated, and, critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity improves phenotypes, albeit inadequately, implying that early detection/prevention strategies are necessary to produce clinically impactful outcomes. Thus, we develop an early detection assay predicting neurodegeneration in at-risk patients.

  Study EGAS50000000160

• Oxidative DNA damage and ubiquitin proteasome system dysfunction underpins neurodegeneration in young adults with a DNA repair disorder

  Xeroderma pigmentosum (XP) is caused by defective nucleotide excision-repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We have identified substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find endoplasmic reticulum stress is upregulated, and, critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity improves phenotypes, albeit inadequately, implying that early detection/prevention strategies are necessary to produce clinically impactful outcomes. Thus, we develop an early detection assay predicting neurodegeneration in at-risk patients.

  Study EGAS50000000162

• An epigenetic single-cell atlas of IDH-mutant glioma reveals the role of ATRX in shaping tumor composition

  Recent single-cell RNA-sequencing studies have identified a hierarchy of cell types that is common to all isocitrate dehydrogenase (IDH) -mutant gliomas. This finding is somewhat paradoxical since the genetic differences between IDH-mutant astrocytomas and IDH-mutant oligodendrogliomas are prognostic, predictive of therapeutic response, and correlated with differences in immune infiltrates. To integrate these disparate findings, we constructed a single-cell atlas of 22 human IDH-mutant primary untreated grade-II/III gliomas.

  Study EGAS00001004523

• The genomic complexity of early T-cell progenitor acute lymphoblastic leukemia

  CREST The accurate identification of structural variations using whole-genome DNA sequencing data generated by next-generation sequencing technology is extremely difficult. To address this challenge, we have developed CREST, an algorithm that uses sequencing reads with partial alignments to the reference human genome (so-called soft-clipped reads) to directly map the breakpoints of somatic structural variations. We applied CREST to paired tumor/normal whole genome sequencing data from five cases of T-lineage acute lymphoblastic leukemia (T-ALL). A total of 110 somatic structural variants were identified, >80% of which were validated by genomic PCR and Sanger sequencing. The validated structural variants included 31 inter-chromosomal translocations, 19 intra-chromosomal translocations, one inversion, 22 deletions and 16 insertions. A comparison of the results generated with CREST to those obtained using the traditional paired-end discordant mapping methods demonstrate CREST to have a much higher sensitivity and specificity. In addition, application of CREST to publicly available whole-genome sequencing data from the human melanoma cancer cell line COLO-829 demonstrated the identification of 50 novel structural variations not detected using the standard methods, 20 of which were selected for validation with a 90% success rate. These data demonstrate that direct mapping of soft-clipped reads offers an improved method for detecting structural variants at the nucleotide level of resolution. T-ALL Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

  Study phs000340

• Ampliseq library dataset

  This is the dataset for Ampliseq sequencing

  Dataset EGAD50000000536