Effective variant filtering and expected candidate variant yield in studies of rare human disease.
Effective variant filtering and expected candidate variant yield in studies of rare human disease.
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DOI：
10.1038/s41525-021-00227-3
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发表时间：
2021-07-15
影响因子：
5.3
通讯作者：
Quinlan AR
中科院分区：
文献类型：
--
作者：
Pedersen BS;Brown JM;Dashnow H;Wallace AD;Velinder M;Tristani-Firouzi M;Schiffman JD;Tvrdik T;Mao R;Best DH;Bayrak-Toydemir P;Quinlan AR
在对罕见病家族的研究中，筛查新生突变以及解释表型的隐性或显性变异是很常见的。然而，用于优先考虑高置信度变量的过滤策略和软件因研究而异。为了建立罕见病研究的建议，我们探索了变异（SNP和INDEL）过滤的有效指南，并报告了新生显性、隐性和常染色体显性遗传模式的预期候选数量。我们通过两个以家庭为基础的全基因组测序队列，以及两个全外显子组测序的家庭队列，得出了这些指南。这些过滤器应用于常见的属性，包括基因型质量、测序深度、等位基因平衡和群体等位基因频率。由此产生的指南得出，每个外显子组约有10个候选SNP和INDEL变异，每个基因组18个隐性和新生显性遗传模式，而常染色体显性遗传的候选基因则更多。对于基于家庭的全基因组测序研究，这个数字包括平均3个新生，10个复合杂合，1个常染色体隐性，4个x连锁变异，以及大约100个常染色体显性遗传的候选变异。我们开发的slivar软件用于建立并快速将这些过滤器应用于VCF文件，可在MIT许可下在https://github.com/brentp/slivar获得，其中包括罕见病分析最佳实践的文档和建议。
In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.
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影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
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