利用大型基因组数据集探索与遗传性视网膜疾病相关基因的突变景观：鉴定功能丧失不耐受和错义突变的突出倾向。
Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes.
机构信息
Ophthalmology, University College London Institute of Ophthalmology, London, UK.
Ophthalmology, Moorfields Eye Hospital City Road Campus, London, UK.
出版信息
BMJ Open Ophthalmol. 2022 Aug;7(1). doi: 10.1136/bmjophth-2022-001079. Epub 2022 Aug 25.
BACKGROUND
Large databases permit quantitative description of genes in terms of intolerance to loss of function ('haploinsufficiency') and prevalence of missense variants. We explored these parameters in inherited retinal disease (IRD) genes.
METHODS
IRD genes (from the 'RetNet' resource) were classified by probability of loss of function intolerance (pLI) using online Genome Aggregation Database (gnomAD) and DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) databases. Genes were identified having pLI ≥0.9 together with one or both of the following: upper bound of CI <0.35 for observed to expected (o/e) ratio of loss of function variants in the gnomAD resource; haploinsufficiency score <10 in the DECIPHER resource. IRD genes in which missense variants appeared under-represented or over-represented (Z score for o/e ratio of <-2.99 or >2.99, respectively) were also identified. The genes were evaluated in the gene ontology Protein Analysis THrough Evolutionary Relationships (PANTHER) resource.
RESULTS
Of 280 analysed genes, 39 (13.9%) were predicted loss of function intolerant. A greater proportion of X-linked than autosomal IRD genes fulfilled these criteria, as expected. Most autosomal genes were associated with dominant disease. PANTHER analysis showed >100 fold enrichment of spliceosome tri-snRNP complex assembly. Most encoded proteins were longer than the median length in the UniProt database. Fourteen genes (11 of which were in the 'haploinsufficient' group) showed under-representation of missense variants. Six genes (, , , , , ) showed over-representation of missense variants.
CONCLUSION
A minority of IRD-associated genes appear to be 'haploinsufficient'. Over-representation of spliceosome pathways was observed. When interpreting genetic tests, variants found in genes with over-representation of missense variants should be interpreted with caution.
背景
大型数据库允许根据基因对功能丧失的耐受程度（“杂合功能不全”）和错义变异的流行率来对基因进行定量描述。我们在遗传性视网膜疾病（IRD）基因中探索了这些参数。
方法
IRD 基因（来自“RetNet”资源）根据在线基因组聚集数据库（gnomAD）和使用 Ensembl 资源的基因组变异和表型数据库（DECIPHER）中的可能性丧失功能不耐受性（pLI）进行分类。具有 pLI≥0.9 且符合以下两种情况之一的基因被鉴定出来：在 gnomAD 资源中观察到的功能丧失变体的观察到的与预期的（o/e）比值的置信区间上限<0.35；在 DECIPHER 资源中杂合功能不全评分<10。还确定了错义变体出现代表性不足或过代表的 IRD 基因（o/e 比值的 Z 分数分别为<-2.99 或>2.99）。这些基因在基因本体论蛋白质通过进化关系分析（PANTHER）资源中进行了评估。
结果
在分析的 280 个基因中，有 39 个（13.9%）被预测为丧失功能不耐受。正如预期的那样，与常染色体遗传的 IRD 基因相比，X 连锁基因的比例更高。大多数常染色体基因与显性疾病有关。PANTHER 分析显示剪接体三 snRNP 复合物组装的富集倍数超过 100 倍。大多数编码的蛋白质比 UniProt 数据库中的中位数长度长。14 个基因（其中 11 个在“杂合功能不全”组中）显示错义变体代表性不足。6 个基因（、、、、、）显示错义变体代表性过多。
结论
少数与 IRD 相关的基因似乎是“杂合功能不全”。观察到剪接体途径的过表达。在解释遗传测试时，应谨慎解释错义变体代表性过多的基因中的变体。
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