Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

Abstract

Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease.

Figure 1

Radar diagram of symptoms across amyloidogenic mutations. The percentages are calculated with respect to the total number of organ involvements reported for each TTR mutation. The full colour version of this figure is available at European Journal of Human Genetics online.

Figure 2

Hierarchical clustering based on clinical symptoms and amyloidogenic mutation reported in the 129 patients with TTR amyloidosis. Red boxes highlight the significant clusters (approximately unbiased (AU) P>95% bootstrap probability (BP)). Gastr.Int, gastrointestinal involvement; SNA, autonomic neurological involvement; SNP, peripheral neurological involvement. The full colour version of this figure is available at European Journal of Human Genetics online.

Figure 3

Functional annotation of the variants identified by TTR gene re-sequencing.

Figure 4

Hierarchical clustering using tissue-specific polygenic score of the 55 patients re-sequenced. On the top the 55 patients and on the left the 46 considered tissues. Red boxes highlight the significant clusters (approximately unbiased P>95%). Red, green, and black colors correspond to genetically determined overexpression, under-expression, and little differential expression, respectively. The color scheme is also reported at the top of the figure. The full colour version of this figure is available at European Journal of Human Genetics online.