Genetic Modifiers and Rare Mendelian Disease

Abstract

Despite advances in high-throughput sequencing that have revolutionized the discovery of gene defects in rare Mendelian diseases, there are still gaps in translating individual genome variation to observed phenotypic outcomes. While we continue to improve genomics approaches to identify primary disease-causing variants, it is evident that no genetic variant acts alone. In other words, some other variants in the genome (genetic modifiers) may alleviate (suppress) or exacerbate (enhance) the severity of the disease, resulting in the variability of phenotypic outcomes. Thus, to truly understand the disease, we need to consider how the disease-causing variants interact with the rest of the genome in an individual. Here, we review the current state-of-the-field in the identification of genetic modifiers in rare Mendelian diseases and discuss the potential for future approaches that could bridge the existing gap.

Systems Biology Approaches Reveal Potential Phenotype-Modifier Genes in Neurofibromatosis Type 1

“…Recently, a review pointed out the main methods with which to discover novel phenotype-modifier genes in Mendelian diseases and formulate hypotheses about other pathways than Ras-NF1 that could be phenotype modifiers [ 44 ]. The most used methods to select candidate modifier genes are whole-genome sequencing, genome-wide association studies, and experimental approaches using animal models.…”

“…Network analysis makes it possible to combine different multi-omics studies, a strategy that has been applied in several personalized medicine studies evaluating genetic syndromes with phenotypic variability [ 47 , 48 , 49 ]. Recently, many projects and consortiums were created, gathering a huge amount of public results with germline and somatic mutation databases, transcriptomics, proteomics, and metabolomics data that can now be evaluated with a systems biology tools [ 44 ]. The analysis proposed here can be seen as an optimization in the search for candidate genes acting as phenotype modifiers in NF1, which can later be confirmed by the more robust molecular and functional assays.…”

Zebrafish Models of LAMA2-Related Congenital Muscular Dystrophy (MDC1A)

“…Despite some limitations (Gut et al, 2017 ), these genome-editing approaches allow for the generation of a theoretically unlimited number of zebrafish mutants, which could ultimately enable scientists to systematically and comprehensively study full allele series for disorders such as LAMA2-MD. Lastly, performing genetic modifiers screens in caf zebrafish with methodologies including ENU mutagenesis and CRISPR gene editing (McGovern et al, 2015 ; Quattrocelli et al, 2017a , b ; Rahit and Tarailo-Graovac, 2020 ; Volpatti et al, 2020 ) should enable the identification of genetic interactions and novel disease modifiers, data which would greatly advance our understanding of the pathomechanisms and phenotypic variability of LAMA2-MD.…”

Evaluation of a new variant in the aggrecan gene potentially associated with chondrodysplastic dwarfism in Miniature horses

“…Indeed, a mutation may not always cause the same effects, or it may lead to different phenotypes of the same disorder in different individuals 23,24 . Several genetic modifiers can produce unexpected phenotypes of the primary disease-causing variant 25 , and the genetic background of Miniature horses and Shetland ponies, which were selected for diminutive size over the www.nature.com/scientificreports/ years, differs from horses of large breeds [26][27][28][29] and may generate a predisposition to the condition characterized as dwarfism due to ACAN variants. In addition, D1, D2, D3*, and D4 can affect height measurements at the withers in Miniature horses; therefore, ACAN variant carriers are smaller than non-carriers 30 .…”