Search Results - EGA European Genome-Phenome Archive

Dataset for transcriptomic sequencing of Merkel cell carcinoma(MCC) samples

This dataset contains transcriptome sequencing for 5 samples of MCC tumors . The sequencing was performed on Illumina NextSeq 6000 . The sequencing was always paired.

Dataset EGAD00001015702

WGBS data for EGAS00001004660

WGBS data for EGAS00001004660, "Aggressive PDACs show hypomethylation of repetitive elements and the execution of an intrinsic IFN program linked to a ductal cell-of-origin"

Dataset EGAD00001006538

Trio Sequencing results for the AnkyrinG MIPS screening study

Approximately 1000 trio's with varying degrees of cognitive disorders. All samples have been sequenced for the AnkyrinG interactome using MIPS technology. Data is presented as BAM and unfiltered VCF files.

Dataset EGAD00001006823

RNAseq for Patients of NIBIT-M4 clinical trial

Dataset EGAD00001009702

Whole genome sequencing of AML samples at presentation, remission, and relapse

Whole genome sequencing of AML blood or bone marrow at presentation and remission for 5 patients. Relapse samples are included for 2 patients, totaling 12 WGS BAM files.

Dataset EGAD00001005120

A96210C

Whole genome sequencing for single cells for library A96210C 1191 samples; filetype=bam

Dataset EGAD00001008254

Single Cell Genome Sequence for DLP+ library A96210B

Single Cell Genome Sequence for high grade serous ovarian carcinoma patient SA1047B on DLP+ library A96210B

Dataset EGAD00001009475

WGS data for ependymomas (5 tumor-control pairs)

Whole genome sequencing data for ependymomas (5 tumor-control pairs). See Mack, Witt et al. Nature 506(7489):445-50, 2014 (PMID: 24553142).

Dataset EGAD00001000950

WES/WXS data for ependymomas (42 tumor-control pairs)

Whole exome sequencing data for ependymomas (42 tumor-control pairs). See Mack, Witt et al. Nature 506(7489):445-50, 2014 (PMID: 24553142).

Dataset EGAD00001000951

Whole Genome Sequencing for the paper titled "Orthotopic Patient-Derived Xenografts of Pediatric Solid Tumors"

Dataset EGAD00001003435

DATA FILES FOR Ph-likeALL WES

Dataset EGAD00001001054

H3Africa H3AChipDesign MalSic

The dataset includes BAM, FASTQ and decompressed gVCF files for 50 samples from Benin generated for the H3Africa Chip Design Study.

Dataset EGAD00001004557

WGS DATA FILES FOR SJPhLike

Dataset EGAD00001000976

Whole genome sequencing of 98 tumour-normal pairs for the pancreatic neuroendocrine cancer project

Whole genome sequencing of 98 tumour-normal pairs for the PAEN-AU pancreatic neuroendocrine cancer project.

Dataset EGAD00001002684

Hospital for Sick Children Infant Glioma RNA Sequencing

Whole transcriptome (n=4) and targetted RNA sequencing (n=15) .bam files of infantile glioma samples reported on at the Hospital for Sick Children

Dataset EGAD00001005092

Identification Of Pathogenic Mutations And Application Of Polygenic Risk Scores In Early-Onset Diabetes Patients

Maturity-onset Diabetes of the Young (MODY) presents a diagnostic challenge. In this study we investigate the genetic background of Latvian early-onset diabetes patients, using whole-genome sequencing data. Additionally, we investigate the utility of previously published and available type 1 diabetes (T1D) and type 2 diabetes (T2D) polygenic risk scores in differentiating monogenic diabetes (MODY) from T1D and T2D cases.

Study EGAS50000000991

ChIP-seq data in MSC_Pat and EWIma1 (FLI1 & H3K27ac)

Ewing sarcoma is characterized by pathognomonic translocations fusing most frequently EWSR1 with FLI1 (EF1). In addition, Ewing sarcoma can also display alterations in STAG2, TP53 and CDKN2A (SPC). Starting from Ewing sarcoma derived human mesenchymal stem cells (MSCpat), we recapitulated this translocation and SPC alterations using a CRISPR/cas9 approach and generated a bona fide Ewing sarcoma model (EWIma1) displaying transcriptomic and epigenetic hallmarks of EwS.

Study EGAS50000001172

RNA-seq data in hMPC, MSC_Pat and EWIma

Ewing sarcoma is characterized by pathognomonic translocations fusing most frequently EWSR1 with FLI1 (EF1). In addition, Ewing sarcoma can also display alterations in STAG2, TP53 and CDKN2A (SPC). Starting from Ewing sarcoma derived human mesenchymal stem cells (MSCpat), we recapitulated this translocation and SPC alterations using a CRISPR/cas9 approach and generated a bona fide Ewing sarcoma model (EWIma1) displaying transcriptomic and epigenetic hallmarks of EwS.

Study EGAS50000001173

Study of the role of aneuploidy in cB-ALL

We modeled two proposed routes to hyperdiploidy, chromosome missegregation and cytokinesis failure, by transiently exposing human fetal liver–derived HSPCs to reversine or cytochalasin-D. Induced hyperdiploidy impaired fitness and delayed differentiation in vitro, causing hyperdiploid cells to be rapidly outcompeted by euploid counterparts. Nonetheless, hyperdiploid cells engrafted immunodeficient mice, where rare clones persisted long-term and acquired non-random chromosomal gains frequently observed in cB-ALL.

Study EGAS50000001613

Genomic characterization of germ-cell tumors in childhood

Germ cell tumors (GCTs) are rare neoplasms affecting approximately 3.5% of pediatric patients, with diverse histological subtypes. Despite their low mutational burden, prevalent alterations in KIT, KRAS, and NRAS genes are observed, but molecular understanding of pediatric GCTs lags behind adult counterparts. We aimed to elucidate the genomic landscape of 16 pediatric GCT patients via whole exome sequencing (WES), which revealed somatic alterations resembling those in adult GCTs.

Study EGAS50000000619

HG Transcriptome sequencing in the INTERVAL cohort

We performed bulk RNA-sequencing on peripheral blood collected from 4,732 blood donors recruited as part of the INTERVAL study. Using these data, we mapped gene expression and splicing quantitative trait loci (QTLs). Then, we integrated these data with protein, metabolite and lipid QTLs in the same individuals. The study aimed to identify the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans.

Study EGAS00001003346

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

Molecular characterization of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis

Patients with hepatocellular carcinoma (HCC) associated to non-alcoholic steatohepatitis (NASH) are increasing globally, but their molecular traits are not well characterized. Our molecular characterization revealed higher rates of ACVR2A mutations (10%) – a potential tumour suppressor, presence of a novel mutational signature (MutSig-NASH-HCC), a more relevant role of Wnt/TGF-β proliferation subclass in tumours (42%) and immunosuppressive traits in the adjacent non-tumoral tissue.

Study EGAS00001005222

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

Study the genetic susceptibility of esophagus squamous cell carcinomas (ESCC) in high-risk area Henan Chinese

This study utilized a genetically-enriched cohort of patients with familial ESCC from the high-risk Henan region, located near the Tai-Hang Mountain region in Northern China, to identify high penetrance ESCC predisposition genes using a comprehensive unbiased whole-exome sequencing (WES) strategy. Subsequent validate the prevalence of rare damage variants by targeted gene sequencing in a large sample size.

Study EGAS00001003423

Vitamin C boosts DNA demethylation in TET2 germline mutation carriers

We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte predominant Hodgkin lymphoma. In a clinical trial of one year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members.

Study EGAS00001006916

Whole-exome variant calling of individuals from the study of sepsis and acute distress respiratory syndrome in Spain

Research study of genetic susceptibility in sepsis and acute distress respiratory syndrome (ARDS). ARDS is a lethal condition, often derived from sepsis, lacking effective targeted treatments. Growing evidence indicates that the genetic component significantly influences susceptibility and severity of ARDS. We used whole-exome sequencing data in case-control studies to characterize genetic factors associated with an increase of ARDS risk.

Study EGAS50000001119

Single Cell RNA Sequencing of Tendon Scar Tissue (Tenolysis)

This human tenolysis sample was collected as a control (non-diabetic sample) as part of larger study described below.The purpose of the larger study is to define the cellular and molecular environment in tendons, pulleys, synovial sheath, tendon scar tissue, and palmar fascia samples. The samples are isolated from discarded tissues from patients who undergo lower limb amputation surgery, dupuytren's disease, trigger finger release, tenolysis surgery, tenosynovitis surgery, distal biceps tendon repair, common extensor debridement and repair, common flexor debridement and repair, or proximal long head of the biceps tenodesis.The dramatic increase in Type 2 Diabetes Mellitus (T2DM) as part of the obesity epidemic is one of the most pressing health challenges facing the U.S. Type II diabetes results in systemic inflammation and is characterized by metabolic dysfunction including elevated plasma glucose levels (hyperglycemia). There is a clear link between T2DM and musculoskeletal pathologies; T2DM accelerates the progression of osteoarthritis, and increases fracture risk. Moreover, T2DM impairs tendon homeostasis and repair, and increases the risk and severity of tenosynovitis (infection of the tendon and sheath), however there remains a paucity of information regarding the molecular mechanisms of diabetes-induced changes in tendon function. Flexor and extensor tendons facilitate digit range of motion (ROM) and movement of the hand. Tendon gliding can be impaired by tendon fibrosis and an inability to fit within the surrounding synovial sheath, or due to the formation of fibrous adhesions between the tendon and synovial sheath during healing. Fibrosis and increased disorganization of the extracellular matrix are hallmarks of the diabetic hand phenotype observed in T2DM patients. T2DM dramatically affects the baseline function of tendons; up to 50% of diabetic patients experience impaired hand function, including increased rates of tenosynovitis, and carpal tunnel syndrome. In addition to decrements in tendon gliding function, deficits in mechanical properties are also observed, rendering diabetic tendons more susceptible to rupture. Considering that the complication rate of primary flexor tendon repairs is as high as 40% in non-diabetic patients, and that T2DM further impairs tendon healing, it is imperative to understand the cellular and molecular components of diabetic tendinopathy. The study will define the overall cellular and molecular environment in tendon pulleys, palmar fascia, synovial sheath tissue, and scar tissue (tenolysis and tenosynovitis samples) as a function of type II diabetes.

Study phs004076

NIDDM-Atherosclerosis Study (NIDDM-Athero)

The NIDDM-Atherosclerosis Study, funded by NHLBI, was designed as a family study to examine the genetic basis of subclinical atherosclerosis and diabetes in Hispanic families. Family members of probands with T2D were recruited in the Los Angeles area. The baseline examination of the cohort included the euglycemic hyperinsulinemic clamp test from which the two key phenotypes were obtained: insulin sensitivity (M) and metabolic clearance rate of insulin (MCRI). Genome-wide genotyping was obtained under separate funding by NIDDK as a part of the GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium.

Study phs001130

NHLBI TOPMed: Genetic Epidemiology Network of Salt Sensitivity (GenSalt)

The GenSalt study aims to identify genes which interact with dietary sodium and potassium intake to influence blood pressure in Han Chinese participants from rural north China. Whole genome sequencing will be conducted among 1,860 participants of the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Study. We will work in collaboration with participating TOPMed studies to identify novel common, low-frequency and rare variants associated with an array of cardiometabolic phenotypes. In addition, we will explore the relation of low-frequency and rare variants with salt-sensitivity among GenSalt study participants.

Study phs001217

Single-Cell Analysis of the Multiple Myeloma Microenvironment after Gamma-Secretase Inhibition and CAR T-Cell Therapy

We examined the effects of gamma-secretase inhibition (GSI) on the bone marrow microenvironment in multiple myeloma patients before anti-B-cell maturation antigen (BCMA) CAR T-cell therapy. Single-nuclei RNA and ATAC sequencing revealed significant changes in gene expression and chromatin accessibility, especially in monocytes and tumor cells, following exposure to GSI. The findings suggest that GSI influences not only BCMA signaling but also broader cellular interactions within the tumor microenvironment. De-identified sequencing data from the study is available through dbGaP.

Study phs003741

Single-Cell RNA-Sequencing of Tumor and Immune Cells from Patients with Asymptomatic Waldenstrom's Macroglobulinemia

We performed single-cell RNA-seq on tumor and immune cells from 30 patients with IgM Monoclonal Gammopathy of Undetermined Significance (IgM MGUS), Smoldering Waldenstrom's Macroglobulinemia (SWM), and overt Waldenstrom's Macroglobulinemia (WM) to identify tumor-intrinsic and immune biomarkers of disease progression in patients with asymptomatic WM. We identified subtypes within MYD88-mutant WM that are associated with clinical presentation and/or patient outcomes. We also characterized immune dysregulation in patients with asymptomatic WM, and demonstrated disordered interferon stimulation in T and NK cells of patients.

Study phs003787

Deciphering the complex clonal heterogeneity of polycythemia vera and the response to interferon alpha

We integrated colony formation and differentiation assays with single-cell RNA sequencing and single-cell genotyping in PV patient-derived cells vs. healthy controls to dissect how IFNa targets diseased clones during erythroid differentiation. Our findings indicate that PV-derived clones either undergo apoptosis or pass through their typical differentiation cycle, contributing to the long-term exhaustion of mutant cells in the bone marrow. The pivotal roles of ribosomal genes and clonal prerequisites in the therapeutic mechanism of IFNa are underscored by our study.

Study EGAS50000000904

An investigation into the effects of progestin on follicular development and oocyte maturation during controlled ovarian stimulation using the Progestin-Primed Ovarian Stimulation (PPOS).

In recent years, the Progestin-Primed Ovarian Stimulation (PPOS) method, utilizing progestin as ovulation suppressants, has gained traction as a controlled ovarian stimulation (COS) strategy in assisted reproductive technology (ART). However, the impact of progestin agents on follicular fluid, granulosa cells, and cumulus cells at the levels of gene and protein expression has not been fully assessed. This study aims to evaluate the effects of progestin agents, used in the PPOS method, on follicular development and oocyte maturation.

Study JGAS000770

Celiac disease meta-analysis

Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4,125 additional Caucasian samples including an Argentinian cohort genotyped on the Immunochip. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations.

Study EGAS00001003805

Whole genome sequencing of colon organoid cultures with artificially induced oncogenic mutations

Using the CRISPR-Cas9 genome editing system, various oncogenic mutations were introduced in the genome of normal adult stem cells derived from the colon. The resulting clonal cultures were subjected to whole genome sequencing. In addition, the cultures were transplanted in a mouse and the resulting primary and metastatic tumors were also subjected to whole genome sequencing. The initial bulk culture, which was used to generate the mutations, was also whole genome sequenced and served as a reference sample to filter germline variants.

Study EGAS00001001969

Genetic sequencing of MODY patients.

Maturity-onset Diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. Using next generation sequencing, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Our findings report that HNF1A and ABCC8 are among the most frequently mutated MODY genes in south India.

Study EGAS00001001699

Genome-wide SNP genotyping and DNA methylation epigenotyping of African rainforest hunter-gatherers and neighbouring agriculturalists

The epigenomic landscape of the human genome, in particular DNA methylation, is increasingly recognised as an important driver of phenotypic diversity in health and disease. However, the impact that genetic variation and changes in lifestyle and ecological habitat have on this epigenetic mark remains unknown. To address this question, we analysed genome-wide SNP and DNA methylation profiles of 362 individuals from African populations of rainforest hunter-gatherers and sedentary farmers with different past and present lifestyles and ecologies.

Study EGAS00001001066

Genome-wide search to find the genetic elements underlying visual contour perception

Contour integration is a key function of the visual system to deal with occlusion and discontinuity in natural scenes. The current study is the first one to investigate the genetic basis of this visual function in humans. A total of 2619 normal participants were tested on their ability to detect continuous contours embedded in a cluttered background with a standard psychophysical protocol. Multi-level genomic analysis was performed, involving heritability estimation based on single nucleotide polymorphism (SNP) and association testing at SNP and gene levels.

Study EGAS00001003639

Genomic Landscape of Pediatric Myelodysplastic Syndromes

Pediatric myelodysplastic syndromes (MDS) are a rare disease and unlike their adult counterpart, very little is known about their genomic landscape. We characterized a cohort of patients from a single institution by whole exome sequencing, as well as a subset of patients by whole genome sequencing, RNA-sequencing and targeted deep sequencing. We found a spectrum of mutations, both somatic and germline, that are distinct from those observed in adult MDS. In turn, we observed mutations commonly observed in other pediatric myeloid tumors.

Study EGAS00001002202

The mutational landscape of primary central nervous system lymphoma (Hipo H050, A050, XD013)

]Primary lymphomas of the central nervous system (PCNSL) are diffuse large B-cell lymphomas (DLBCLs) which are confined to the central nervous system (CNS). Despite extensive research, the molecular alterations leading to PCNSL have not been fully elucidated. In order to provide a comprehensive description of the mutational landscape in PCNSL, we here performed integrative whole genome and transcriptome sequencing analysis of 51 lymphomas presenting in the CNS, including 42 EBV-negative PCNSL, 6 secondary CNS lymphomas (SCNSL) and 3 EBV+ CNSL.

Study EGAS00001005339

ImmunoAgeing_Longitudinal

The objective is to establish whether immunosenescence is associated with the development of clonal haematopoiesis in a healthy ageing population. This will be addressed in collaboration with the European consortium running the ImmunoAgeing project (www.immunoageing.eu). Genomic DNA derived from the peripheral blood of 394 individuals at 3-5 time-points over a 20-year period will be analysed. RNA bait pulldown (Agilent) will be used to perform targeted sequencing of genes known to be recurrently mutated in myeloid malignancies The presence, size and nature of clonal haematopoiesis will be correlated with quantitative measures of immunosenescence.

Study EGAS00001003183

Genomic evolution and natural history of myeloproliferative neoplasms on therapy - triple-negative-ET

Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

Dataset EGAD00001016066

Genomic evolution and natural history of myeloproliferative neoplasms on therapy - SCC_CALRmutated ET

Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.

Dataset EGAD00001016068

A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma

We conducted whole-genome sequencing of probands from several melanoma families, identifying one individual carrying a novel germline variant (c.G1075A, NM_000248.3; p.E318K, NP_000239.1; rs149617956) in the melanoma lineage-specific oncogene MITF. While the variant cosegregated with melanoma in some, but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a LOD score of 2.7 under a dominant model, suggesting E318K as a possible intermediate risk variant. Consistent with this, E318K was significantly associated with melanoma in a large Australian case-control sample, giving an odds ratio (OR) of 2.33, 95% CI 1.21-4.70 (case and control carrier frequency, 0.0165 and 0.0072, respectively; P=0.008). Likewise, it was similarly associated in an independent case-control sample from the United Kingdom (UK P=0.012; combined P=0.0003, OR 2.19, 95% CI 1.41-3.45). In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma (OR 2.95, 95% CI 1.23-6.92), multiple primary melanomas (OR 4.22, 95% CI 1.52-10.91), or both (OR 8.37, 95% CI 2.58-23.80). The variant allele was also associated with increased nevus count (combined P=0.002, OR 2.54, 95% CI 1.42-4.55) and non-blue eye color (combined P=0.008, OR 2.01, 95% CI 1.11-3.81). Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma predisposition gene and highlights the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

Study phs000419

Repeat expansions with small TTTCA insertions in MARCHF6 cause Familial Adult Myoclonus without Epilepsy

Familial Adult Myoclonic Epilepsy (FAME) is a rare autosomal dominant disorder characterized by cortical tremulous myoclonus and generalized tonic clonic (GTCS) or myoclonic seizures. Intrafamilial variability regarding the prevalence of seizure has been reported. Despite apparent genetic heterogeneity, FAME is caused by the same TTTTA/TTTCA pentanucleotide repeat expansion in introns of seven different genes with no common function. Expansions containing only TTTTA repeats are benign, and only expansions including a TTTCA expansion insertion, which can be located 3' to the TTTTA expansion or in the middle of the TTTTA repeats, are pathogenic. We aimed to identify the underlying genetic cause of dominant cortical myoclonus without GTCS in two unrelated families. We used a combination of repeat-primed PCR, long-range PCR and nanopore sequencing to detect and characterize expansions at known FAME loci. We report a novel configuration of the FAME3 repeat expansion in MARCHF6 segregating with cortical myoclonus without epilepsy GTCS in both families. This expansion predominantly comprises elongated TTTTA repeats, ranging from 388 to 454 repeats, with the presence of only 5-11 TTTCA repeats at its 3' terminus (i.e., 5’-(TTTTA)~388-454(TTTCA)5-11-3’). This configuration exhibits greater stability upon meiotic transmission but somatic variability in TTTCA repeat number was detected at low level in blood. We observed an inverse correlation between the number of TTTCA repeats and the age at myoclonus onset. This study shows that as little as five TTTCA juxtaposed with expanded TTTTA expansions is sufficient to cause cortical myoclonus without GTCS. This finding has implications regarding possible pathophysiological mechanisms leading to FAME.

Study EGAS50000000570

Genesis of Two Most Prevalent Variants Causing Combined Pituitary Hormone Deficiency in 21 Populations

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single nucleotide variant markers flanking the 9.6Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations - a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated ancestral origin of both variants: c.[301_302delAG] was carried on 0.2Mb-long haplotype in a majority of European patients arising approximately 101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both haplotypes were transmitted to Latin American patients approximately 13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot-spots as previously assumed, but are founder variants.

Study EGAS00001001165

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