The Impact of Modern Technologies on Molecular Diagnostic Success Rates, with a Focus on Inherited Retinal Dystrophy and Hearing Loss

Abstract

The identification of pathogenic variants in monogenic diseases has been of interest to researchers and clinicians for several decades. However, for inherited diseases with extremely high genetic heterogeneity, such as hearing loss and retinal dystrophies, establishing a molecular diagnosis requires an enormous effort. In this review, we use these two genetic conditions as examples to describe the initial molecular genetic identification approaches, as performed since the early 90s, and subsequent improvements and refinements introduced over the years. Next, the history of DNA sequencing from conventional Sanger sequencing to high-throughput massive parallel sequencing, a.k.a. next-generation sequencing, is outlined, including their advantages and limitations and their impact on identifying the remaining genetic defects. Moreover, the development of recent technologies, also coined “third-generation” sequencing, is reviewed, which holds the promise to overcome these limitations. Furthermore, we outline the importance and complexity of variant interpretation in clinical diagnostic settings concerning the massive number of different variants identified by these methods. Finally, we briefly mention the development of novel approaches such as optical mapping and multiomics, which can help to further identify genetic defects in the near future.

Progress in Gene Editing Tools and Their Potential for Correcting Mutations Underlying Hearing and Vision Loss

“…Besides progress in imaging technologies for clinical investigations (Rossi et al, 2011), increased efforts have been devoted to improve early genetic diagnosis for blindness and deafness disorders (Kremer, 2019;Thompson et al, 2020;de Bruijn et al, 2021). Current treatments for hearing loss are limited to hearing aids and cochlear implants, which partially restore hearing abilities (Müller and Barr-Gillespie, 2015;Kleinlogel et al, 2020).…”

Novel gene discovery for hearing loss and other routes to increased diagnostic rates

“…Options to elucidate such effects are iPSC-derived inner ear cells that are being more broadly implemented (see article by Romano, this issue). The relevance of technologies in molecular genetic testing for hearing loss is reviewed in de Bruijn et al (2021).…”

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…The technical possibilities to investigate disease processes at the genomic level have exploded over the past decades (reviewed in ( de Bruijn et al, 2021 )), and consequently huge collections of DNA sequence variabilities between individuals have been gathered. Whole exome sequencing (WES) and increasingly whole genome sequencing (WGS) approaches have yielded numerous allele variants for genes that differ at specific nucleotide positions (SNPs, single nucleotide polymorphisms) or represent structural variants (i.e.…”

“…Furthermore, gene expression levels may be influenced by copy number variations (CNVs) as well. And whereas in the 90s disease gene identification relied on family-based linkage studies using a collection of genomic markers ( de Bruijn et al, 2021 ), one can nowadays turn to genome-wide approaches with samples from unrelated individuals in genome-wide association studies (GWAS) or transcriptome-wide association studies ( Gamazon et al, 2015 ; Visscher et al, 2017 ). Tailored databases open up rich resources for consultation by the research community.…”