Abouelhoda Mohamed, Faquih Tariq, El-Kalioby Mohamed, Alkuraya Fowzan S
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Saudi Human Genome Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia.
Genome Biol. 2016 Nov 24;17(1):235. doi: 10.1186/s13059-016-1102-1.
The pathogenicity of many Mendelian variants has been challenged by large-scale sequencing efforts. However, many rare and benign "disease mutations" are difficult to analyze due to their rarity. The Saudi Arabian variome is enriched for homozygosity due to inbreeding, a key advantage that can be exploited for the critical examination of previously published variants.
We collated all "disease-related mutations" listed in the Human Gene Mutation Database (HGMD) and ClinVar, including "variants of uncertain significance" (VOUS). We find that the use of public databases including 1000 Genomes, ExAC, and Kaviar can reclassify many of these variants as likely benign. Our Saudi Human Genome Program (SHGP) can reclassify many variants that are rare in public databases. Furthermore, SGPD allows us to observe many previously reported variants in the homozygous state and our extensive phenotyping of participants makes it possible to demonstrate the lack of phenotype for these variants, thus challenging their pathogenicity despite their rarity. We also find that 18 VOUS BRCA1 and BRCA2 variants that are listed in BRCA Exchange are present at least once in the homozygous state in patients who lack features of Fanconi anemia. Reassuringly, we could reciprocally demonstrate that none of those labeled as "pathogenic" were observed in the homozygous statue in individuals who lack Fanconi phenotype in our database.
Our study shows the importance of revisiting disease-related databases using public resources as well as of population-specific resources to improve the specificity of the morbid genome of Mendelian diseases in humans.
大规模测序工作对许多孟德尔变异的致病性提出了挑战。然而，许多罕见且良性的“疾病突变”因其稀有性而难以分析。由于近亲繁殖，沙特阿拉伯变异组中纯合性富集，这是一个关键优势，可用于对先前发表的变异进行批判性研究。
我们整理了人类基因突变数据库（HGMD）和ClinVar中列出的所有“疾病相关突变”，包括“意义未明的变异”（VOUS）。我们发现，使用包括千人基因组计划、外显子组聚集数据库（ExAC）和Kaviar在内的公共数据库，可以将其中许多变异重新分类为可能良性。我们的沙特人类基因组计划（SHGP）可以重新分类许多在公共数据库中罕见的变异。此外，沙特人类基因组计划使我们能够观察到许多先前报道的处于纯合状态的变异，并且我们对参与者进行的广泛表型分析使得有可能证明这些变异缺乏表型，因此尽管它们罕见，但仍对其致病性提出了挑战。我们还发现，BRCA交换数据库中列出的18个意义未明的BRCA1和BRCA2变异在缺乏范可尼贫血特征的患者中至少有一次以纯合状态出现。令人放心的是，我们可以相互证明，在我们数据库中缺乏范可尼表型的个体的纯合状态中未观察到任何标记为“致病性”的变异。
我们的研究表明，利用公共资源以及特定人群资源重新审视疾病相关数据库对于提高人类孟德尔疾病病态基因组的特异性非常重要。
