Pedigree based DNA sequencing pipeline for germline genomes of cancer families
(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
- Försti, Asta LU ; Kumar, Abhishek ; Paramasivam, Nagarajan ; Schlesner, Matthias ; Catalano, Calogerina ; Dymerska, Dagmara ; Lubinski, Jan ; Eils, Roland and Hemminki, Kari LU
- organization
- publishing date
- 2016
- 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
- article number
- 16
- publisher
- Termedia Publishing House Ltd.
- external identifiers
-
- scopus:85007607419
- pmid:27508007
- 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
- 2024-06-14 22:29:13
@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>}},
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}},
keywords = {{Family-based; Genetic risk factors; Germline genetics; Mutation}},
language = {{eng}},
number = {{1}},
publisher = {{Termedia Publishing House Ltd.}},
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}},
doi = {{10.1186/s13053-016-0058-1}},
volume = {{14}},
year = {{2016}},
}