Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy

Abstract

Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous distal symmetric polyneuropathy. Whole-exome sequencing (WES) of 40 individuals from 37 unrelated families with CMT-like peripheral neuropathy refractory to molecular diagnosis identified apparent causal mutations in ~45% (17/37) of families. Three candidate disease genes are proposed, supported by a combination of genetic and in vivo studies. Aggregate analysis of mutation data revealed a significantly increased number of rare variants across 58 neuropathy associated genes in subjects versus controls; confirmed in a second ethnically discrete neuropathy cohort, suggesting mutation burden potentially contributes to phenotypic variability. Neuropathy genes shown to have highly penetrant Mendelizing variants (HMPVs) and implicated by burden in families were shown to interact genetically in a zebrafish assay exacerbating the phenotype established by the suppression of single genes. Our findings suggest that the combinatorial effect of rare variants contributes to disease burden and variable expressivity.

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

“…They concluded that, since the family represented a single observation, the significance of the clinical finding of variability of expression was unclear. We suggest that mutational burden or genetic load may contribute to clinical variability and disease severity, as has been shown in patients with CharcotMarie-Tooth disease, wherein genetic burden contributes to phenotypic variability and complex neuropathy (38).…”

“…Moreover, we identified a potential mutational burden in 6 patients with homozygous or compound heterozygous mutations in 2 different known genes. In 4 of 6 patients, both identified genes were previously associated with an arthrogryposis disorder, and the mutational burden may have contributed to the clinical severity observed (38); meanwhile, in 2 of 6 patients, the identified genes -in addition to known arthrogryposis genes -were associated with different disorders without arthrogryposis and resulted in an apparent blended phenotype with clinical manifestations of both disorders (40,67). Arthrogryposis is observed in a broad group of genetically heterogeneous disorders with unknown molecular etiology in the considerable majority.…”

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

“…In general populations, SNPs have been recognized as predictive markers in complex traits such as height (Visscher et al 2010), and associated with multiple common diseases, including type II diabetes mellitus (Flannick and Florez 2016), Crohn disease (Franke et al 2010), schizophrenia (International Schizophrenia et al 2009; Lee et al 2012), and breast cancer (Han et al 2016). Further validation of the association significance of these SNPs includes functional validation in model organisms such as mice (Flint and Eskin 2012), zebrafish (Gonzaga-Jauregui et al 2015), Drosophila (Yoon et al 2017), plant (Crossa et al 2010), or other experimental organisms, and informatic validation supported by tools like PLINK (Purcell et al 2007) and GCTA (Yang et al 2011). However, it remains a challenge to generally interpret the functional significance and gene/variant allele involved for novel disease-associated SNPs identified from either genome-wide association studies (GWAS) or next-generation sequencing (NGS) data.…”

Challenges confronting precision medicine in the context of inherited retinal disorders

“…On average, there are additional 2.3 damaging variations in patients with Charcot-MarieTooth (CMT) disease compared to 1.3 in controls. [55] How do we define these additional damaging variations and how do we confirm if these multiple variants are having a combined effect in a single affected individual? This will no doubt become one of the most difficult challenges when trying to further extend the precise molecular diagnosis of diseases such as IRD.…”