Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester M13 9PT, UK.
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.
Genes (Basel). 2020 Feb 9;11(2):179. doi: 10.3390/genes11020179.
Inherited eye disorders (IED) are a heterogeneous group of Mendelian conditions that are associated with visual impairment. Although these disorders often exhibit incomplete penetrance and variable expressivity, the scale and mechanisms of these phenomena remain largely unknown. Here, we utilize publicly-available genomic and transcriptomic datasets to gain insights into variable penetrance in IED. Variants in a curated set of 340 IED-implicated genes were extracted from the Human Gene Mutation Database (HGMD) 2019.1 and cross-checked with the Genome Aggregation Database (gnomAD) 2.1 control-only dataset. Genes for which >1 variants were encountered in both HGMD and gnomAD were considered to be associated with variable penetrance ( = 56). Variability in gene expression levels was then estimated for the subset of these genes that was found to be adequately expressed in two relevant resources: the Genotype-Tissue Expression (GTEx) and Eye Genotype Expression (EyeGEx) datasets. We found that genes suspected to be associated with variable penetrance tended to have significantly more variability in gene expression levels in the general population ( = 0.0000015); this finding was consistent across tissue types. The results of this study point to the possible influence of and/or -acting elements on the expressivity of variants causing Mendelian disorders. They also highlight the potential utility of quantifying gene expression as part of the investigation of families showing evidence of variable penetrance.
遗传性眼病（IED）是一组异质性的孟德尔疾病，与视力损害有关。尽管这些疾病通常表现出不完全外显率和可变表达性，但这些现象的规模和机制在很大程度上仍然未知。在这里，我们利用公开的基因组和转录组数据集来深入了解 IED 中的可变外显率。从人类基因突变数据库（HGMD）2019.1 中提取了一个经过精心整理的 340 个 IED 相关基因的变异集，并与基因组聚集数据库（gnomAD）2.1 仅对照数据集进行了交叉检查。在 HGMD 和 gnomAD 中都遇到 >1 个变异的基因被认为与可变外显率相关（=56）。对于在两个相关资源中发现表达充分的这些基因的子集，然后估计基因表达水平的变异性：基因型组织表达（GTEx）和眼部基因型表达（EyeGEx）数据集。我们发现，疑似与可变外显率相关的基因在一般人群中的基因表达水平变化明显更大（=0.0000015）；这一发现与组织类型一致。这项研究的结果表明， 和/或 作用元件可能对引起孟德尔疾病的变异的表达性有影响。它们还突出了定量基因表达作为调查表现出可变外显率证据的家庭的一部分的潜在效用。
