Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data.
BMC Genomics
; 19(1): 46, 2018 01 15.
Article
em En
| MEDLINE
| ID: mdl-29334895
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Variação Genética
/
Alelos
/
Sequenciamento do Exoma
Tipo de estudo:
Diagnostic_studies
/
Guideline
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article