Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation
Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation
复制标题
DOI：
10.1038/gim.2017.22
复制
发表时间：
2017-10-01
影响因子：
8.8
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
--
作者：
Monies, Dorota;Maddirevula, Sateesh;Alkuraya, Fowzan S.
目的：本研究的目的是描述严格显性基因中的隐性等位基因。识别隐性突变的基因，只有显性疾病或风险等位基因已被报道，可以扩大我们的理解，这些基因的医学相关性的表型和机制。沙特人口是丰富的纯合性，这增强了等位基因的纯合发生，包括致病等位基因的基因，已与显性遗传pattern.Methods：外显子组测序的患者可能隐性表型的近亲家庭进行。在一个家庭中，死亡的孩子的基因型推断从他们的父母由于缺乏可用的samples.Results：我们描述了11个隐性变异（其中5个是第一次在这里报告）在11个基因，只有显性疾病或风险等位基因已被报道。观察到的这些隐性变体的表型是新的（例如，FBN2相关肌病和CSF1R相关脑畸形和骨硬化症），典型（例如，ACTG 2相关内脏肌病）或明显健康状态（例如，结论：我们的研究结果表明，在基因组测序和“反向表型分析”的时代，显性基因中的隐性变异不应该被解雇的基础上感知的“不相容性”与患者的表型之前仔细考虑。
Purpose: The purpose of this study is to describe recessive alleles in strictly dominant genes. Identifying recessive mutations in genes for which only dominant disease or risk alleles have been reported can expand our understanding of the medical relevance of these genes both phenotypically and mechanistically. The Saudi population is enriched for autozygosity, which enhances the homozygous occurrence of alleles, including pathogenic alleles in genes that have been associated only with a dominant inheritance pattern.Methods: Exome sequencing of patients from consanguineous families with likely recessive phenotypes was performed. In one family, the genotype of the deceased children was inferred from their parents due to lack of available samples.Results: We describe the identification of 11 recessive variants (5 of which are reported here for the first time) in 11 genes for which only dominant disease or risk alleles have been reported. The observed phenotypes for these recessive variants were novel (e.g., FBN2-related myopathy and CSF1R-related brain malformation and osteopetrosis), typical (e.g., ACTG2-related visceral myopathy), or an apparently healthy state (e.g., PDE11A), consistent with the corresponding mouse knockout phenotypes.Conclusion: Our results show that, in the era of genomic sequencing and "reverse phenotyping," recessive variants in dominant genes should not be dismissed based on perceived "incompatibility" with the patient's phenotype before careful consideration.