A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders.
A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders.
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DOI：
10.1101/gr.160465.113
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发表时间：
2014-04
期刊：
影响因子：
7
通讯作者：
DDD Study
中科院分区：
文献类型：
--
作者：
King DA;Fitzgerald TW;Miller R;Canham N;Clayton-Smith J;Johnson D;Mansour S;Stewart F;Vasudevan P;Hurles ME;DDD Study
父母-子女三人组的外显子组测序是一种流行的策略，用于识别患有罕见疾病的儿童的致病遗传变异。这种方法的优势在于利用了遗传信息，这有助于从头变异识别、复合杂合性的推断和遗传异常的鉴定。单亲二体性描述了一对同源染色体仅从一个亲本遗传。这种畸变在遗传病研究中很重要，因为它会导致印记疾病和隐性疾病。我们已经开发了一种软件工具来检测单亲二体性从孩子-母亲-父亲基因型数据，使用二项式测试，以确定染色体的显着负担的单亲遗传基因型。该工具是第一个读取VCF格式的基因型，进行整合的拷贝数过滤，并使用固有的统计测试，用于不同的基因分型密度和噪声特性的平台。仿真结果表明，与以前开发的方法相比，具有上级的准确性。我们对来自解密发育障碍项目的1057个三人组实施了该方法，该项目是一项基于三人组的罕见疾病研究，并检测到6个经验证的事件，与UPD的人群患病率（1/3500）相比，这是一个显著的富集，表明这些事件中的大多数是致病性的。这些事件之一代表了一个已知的印记疾病，外显子组分析已经确定了罕见的纯合候选变体，主要是在UPD染色体的等二体区域，其中，除其他变体外，提供了进一步的遗传和功能评估的目标。
Exome sequencing of parent-offspring trios is a popular strategy for identifying causative genetic variants in children with rare diseases. This method owes its strength to the leveraging of inheritance information, which facilitates de novo variant calling, inference of compound heterozygosity, and the identification of inheritance anomalies. Uniparental disomy describes the inheritance of a homologous chromosome pair from only one parent. This aberration is important to detect in genetic disease studies because it can result in imprinting disorders and recessive diseases. We have developed a software tool to detect uniparental disomy from child–mother–father genotype data that uses a binomial test to identify chromosomes with a significant burden of uniparentally inherited genotypes. This tool is the first to read VCF-formatted genotypes, to perform integrated copy number filtering, and to use a statistical test inherently robust for use in platforms of varying genotyping density and noise characteristics. Simulations demonstrated superior accuracy compared with previously developed approaches. We implemented the method on 1057 trios from the Deciphering Developmental Disorders project, a trio-based rare disease study, and detected six validated events, a significant enrichment compared with the population prevalence of UPD (1 in 3500), suggesting that most of these events are pathogenic. One of these events represents a known imprinting disorder, and exome analyses have identified rare homozygous candidate variants, mainly in the isodisomic regions of UPD chromosomes, which, among other variants, provide targets for further genetic and functional evaluation.
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影响因子：
3.7
作者：
Lenders M;Duning T;Schelleckes M;Schmitz B;Stander S;Rolfs A;Brand SM;Brand E
通讯作者：
Brand E
影响因子：
4
作者：
Bruno, D. L.;White, S. M.;Slater, H. R.
通讯作者：
Slater, H. R.
DOI：
10.1002/ajmg.1320060207
发表时间：
1980-01-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
ENGEL, E
通讯作者：
ENGEL, E
影响因子：
5.3
作者：
Augustin, I;Korte, S;Brose, N
通讯作者：
Brose, N
影响因子：
4
作者：
KOCH, MC;RICKER, K;JENTSCH, TJ
通讯作者：
JENTSCH, TJ