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Eur J Hum Genet. 2017 Sep;25(9):1055-1060. doi: 10.1038/ejhg.2017.95. Epub 2017 Jun 21.

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

Author information

1
Department of Biology, University of Rome Tor Vergata, Rome, Italy.
2
Clinical Pathophysiology Center, AFaR Foundation - 'San Giovanni Calibita' Fatebenefratelli Hospital, Rome, Italy.
3
Department of Geriatrics, Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.
4
Department of Neurosciences, Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.
5
Department of Orthopedics, Institute of Neurology, Catholic University of the Sacred Heart, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.
6
'Centro Clinico NEMO', Rome, Italy.
7
Division of Neurology and Neurorehabilitation, San Giuseppe Hospital, IRCCS-Istituto Auxologico Italiano, Piancavallo (VB), Italy.
8
Department of Neuroscience, University of Turin, Turin, Italy.
9
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
10
Unit of Neurology, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
11
Regional Amyloid Centre, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
12
Genetic Diagnostics Unit, Laboratory Department, Careggi University Hospital, Florence, Italy.
13
Division of Neurology, 'Vito Fazzi Hospital', Lecce, Italy.
14
Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
15
VA CT Healthcare Center, West Haven, CT, USA.

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.

PMID:
28635949
PMCID:
PMC5558178
DOI:
10.1038/ejhg.2017.95
[Indexed for MEDLINE]
Free PMC Article

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