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Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

Gene co-expression networks (GCNs) can be prepared using a variety of mathematical approaches based on data sampled across diverse developmental processes, tissue types, pathologies, mutant backgrounds, and stress conditions. These networks are used to identify genes with similar expression dynamics but are prone to introducing false-positive and false-negative relationships, especially in the instance of large and heterogenous datasets. With the aim of optimizing the relevance of edges in GCNs and enhancing global biological insight, we propose a novel approach that involves a data-centering step performed simultaneously per gene and per sub-experiment, called centralization within sub-experiments (CSE). Using a gene set encoding the plant mitochondrial proteome as a case study, our results show that all CSE-based GCNs assessed had significantly more edges within the majority of the considered functional sub-networks, such as the mitochondrial electron transport chain and its complexes, than GCNs not using CSE; thus demonstrating that CSE-based GCNs are efficient at predicting canonical functions and associated pathways, here referred to as the core gene network. Furthermore, we show that correlation analyses using CSE-processed data can be used to fine-tune prediction of the function of uncharacterized genes; while its use in combination with analyses based on non-CSE data can augment conventional stress analyses with the innate connections underpinning the dynamic system being examined. Therefore, CSE is an effective alternative method to conventional batch correction approaches, particularly when dealing with large and heterogenous datasets. The method is easy to implement into a pre-existing GCN analysis pipeline and can provide enhanced biological relevance to conventional GCNs by allowing users to delineate a core gene network. Author Summary Gene co-expression networks (GCNs) are the product of a variety of mathematical approaches that identify causal relationships in gene expression dynamics but are prone to the misdiagnoses of false-positives and false-negatives, especially in the instance of large and heterogenous datasets. In light of the burgeoning output of next-generation sequencing projects performed on a variety of species, and developmental or clinical conditions; the statistical power and complexity of these networks will undoubtedly increase, while their biological relevance will be fiercely challenged. Here, we propose a novel approach to generate a "core" GCN with enhanced biological relevance. Our method involves a data-centering step that effectively removes all primary treatment/tissue effects, which is simple to employ and can be easily implemented into pre-existing GCN analysis pipelines. The gain in biological relevance resulting from the adoption of this approach was assessed using a plant mitochondrial case study.