Whole exome sequencing study of cholesteatoma patients from affected families
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PROVIDER: EGAS00001006147 | EGA |
REPOSITORIES: EGA
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Project description:Whole Exome Sequencing of Multiplex Cleft Families: CIDR
| PRJNA85093 | ENA
Project description:Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25-38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. WES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (padj < 0.006) and schizophrenia (padj = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.
| S-EPMC7026119 | biostudies-literature
Project description:Epi4K: Whole Exome Sequencing in Multiplex Families and Pairs
| PRJNA437686 | ENA
Project description:Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.
| S-EPMC4372548 | biostudies-literature
Project description:Exome sequencing of chordoma families and sporadic cases
| PRJNA369586 | ENA
Project description:PurposeThis study was conducted to investigate potential candidate pathogenic genes in early-onset high myopia (eoHM) in families with eoHM.MethodsWhole-exome sequencing was performed on probands with eoHM to identify potential pathogenic genes. Sanger sequencing was used to verify the identified gene mutations causing eoHM in first-degree relatives of the proband. The identified mutations were screened out by bioinformatics analysis combined with segregation analysis.ResultsA total of 131 variant loci, involving 97 genes, were detected in the 30 families. A total of 28 genes (37 variants), which were carried by 24 families, were verified and analyzed by Sanger sequencing. We identified five genes and 10 loci associated with eoHM, which have not been reported in previous research. Hemizygous mutations in COL4A5, NYX, and CACNA1F were detected in this study. Inherited retinal disease-associated genes were found in 76.67% (23/30) of families. Genes that can be expressed in the retina in the Online Mendelian Inheritance in Man database were found in 33.33% (10/30) of families. Mutations in the genes associated with eoHM, including CCDC111, SLC39A5, P4HA2, CPSF1, P4HA2, and GRM6, were detected. The mutual correlation between candidate genes and phenotype of fundus photography was revealed in our study. The eoHM candidate gene mutation types contain five categories: missense mutations (78.38%), nonsense (8.11%), frameshift mutation (5.41%), classical splice site mutation (5.41%), and initiation codon mutation (2.70%).ConclusionsCandidate genes carried by patients with eoHM are closely related to inherited retinal diseases. Genetic screening in children with eoHM facilitates the early identification and intervention of syndromic hereditary ocular disorders and certain hereditary ophthalmopathies.
| S-EPMC10198284 | biostudies-literature
Project description:A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility. After filtering, 18 candidate variants in DNA damage response (DDR) pathway genes were screened in 129 female HBOC patients, up to 989 female controls, and 31 breast tumours by Sanger sequencing/TaqMan assays. In addition, two variants were further studied in 49 male BC patients and 909 male controls. Second, all variants predicted to affect function in six early-onset BC patients were analysed in detail. Variants in ATM, MYC, PLAU, RAD1, and RRM2B were enriched in female HBOC patients compared with controls (odds ratio 1.16-2.16). A rare nonsynonymous variant in RAD50 was detected in a male BC patient. In addition, a very rare BRCA1 variant was identified in a single high-risk family. None of the variants showed wild-type allele loss in breast tumours. Furthermore, novel variants predicted to affect function were detected in early-onset patients in genes, which target DNA repair and replication, signalling, apoptosis, and cell cycle pathways. Family-specific enrichment of multiple DDR pathway gene defects likely explains BC predisposition in the studied families. These findings provide new information on potential BC-related pathways and an excellent premise for future studies.
| S-EPMC5159774 | biostudies-literature
Project description:The posterior fossa of the cranium contains the cerebellum and brainstem. Processes that reduce the volume of the posterior fossa squeeze the cerebellum and brainstem caudally, resulting in Chiari I malformation (CM1). CM1 causes neck pain, balance issues, decreased motor skills and headaches in those affected. We have posterior fossa measurements and whole exome sequence data on individuals from 7 extended families from Russia that have a family history of CM1. We performed parametric linkage analyses using an autosomal dominant inheritance model with a disease allele frequency of 0.01 and a penetrance of 0.8 for carriers and 0.0 for non-carriers. Variant-based two-point linkage analysis and gene-based linkage analysis was performed. Our results found a genome-wide significant signal on chromosome 1q43-44 (max HLOD?=?3.3) in the variant-based analysis and 12q23 (max HLOD?=?4.2) in the gene-based analysis. In both cases, the signal was driven by a single (different) family that contained a long, linked haplotype across the region in question. Using functional annotation, we were able to identify several rare nonsynonymous variants that were enriched in each family. The best candidate genes were rs765865412:G>A in MYBPC1 for the 12q haplotype and rs61749963:A>G in COX20 for the 1q haplotype. Good candidate variants in the 1q haplotype were also identified in CEP170 and AKT. Further laboratory work is planned to verify the causality of these genes.
| S-EPMC6777520 | biostudies-literature
Project description:CIDR_NINDS_Whole Exome and Targeted Sequencing in Tourette Syndrome Multiplex Families
| PRJNA75925 | ENA
Project description:In an effort to identify rare alleles associated with SLE, we have performed whole exome sequencing of the most distantly related affected individuals from two large Icelandic multicase SLE families followed by Ta targeted genotyping of additional relatives. We identified multiple rare likely pathogenic variants in nineteen genes co-segregating with the disease through multiple generations. Gene co-expression and protein-protein interaction analysis identified a network of highly connected genes comprising several loci previously implicated in autoimmune diseases. These genes were significantly enriched for immune system development, lymphocyte activation, DNA repair, and V(D)J gene recombination GO-categories. Furthermore, we found evidence of aggregate association and enrichment of rare variants at the FAM71E1/EMC10 locus in an independent set of 4,254 European SLE-cases and 4,349 controls. Our study presents evidence supporting that multiple rare likely pathogenic variants, in newly identified genes involved in known disease pathogenic pathways, segregate with SLE at the familial and population level.
| S-EPMC5993790 | biostudies-literature