Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data
Abstract Background The conventional variant calling of pathogenic alleles in exome and genome sequencing requires the presence of the non-pathogenic alleles as genome references. This hinders the correct identification of variants with minor and/or pathogenic reference alleles warranting additional...
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| Format: | Article |
| Language: | English |
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BMC
2018-01-01
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| Series: | BMC Genomics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12864-018-4433-3 |
| _version_ | 1819206560914604032 |
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| author | Mahmoud Koko Mohammed O. E. Abdallah Mutaz Amin Muntaser Ibrahim |
| author_facet | Mahmoud Koko Mohammed O. E. Abdallah Mutaz Amin Muntaser Ibrahim |
| author_sort | Mahmoud Koko |
| collection | DOAJ |
| description | Abstract Background The conventional variant calling of pathogenic alleles in exome and genome sequencing requires the presence of the non-pathogenic alleles as genome references. This hinders the correct identification of variants with minor and/or pathogenic reference alleles warranting additional approaches for variant calling. Results More than 26,000 Exome Aggregation Consortium (ExAC) variants have a minor reference allele including variants with known ClinVar disease alleles. For instance, in a number of variants related to clotting disorders, the phenotype-associated allele is a human genome reference allele (rs6025, rs6003, rs1799983, and rs2227564 using the assembly hg19). We highlighted how the current variant calling standards miss homozygous reference disease variants in these sites and provided a bioinformatic panel that can be used to screen these variants using commonly available variant callers. We present exome sequencing results from an individual with venous thrombosis to emphasize how pathogenic alleles in clinically relevant variants escape variant calling while non-pathogenic alleles are detected. Conclusions This article highlights the importance of specialized variant calling strategies in clinical variants with minor reference alleles especially in the context of personal genomes and exomes. We provide here a simple strategy to screen potential disease-causing variants when present in homozygous reference state. |
| first_indexed | 2024-12-23T05:09:33Z |
| format | Article |
| id | doaj.art-8a77779fd7f94aaf9c419c7a9ec53cf7 |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-12-23T05:09:33Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-8a77779fd7f94aaf9c419c7a9ec53cf72022-12-21T17:59:00ZengBMCBMC Genomics1471-21642018-01-011911810.1186/s12864-018-4433-3Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome dataMahmoud Koko0Mohammed O. E. Abdallah1Mutaz Amin2Muntaser Ibrahim3Department of Molecular Biology, Institute of Endemic Diseases, University of KhartoumDepartment of Molecular Biology, Institute of Endemic Diseases, University of KhartoumDepartment of Molecular Biology, Institute of Endemic Diseases, University of KhartoumDepartment of Molecular Biology, Institute of Endemic Diseases, University of KhartoumAbstract Background The conventional variant calling of pathogenic alleles in exome and genome sequencing requires the presence of the non-pathogenic alleles as genome references. This hinders the correct identification of variants with minor and/or pathogenic reference alleles warranting additional approaches for variant calling. Results More than 26,000 Exome Aggregation Consortium (ExAC) variants have a minor reference allele including variants with known ClinVar disease alleles. For instance, in a number of variants related to clotting disorders, the phenotype-associated allele is a human genome reference allele (rs6025, rs6003, rs1799983, and rs2227564 using the assembly hg19). We highlighted how the current variant calling standards miss homozygous reference disease variants in these sites and provided a bioinformatic panel that can be used to screen these variants using commonly available variant callers. We present exome sequencing results from an individual with venous thrombosis to emphasize how pathogenic alleles in clinically relevant variants escape variant calling while non-pathogenic alleles are detected. Conclusions This article highlights the importance of specialized variant calling strategies in clinical variants with minor reference alleles especially in the context of personal genomes and exomes. We provide here a simple strategy to screen potential disease-causing variants when present in homozygous reference state.http://link.springer.com/article/10.1186/s12864-018-4433-3Minor reference allelesVariant callingHuman exomeNext generation sequencing |
| spellingShingle | Mahmoud Koko Mohammed O. E. Abdallah Mutaz Amin Muntaser Ibrahim Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data BMC Genomics Minor reference alleles Variant calling Human exome Next generation sequencing |
| title | Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data |
| title_full | Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data |
| title_fullStr | Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data |
| title_full_unstemmed | Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data |
| title_short | Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data |
| title_sort | challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data |
| topic | Minor reference alleles Variant calling Human exome Next generation sequencing |
| url | http://link.springer.com/article/10.1186/s12864-018-4433-3 |
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