scholarly journals Deep whole genome sequencing of multiple proband tissues and parental blood reveals the complex genetic etiology of congenital diaphragmatic hernias

2020 ◽  
Author(s):  
EL Bogenschutz ◽  
ZD Fox ◽  
A Farrell ◽  
J Wynn ◽  
B Moore ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Copy Number Variants ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Genetic Etiology ◽  
Intergenic Regions ◽  
Thoracic And Abdominal ◽  
Diaphragmatic Hernias

ABSTRACTThe diaphragm is a mammalian muscle critical for respiration and separation of the thoracic and abdominal cavities. Defects in the development of the diaphragm are the cause of congenital diaphragmatic hernia (CDH), a common birth defect. In CDH, weaknesses in the developing diaphragm allow abdominal contents to herniate into the thoracic cavity and impair lung development, leading to a high neonatal mortality. The genetic etiology of CDH is complex. Single nucleotide variants (SNVs), insertion/deletions (indels), and structural/copy number variants in more than 150 genes have been associated with CDH, although few genes are recurrently mutated in multiple patients and recurrently mutated genes can be incompletely penetrant. This suggests that multiple genetic variants in combination, other not yet investigated classes of variants, and/or nongenetic factors contribute to CDH susceptibility. However, to date no studies have comprehensively investigated the contribution of all possible classes of variants throughout the genome to the etiology of CDH. In our study, we used a unique cohort of four patients with isolated CDH with samples from blood, skin, and diaphragm connective tissue and parental blood samples and deep whole genome sequencing to assess germline and somatic de novo and inherited variants of various sizes (SNVs, indels, and structural variants) in exons, introns, UTRs, and intergenic regions. In each patient we found a different mutational landscape that included germline de novo, and inherited SNVs and indels in multiple genes. We also found in two patients an inherited 343 bp deletion interrupting an annotated enhancer of the CDH associated gene, GATA4, and we hypothesize that this common deletion (found in 1-2% of the population) acts as a sensitizing allele for CDH. Overall, our comprehensive reconstruction of the genetic architecture of four CDH individuals demonstrates that the etiology of CDH is heterogeneous and multifactorial.AUTHOR SUMMARYDeep whole genome sequencing of family trios shows that etiology of congenital diaphragmatic hernias is heterogeneous and multifactorial.

scholarly journals Contributions of de novo variants to systemic lupus erythematosus

2020 ◽  
Vol 29 (1) ◽  
pp. 184-193 ◽  
Author(s):  
Jonas Carlsson Almlöf ◽  
Sara Nystedt ◽  
Aikaterini Mechtidou ◽  
Dag Leonard ◽  
Maija-Leena Eloranta ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Lupus Erythematosus ◽  
De Novo ◽  
Whole Genome ◽  
Gene Promoters ◽  
Single Nucleotide Variants ◽  
Systemic Lupus ◽  
Promoter Regions

AbstractBy performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants.

scholarly journals Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox–Gastaut syndrome

2021 ◽  
Vol 3 (3) ◽  
Author(s):  
Farah Qaiser ◽  
Tara Sadoway ◽  
Yue Yin ◽  
Quratulain Zulfiqar Ali ◽  
Charlotte M Nguyen ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Tandem Repeat ◽  
Copy Number ◽  
Copy Number Variants ◽  
Spinocerebellar Ataxia Type ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Repeat Expansions

Abstract Epilepsies are a group of common neurological disorders with a substantial genetic basis. Despite this, the molecular diagnosis of epilepsies remains challenging due to its heterogeneity. Studies utilizing whole-genome sequencing may provide additional insights into genetic causes of epilepsies of unknown aetiology. Whole-genome sequencing was used to evaluate a cohort of adults with unexplained developmental and epileptic encephalopathies (n = 30), for whom prior genetic tests, including whole-exome sequencing in some cases, were negative or inconclusive. Rare single nucleotide variants, insertions/deletions, copy number variants and tandem repeat expansions were analysed. Seven pathogenic or likely pathogenic single nucleotide variants, and two pathogenic deleterious copy number variants were identified in nine patients (32.1% of the cohort). One of the copy number variants, identified in a patient with Lennox–Gastaut syndrome, was too small to be detected by chromosomal microarray techniques. We also identified two tandem repeat expansions with clinical implications in two other patients with Lennox–Gastaut syndrome: a CGG repeat expansion in the 5′untranslated region of DIP2B, and a CTG expansion in ATXN8OS (previously implicated in spinocerebellar ataxia type 8). Three patients had KCNA2 pathogenic variants. One of them died of sudden unexpected death in epilepsy. The other two patients had, in addition to a KCNA2 variant, a second de novo variant impacting potential epilepsy-relevant genes (KCNIP4 and UBR5). Overall, whole-genome sequencing provided a genetic explanation in 32.1% of the total cohort. This is also the first report of coding and non-coding tandem repeat expansions identified in patients with Lennox–Gastaut syndrome. This study demonstrates that using whole-genome sequencing, the examination of multiple types of rare genetic variation, including those found in the non-coding region of the genome, can help resolve unexplained epilepsies.

scholarly journals Performance of copy number variants detection based on whole-genome sequencing by DNBSEQ platforms

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Junhua Rao ◽  
Lihua Peng ◽  
Xinming Liang ◽  
Hui Jiang ◽  
Chunyu Geng ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Technology Use ◽  
Copy Number ◽  
Massively Parallel Sequencing ◽  
Copy Number Variants ◽  
Whole Genome ◽  
Sequencing Data ◽  
Single Nucleotide Variants ◽  
Cnv Detection

Abstract Background DNBSEQ™ platforms are new massively parallel sequencing (MPS) platforms that use DNA nanoball technology. Use of data generated from DNBSEQ™ platforms to detect single nucleotide variants (SNVs) and small insertions and deletions (indels) has proven to be quite effective, while the feasibility of copy number variants (CNVs) detection is unclear. Results Here, we first benchmarked different CNV detection tools based on Illumina whole-genome sequencing (WGS) data of NA12878 and then assessed these tools in CNV detection based on DNBSEQ™ sequencing data from the same sample. When the same tool was used, the CNVs detected based on DNBSEQ™ and Illumina data were similar in quantity, length and distribution, while great differences existed within results from different tools and even based on data from a single platform. We further estimated the CNV detection power based on available CNV benchmarks of NA12878 and found similar precision and sensitivity between the DNBSEQ™ and Illumina platforms. We also found higher precision of CNVs shorter than 1 kbp based on DNBSEQ™ platforms than those based on Illumina platforms by using Pindel, DELLY and LUMPY. We carefully compared these two available benchmarks and found a large proportion of specific CNVs between them. Thus, we constructed a more complete CNV benchmark of NA12878 containing 3512 CNV regions. Conclusions We assessed and benchmarked CNV detections based on WGS with DNBSEQ™ platforms and provide guidelines for future studies.

scholarly journals Whole genome sequencing in multiplex families reveals novel inherited and de novo genetic risk in autism

2018 ◽  
Author(s):  
Elizabeth K. Ruzzo ◽  
Laura Pérez-Cano ◽  
Jae-Yoon Jung ◽  
Lee-kai Wang ◽  
Dorna Kashef-Haghighi ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
De Novo ◽  
Autism Spectrum ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Risk Genes ◽  
Protein Protein Interaction ◽  
Genetics Research ◽  
Multiplex Families

AbstractGenetic studies of autism spectrum disorder (ASD) have revealed a complex, heterogeneous architecture, in which the contribution of rare inherited variation remains relatively un-explored. We performed whole-genome sequencing (WGS) in 2,308 individuals from families containing multiple affected children, including analysis of single nucleotide variants (SNV) and structural variants (SV). We identified 16 new ASD-risk genes, including many supported by inherited variation, and provide statistical support for 69 genes in total, including previously implicated genes. These risk genes are enriched in pathways involving negative regulation of synaptic transmission and organelle organization. We identify a significant protein-protein interaction (PPI) network seeded by inherited, predicted damaging variants disrupting highly constrained genes, including members of the BAF complex and established ASD risk genes. Analysis of WGS also identified SVs effecting non-coding regulatory regions in developing human brain, implicating NR3C2 and a recurrent 2.5Kb deletion within the promoter of DLG2. These data lend support to studying multiplex families for identifying inherited risk for ASD. We provide these data through the Hartwell Autism Research and Technology Initiative (iHART), an open access cloud-computing repository for ASD genetics research.

scholarly journals Detection of de novo single nucleotide variants in offspring of atomic-bomb survivors close to the hypocenter by whole-genome sequencing

2017 ◽  
Vol 63 (3) ◽  
pp. 357-363 ◽  
Author(s):  
Makiko Horai ◽  
Hiroyuki Mishima ◽  
Chisa Hayashida ◽  
Akira Kinoshita ◽  
Yoshibumi Nakane ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Atomic Bomb ◽  
De Novo ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Atomic Bomb Survivors

0306 Exploring the feasibility of using copy number variants as genetic markers through large-scale whole genome sequencing experiments

2016 ◽  
Vol 94 (suppl_5) ◽  
pp. 146-146
Author(s):  
D. M. Bickhart ◽  
L. Xu ◽  
J. L. Hutchison ◽  
J. B. Cole ◽  
D. J. Null ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genetic Markers ◽  
Genome Sequencing ◽  
Copy Number ◽  
Large Scale ◽  
Copy Number Variants ◽  
Whole Genome

scholarly journals Effective variant filtering and expected candidate variant yield in studies of rare human disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Brent S. Pedersen ◽  
Joe M. Brown ◽  
Harriet Dashnow ◽  
Amelia D. Wallace ◽  
Matt Velinder ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Rare Disease ◽  
Genome Sequencing ◽  
Autosomal Dominant ◽  
De Novo ◽  
Autosomal Dominant Inheritance ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Dominant Inheritance ◽  
Family Based

AbstractIn studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

Abstract 343: Bayesian Selection of Modifier Genes in Hypertrophic Cardiomyopathy Through Whole Genome Sequencing

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Matthew Wheeler ◽  
Daryl Waggott ◽  
Megan Grove ◽  
Frederick Dewey ◽  
Cuiping Pan ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
A Priori ◽  
Copy Number Variants ◽  
Whole Genome Sequence ◽  
Monogenic Disease ◽  
Whole Genome ◽  
Genetic Modifiers ◽  
Structural Variants

Background: Technological advances have greatly reduced the cost of whole genome sequencing. For single individuals clinical application is apparent, while exome sequencing in tens of thousands of people has allowed a more global view of genetic variation that can inform interpretation of specific variants in individuals. We hypothesized that genome sequencing of patients with monogenic cardiomyopathy would facilitate discovery of genetic modifiers of phenotype. Methods and Results: We identified 48 individuals diagnosed with cardiomyopathy and with putative mutations in MYH7, the gene encoding beta myosin heavy chain. We carried out whole genome sequencing and applied a newly developed analytical pipeline optimized for discovery of genes modifying severity of clinical presentation and outcomes. Using a combination of external priors and rare variant burden tests we scored genes as potential modifiers. There were 96 genes that reached a modifier score of 6 out of 12 or better (9=2, 8=8, 7=17, 6=69). We identified NCKAP1, a gene that regulates actin filament dynamics, and CAMSAP1, a calmodulin regulate gene that regulates microtubule dynamics, as top scoring modifiers of hypertrophic cardiomyopathy phenotypes (score=9) while LDB2, RYR2, FBN1 and ATP1A2 had modifier scores of 8. Of the top scoring genes, 21 out of 96 were identified as candidates a priori. Our candidate prioritization scheme identified the previously described modifiers of cardiomyopathy phenotype, FHOD3 and MYBPC3, as top scoring genes. We identified structural variants in 21 clinically sequenced cardiomyopathy associated genes, 13 of which were at less than 10% frequency. Copy number variants in ILK and CSRP3 were nominally associated with ejection fraction (p=0.03), while 8 genes showed copy gains (GLA, FKTN, SGCD, TTN, SOS1, ANKRD1, VCL and NEBL). Structural variants were found in CSRP3, MYL3 and TNNC1, all of which have been implicated as causative for HCM. Conclusion: Evaluation of the whole genome sequence, even in the case of putatively monogenic disease, leads to important diagnostic and scientific insights not revealed by panel-based sequencing.

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