Exome Sequencing to Identify Causes of Leukaemia Predisposing Congenital Neutropenias
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ABSTRACT:
PROVIDER: EGAS00001000100 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:The objective of this study is to identify the causative genes in two unrelated congenital neutropenia families. We aim to whole exome sequence the affected individuals, unaffected siblings and parents in both cases in an effort to idenitfy the causative genetic mutation. Exome capture will be performed using Agilent SureSelect system. Subsequently, exome libraries will sequenced using the Illumina HiSeq platform. Sequence variant calling will be done in house and common variants excluded using public databases and data from unaffected family members. .
This dataset contains all the data available for this study on 2019-08-19.
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Project description:We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. We performed whole exome sequencing to identify the causative variants.
We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family.
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Project description:Background: Moyamoya is a cerebrovascular condition of unknown mechanism characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICA) and the compensatory development of abnormal “moyamoya” vessels. It leads to ischemic and hemorrhagic stroke. We describe a novel autosomal recessive disease leading to severe moyamoya and early onset achalasia and report its cause in 3 unrelated families. Methods: We used a combination of genetic linkage and exome sequencing in 2 consanguineous to identify rare shared variants. Sanger sequencing of GUCY1A3, the sole gene mutated in both families, was then conducted in the third family. Platelets from one of the patients and controls were used to carry out functional studies. Results: Homozygous mutations of GUCY1A3 gene encoding the alpha1 subunit of soluble guanylate cyclase (sGC), the major receptor for Nitric Oxide (NO), were identified in all 3 families. Platelet analysis showed a complete loss of the mutated protein and showed an unexpected stimulatory role of sGC within platelets. Conclusion: The NO/sGC/cGMP pathway is a major pathway controlling vascular smooth muscle (VSMC) relaxation, vascular tone and vascular remodeling. Our data suggest that alterations of this pathway may lead to an abnormal vascular remodeling process in sensitive vascular areas with low blood A total of 17 samples (8 affected and 9 unaffected) were used for this study. Linkage analysis was performed in a single informative consanguine family composed of 2 unaffected parents, 4 affected siblings and 3 unaffected siblings. Two affected samples in two different families were used for the exome sequencing analysis and results were compared to 20 control exomes (in-house exomes from IntegraGen, Evry, France) and 8 HapMap exomes. All samples were used for Sanger Sequencing confirmation.
2014-06-19 | E-GEOD-48099 | biostudies-arrayexpress
Project description:The application of genome sequencing in patients with intellectual disability and congenital anomalies (ID/CA) typically identifies causative mutations only in a minority of cases. We hypothesized that some cases of ID/CA are caused by epigenetic aberrations that dysregulate normal genome function, and that these would be missed by conventional sequencing approaches. We performed Illumina 450k DNA methylation profiling in ~500 individuals with ID/CA, who were negative for causative mutations by microarray, exome- and/or whole genome sequencing. We screened patient methylation profiles for epimutations absent in ~1,500 controls, and validated these by bisulfite sequencing, revealing that epimutations represent large methylation changes specifically on one allele. Parental studies show that approximately half represent de novo events, a rate significantly higher than that seen in controls. We identified seven recurrent events, two of which (FMR1, MEG3) have known disease associations, validating our method for detecting pathogenic epimutations. From large-scale sequencing, population and expression studies we conclude that epimutations are: (i) Frequently associated with extreme outlier and mono-allelic gene expression, with an impact comparable to loss-of-function mutations; (ii) Generally conserved across multiple tissues within an individual, validating the use of blood DNA to study ID/CA; (iii) Can occur secondary to cis-linked regulatory mutations, providing a rationale for interpreting non-coding genetic variants; (iv) Occur sporadically with a remarkably high de novo rate, and (v) Exhibit non-Mendelian inheritance, likely being reset between generations by epigenetic reprogramming during embryogenesis. We conclude that epimutations underlie 5-10% of patients with ID/CA who are refractory to conventional mutation screening, and propose that epigenome profiling represents a promising method for the study of human disease that complements sequence-based approaches.
2017-05-01 | GSE89353 | GEO
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2020-07-20 | GSE145233 | GEO
Project description:Long non-coding RNAs (lncRNAs) can be important components in gene regulatory networks1, but we are only beginning to understand the nature and extent of their involvement in human Mendelian disease. Here we show that deletions of an unannotated lncRNA locus on human chromosome 2 cause a severe congenital limb malformation. Using exome sequencing and array CGH, we identified homozygous 27-63 kb deletions located 300 kb upstream of the engrailed-1 (EN1) gene in patients with a complex limb malformation, featuring mesomelic shortening, syndactyly, and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of limb-specific En1 expression and a double dorsal limb phenotype, recapitulating the human malformation. Genome-wide analysis in the developing mouse limb revealed the presence of a 4-exon long non-coding transcript within the deleted region, which we named Maenli (for Master activator of En1 in the limb). Functional dissection of the Maenli locus showed that limb-specific En1 expression depends on transcription of Maenli and its loss resulted in the double dorsal limb phenotype. Concomitant monoallelic inactivation of En1 and Maenli in double heterozygous mice did not rescue the limb phenotype, indicating that En1 activation in the limb requires the cis-acting regulatory element Maenli. Moreover, our results strongly suggest that En1 activation is dependent on Maenli transcription, but not on the Maenli RNA itself. Thus, Maenli expression in the limb acts in cis to promote En1 transcriptional activation; its loss results in congenital malformation of the limbs, a subset of the full En1 associated phenotype. Together, our findings provide evidence that mutations involving lncRNAs loci can result in human Mendelian disease.
2020-10-25 | GSE137330 | GEO
Project description:Long non-coding RNAs (lncRNAs) can be important components in gene regulatory networks1, but we are only beginning to understand the nature and extent of their involvement in human Mendelian disease. Here we show that deletions of an unannotated lncRNA locus on human chromosome 2 cause a severe congenital limb malformation. Using exome sequencing and array CGH, we identified homozygous 27-63 kb deletions located 300 kb upstream of the engrailed-1 (EN1) gene in patients with a complex limb malformation, featuring mesomelic shortening, syndactyly, and ventral nails (dorsal dimelia). Re-engineering of the human deletions in mice resulted in a complete loss of limb-specific En1 expression and a double dorsal limb phenotype, recapitulating the human malformation. Genome-wide analysis in the developing mouse limb revealed the presence of a 4-exon long non-coding transcript within the deleted region, which we named Maenli (for Master activator of En1 in the limb). Functional dissection of the Maenli locus showed that limb-specific En1 expression depends on transcription of Maenli and its loss resulted in the double dorsal limb phenotype. Concomitant monoallelic inactivation of En1 and Maenli in double heterozygous mice did not rescue the limb phenotype, indicating that En1 activation in the limb requires the cis-acting regulatory element Maenli. Moreover, our results strongly suggest that En1 activation is dependent on Maenli transcription, but not on the Maenli RNA itself. Thus, Maenli expression in the limb acts in cis to promote En1 transcriptional activation; its loss results in congenital malformation of the limbs, a subset of the full En1 associated phenotype. Together, our findings provide evidence that mutations involving lncRNAs loci can result in human Mendelian disease.
2020-10-25 | GSE137332 | GEO