Dataset Information

Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders.

ABSTRACT: Spontaneously arising mouse mutations have served as the foundation for understanding gene function for more than 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, user-defined data mining as well as nomination of mutation candidates through knowledge-based integration of sample and variant data. Using these new tools, putative pathogenic mutations were identified for 91 (53%) of the strains in our study. Despite the increased power offered by potentially unlimited pedigrees and controlled breeding, about half of our exome cases remained unsolved. Using a combination of manual analyses of exome alignments and whole-genome sequencing, we provide evidence that a large fraction of unsolved exome cases have underlying structural mutations. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing.

SUBMITTER: Fairfield H

PROVIDER: S-EPMC4484392 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders.

Fairfield Heather H Srivastava Anuj A Ananda Guruprasad G Liu Rangjiao R Kircher Martin M Lakshminarayana Anuradha A Harris Belinda S BS Karst Son Yong SY Dionne Louise A LA Kane Coleen C CC Curtain Michelle M Berry Melissa L ML Ward-Bailey Patricia F PF Greenstein Ian I Byers Candice C Czechanski Anne A Sharp Jocelyn J Palmer Kristina K Gudis Polyxeni P Martin Whitney W Tadenev Abby A Bogdanik Laurent L Pratt C Herbert CH Chang Bo B Schroeder David G DG Cox Gregory A GA Cliften Paul P Milbrandt Jeffrey J Murray Stephen S Burgess Robert R Bergstrom David E DE Donahue Leah Rae LR Hamamy Hanan H Masri Amira A Santoni Federico A FA Makrythanasis Periklis P Antonarakis Stylianos E SE Shendure Jay J Reinholdt Laura G LG

Genome research 20150427 7

Spontaneously arising mouse mutations have served as the foundation for understanding gene function for more than 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, ...[more]

PMID: 25917818

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Project description:ImportanceClinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.ObjectiveTo report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.Design, setting, and participantsClinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.Main outcomes and measuresClinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.ResultsOf the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.Conclusions and relevanceIn this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.

Project description:Lung cancer remains a substantial health challenge, with distinct genetic factors influencing disease susceptibility and progression. This study aimed to decipher the landscape of DNA repair gene mutations in Pakistani lung cancer patients using Whole Exome Sequencing (WES) and to investigate their potential functional implications through downstream analyses. WES analysis of genomic DNA from 15 lung cancer patients identified clinically important pathogenic mutations in 6 DNA repair genes, including, BReast CAncer gene 1 (BRCA1), BReast CAncer gene 2 (BRCA2), Excision Repair Cross Complementing rodent repair deficiency, complementation group 6 (ERCC6), Checkpoint Kinase 1 (CHEK1), mutY DNA glycosylase (MUTYH), and RAD51D (RAD51 Paralog D). Kaplan-Meier (KM) analysis showed that pathogenic mutations in BRCA1, BRCA2, ERCC6, CHEK1, MUTYH, and RAD51D genes were the prognostic biomarkers of worse OS in lung cancer patients. To explore the functional impact of these mutations, we performed Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Immunohistochemistry (IHC) analyses. Our results revealed a down-regulation in the expression of the mutated genes, indicating a potential link between the identified mutations and reduced gene activity. This down-regulation could contribute to compromised DNA repair efficiency, thereby fostering genomic instability in lung cancer cells. Furthermore, targeted bisulfite sequencing analysis was employed to assess the DNA methylation status of the mutated genes. Strikingly, hypermethylation in the promoters of BRCA1, BRCA2, ERCC6, CHEK1, MUTYH, and RAD51D was observed across lung cancer samples harboring pathogenic mutations, suggesting the involvement of epigenetic mechanism underlying the altered gene expression. In conclusion, this study provides insights into the genetic landscape of DNA repair gene mutations in Pakistani lung cancer patients. The observed pathogenic mutations in BRCA1, BRCA2, ERCC6, CHEK1, MUTYH, and RAD51D, coupled with their down-regulation and hypermethylation, suggest a potential convergence of genetic and epigenetic factors driving genomic instability in lung cancer cells. These findings contribute to our understanding of lung cancer susceptibility and highlight potential avenues for targeted therapeutic interventions in Pakistani lung cancer patients.

Dataset Information

Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders.

Publications

Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders.

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