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Pedigree based DNA sequencing pipeline for germline genomes of cancer families

Försti, Asta LU ; Kumar, Abhishek; Paramasivam, Nagarajan; Schlesner, Matthias; Catalano, Calogerina; Dymerska, Dagmara; Lubinski, Jan; Eils, Roland and Hemminki, Kari LU (2016) In Hereditary Cancer in Clinical Practice 14(1).
Abstract

Background: In the course of our whole-genome sequencing efforts, we have developed a pipeline for analyzing germline genomes from Mendelian types of cancer pedigrees (familial cancer variant prioritization pipeline, FCVPP). Results: The variant calling step distinguishes two types of genomic variants: single nucleotide variants (SNVs) and indels, which undergo technical quality control. Mendelian types of variants are assumed to be rare and variants with frequencies higher that 0.1 % are screened out using human 1000 Genomes (Phase 3) and non-TCGA ExAC population data. Segregation in the pedigree allows variants to be present in affected family members and not in old, unaffected ones. The effectiveness of variant segregation depends on... (More)

Background: In the course of our whole-genome sequencing efforts, we have developed a pipeline for analyzing germline genomes from Mendelian types of cancer pedigrees (familial cancer variant prioritization pipeline, FCVPP). Results: The variant calling step distinguishes two types of genomic variants: single nucleotide variants (SNVs) and indels, which undergo technical quality control. Mendelian types of variants are assumed to be rare and variants with frequencies higher that 0.1 % are screened out using human 1000 Genomes (Phase 3) and non-TCGA ExAC population data. Segregation in the pedigree allows variants to be present in affected family members and not in old, unaffected ones. The effectiveness of variant segregation depends on the number and relatedness of the family members: if over 5 third-degree (or more distant) relatives are available, the experience has shown that the number of likely variants is reduced from many hundreds to a few tens. These are then subjected to bioinformatics analysis, starting with the combined annotation dependent depletion (CADD) tool, which predicts the likelihood of the variant being deleterious. Different sets of individual tools are used for further evaluation of the deleteriousness of coding variants, 5' and 3' untranslated regions (UTRs), and intergenic variants. Conlusions: The likelihood of success of the present genomic pipeline in finding novel high- or medium-penetrant genes depends on many steps but first and foremost, the pedigree needs to be reasonably large and the assignments and diagnoses among the members need to be correct.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Family-based, Genetic risk factors, Germline genetics, Mutation
in
Hereditary Cancer in Clinical Practice
volume
14
issue
1
publisher
Termedia Publishing House
external identifiers
  • scopus:85007607419
  • wos:000382524200001
ISSN
1731-2302
DOI
10.1186/s13053-016-0058-1
language
English
LU publication?
yes
id
d5d1a49a-dc3c-48c2-afd2-a08559ebcbf6
date added to LUP
2017-01-19 11:59:17
date last changed
2017-09-18 11:32:35
@article{d5d1a49a-dc3c-48c2-afd2-a08559ebcbf6,
  abstract     = {<p>Background: In the course of our whole-genome sequencing efforts, we have developed a pipeline for analyzing germline genomes from Mendelian types of cancer pedigrees (familial cancer variant prioritization pipeline, FCVPP). Results: The variant calling step distinguishes two types of genomic variants: single nucleotide variants (SNVs) and indels, which undergo technical quality control. Mendelian types of variants are assumed to be rare and variants with frequencies higher that 0.1 % are screened out using human 1000 Genomes (Phase 3) and non-TCGA ExAC population data. Segregation in the pedigree allows variants to be present in affected family members and not in old, unaffected ones. The effectiveness of variant segregation depends on the number and relatedness of the family members: if over 5 third-degree (or more distant) relatives are available, the experience has shown that the number of likely variants is reduced from many hundreds to a few tens. These are then subjected to bioinformatics analysis, starting with the combined annotation dependent depletion (CADD) tool, which predicts the likelihood of the variant being deleterious. Different sets of individual tools are used for further evaluation of the deleteriousness of coding variants, 5' and 3' untranslated regions (UTRs), and intergenic variants. Conlusions: The likelihood of success of the present genomic pipeline in finding novel high- or medium-penetrant genes depends on many steps but first and foremost, the pedigree needs to be reasonably large and the assignments and diagnoses among the members need to be correct.</p>},
  articleno    = {16},
  author       = {Försti, Asta and Kumar, Abhishek and Paramasivam, Nagarajan and Schlesner, Matthias and Catalano, Calogerina and Dymerska, Dagmara and Lubinski, Jan and Eils, Roland and Hemminki, Kari},
  issn         = {1731-2302},
  keyword      = {Family-based,Genetic risk factors,Germline genetics,Mutation},
  language     = {eng},
  number       = {1},
  publisher    = {Termedia Publishing House},
  series       = {Hereditary Cancer in Clinical Practice},
  title        = {Pedigree based DNA sequencing pipeline for germline genomes of cancer families},
  url          = {http://dx.doi.org/10.1186/s13053-016-0058-1},
  volume       = {14},
  year         = {2016},
}