Hydrops foetalis successfully treated by exchange transfusion.

Abstract

<h3>Abstract</h3> <h3>Background</h3> Macular diseases (MDs) are a subgroup of retinal disorders characterized by central vision loss that represent a major cause of vision impairment. Despite the identification of numerous genes associated with inherited MD (iMD) and risk factors associated with age-related MD (AMD), the extent of genetic and non-genetic factors that influence the expression of MD is still not fully explained. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the <i>ABCA4</i> gene in patients with Stargardt disease in a cost-effective manner to identify associated coding and non-coding variation, however a large portion of patients with MDs still remain genetically unexplained. <h3>Methods</h3> For MD patients, we hypothesized that the missing heritability may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. We used 17,394 smMIPs to sequence the coding regions of 105 genes and non-coding or regulatory loci associated with iMD and AMD, known pseudo-exons, and the mitochondrial genome in two test cohorts that had previously been screened for variants in the entire <i>ABCA4</i> gene. <h3>Results</h3> Sequencing of 379 probands achieved an average nucleotide coverage of 431× across all targets. Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an ‘‘MD-smMIPs panel’’ that allows a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets. <h3>Conclusions</h3> Further analysis will identify known and novel variants in MD-associated genes to offer an accurate clinical diagnosis to patients and their families. Furthermore, this will reveal new genetic associations for MD and potential genetic overlaps between iMD and AMD.