Mendelian gene identification through mouse embryo viability screening.
Mendelian gene identification through mouse embryo viability screening.
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DOI：
10.1186/s13073-022-01118-7
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发表时间：
2022-10-13
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
随着新的疾病基因发现的步伐，测序研究中孟德尔疾病的诊断率继续增加，沿着。然而，目前与疾病无关的新基因的变异解释特别具有挑战性，并且将基因功能证据与评估患者和模式生物之间表型相似性的方法相结合的策略已被证明是成功的。以前已经描述了对功能丧失变异的全谱不耐受性，提供了基因必要性不应被视为简单和固定的二元属性的证据。在这里，我们通过评估来自国际小鼠表型协会的小鼠中纯合子功能丧失导致致死的胚胎阶段，将致死基因集分类为三个致死窗口之一：早期，中期或晚期妊娠致死。我们研究了这些致死性窗口与各种基因特征之间的相关性，这些基因特征包括跨发育的表达、旁系和约束指标以及人类疾病表型。我们探索了一种用于发现新基因的基因相似性方法，并调查了100，000个基因组计划中未解决的案例。我们发现，在妊娠早期致死类别的基因具有独特的特点，并丰富的隐性遗传代谢疾病的基因。我们确定了几个基因共享多种功能与已知的双等位基因形式的先天性代谢缺陷，并发现富集的迹象，双等位基因预测的致病性变异在妊娠早期致命基因在这种疾病类别下招募的患者。我们强调两个新的候选基因与患者和小鼠敲除之间的表型重叠。关于基因敲除小鼠胚胎致死性发生的发育期的信息可用于发现新的疾病基因，这有助于在未解决的罕见疾病病例中优先考虑变异。在线版本包含补充材料，可通过10.1186/s13073-022-01118-7获得。
The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project. We found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts. Information on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases. The online version contains supplementary material available at 10.1186/s13073-022-01118-7.
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作者：
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Bult CJ;Blake JA;Smith CL;Kadin JA;Richardson JE;Mouse Genome Database Group
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Mouse Genome Database Group
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Westerfield M