Dataset Information

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders.

ABSTRACT: 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 (n = 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 (p = 0.0000015); this finding was consistent across tissue types. The results of this study point to the possible influence of cis and/or trans-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.

SUBMITTER: Green DJ

PROVIDER: S-EPMC7074066 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders.

Green David J DJ Sallah Shalaw R SR Ellingford Jamie M JM Lovell Simon C SC Sergouniotis Panagiotis I PI

Genes 20200209 2

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 ...[more]

PMID: 32050448

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Project description:Introduction:Idiopathic focal epilepsy (IFE) is a group of self-limited epilepsies. The etiology for the majority of the patients with IFE remains elusive. We thus screened disease-causing variants in the patients with IFE. Methods:Whole-exome sequencing was performed in a cohort of 323 patients with IFE. Protein modeling was performed to predict the effects of missense variants. The genotype-phenotype correlation of the newly defined causative gene was analyzed. Results:Four novel heterozygous variants in PGM3, including two de novo variants, were identified in four unrelated individuals with IFE. The variants included one truncating variant (c.1432C > T/p.Q478X) and three missense variants (c.478C > T/p.P160S, c.1239C > G/p.N413K, and c.1659T > A/p.N553K), which had no allele frequency in the gnomAD database. The missense variants were predicted to be damaging and affect hydrogen bonds with surrounding amino acids. Mutations Q478X, P160S, and N413K were associated with benign childhood epilepsy with centrotemporal electroencephalograph (EEG) spikes. P160S and N413K were located in the inner side of the enzyme active center. Mutation N553K was associated with benign occipital epilepsy with incomplete penetrance, located in the C-terminal of Domain 4. Further analysis demonstrated that previously reported biallelic PGM3 mutations were associated with severe immunodeficiency and/or congenital disorder of glycosylation, commonly accompanied by neurodevelopmental abnormalities, while monoallelic mutations were associated with milder symptoms like IFE. Conclusion:The genetic and molecular evidence from the present study implies that the PGM3 variants identified in IFE patients lead to defects of the PGM3 gene, suggesting that the PGM3 gene is potentially associated with epilepsy. The genotype-phenotype relationship of PGM3 mutations suggested a quantitative correlation between genetic impairment and phenotypic severity, which helps explain the mild symptoms and incomplete penetrance in individuals with IFE.

Dataset Information

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders.

Publications

Variability in Gene Expression is Associated with Incomplete Penetrance in Inherited Eye Disorders.

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