Abstract
Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic modifier factors and new sequencing technologies are redefining the understanding of genotype-phenotype relationships, even if the interpretations of the numerous identified variants pose several challenges. Methods and results: We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in 3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for the prediction, annotation and visualization of functional variants. Genotype-phenotype correlations were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The 80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants. Conclusions: Our results extend the mutational spectrum of HCM and contribute in defining the molecular pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in a clinical context.
| Original language | English |
|---|---|
| Pages (from-to) | 227-235 |
| Number of pages | 9 |
| Journal | Gene |
| Volume | 577 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 15 2016 |
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Keywords
- Genetic testing
- HCM
- Hypertrophic cardiomyopathy
- Next generations sequencing
- NGS
- Sarcomere
ASJC Scopus subject areas
- Genetics
Cite this
Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy. / Bottillo, Irene; D'Angelantonio, Daniela; Caputo, Viviana; Paiardini, Alessandro; Lipari, Martina; De Bernardo, Carmelilia; Giannarelli, Diana; Pizzuti, Antonio; Majore, Silvia; Castori, Marco; Zachara, Elisabetta; Re, Federica; Grammatico, Paola.
In: Gene, Vol. 577, No. 2, 15.02.2016, p. 227-235.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy
AU - Bottillo, Irene
AU - D'Angelantonio, Daniela
AU - Caputo, Viviana
AU - Paiardini, Alessandro
AU - Lipari, Martina
AU - De Bernardo, Carmelilia
AU - Giannarelli, Diana
AU - Pizzuti, Antonio
AU - Majore, Silvia
AU - Castori, Marco
AU - Zachara, Elisabetta
AU - Re, Federica
AU - Grammatico, Paola
PY - 2016/2/15
Y1 - 2016/2/15
N2 - Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic modifier factors and new sequencing technologies are redefining the understanding of genotype-phenotype relationships, even if the interpretations of the numerous identified variants pose several challenges. Methods and results: We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in 3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for the prediction, annotation and visualization of functional variants. Genotype-phenotype correlations were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The 80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants. Conclusions: Our results extend the mutational spectrum of HCM and contribute in defining the molecular pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in a clinical context.
AB - Background: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disorder characterized by unexplained left ventricle hypertrophy associated with non-dilated ventricular chambers. Several genes encoding heart sarcomeric proteins have been associated to HCM, but a small proportion of HCM patients harbor alterations in other non-sarcomeric loci. The variable expression of HCM seems influenced by genetic modifier factors and new sequencing technologies are redefining the understanding of genotype-phenotype relationships, even if the interpretations of the numerous identified variants pose several challenges. Methods and results: We investigated 62 sarcomeric and non-sarcomeric genes in 41 HCM cases and in 3 HCM-related disorders patients. We employed an integrated approach that combines multiple tools for the prediction, annotation and visualization of functional variants. Genotype-phenotype correlations were carried out for inspecting the involvement of each gene in age onset and clinical variability of HCM. The 80% of the non-syndromic patients showed at least one rare non-synonymous variant (nsSNV) and among them, 58% carried alterations in sarcomeric loci, 14% in desmosomal and 7% in other non-sarcomeric ones without any sarcomere change. Statistical analyses revealed an inverse correlation between the number of nsSNVs and age at onset, and a relationship between the clinical variability and number and type of variants. Conclusions: Our results extend the mutational spectrum of HCM and contribute in defining the molecular pathogenesis and inheritance pattern(s) of this condition. Besides, we delineate a specific procedure for the identification of the most likely pathogenetic variants for a next generation sequencing approach embodied in a clinical context.
KW - Genetic testing
KW - HCM
KW - Hypertrophic cardiomyopathy
KW - Next generations sequencing
KW - NGS
KW - Sarcomere
UR - http://www.scopus.com/inward/record.url?scp=84952864713&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84952864713&partnerID=8YFLogxK
U2 - 10.1016/j.gene.2015.11.048
DO - 10.1016/j.gene.2015.11.048
M3 - Article
C2 - 26656175
AN - SCOPUS:84952864713
VL - 577
SP - 227
EP - 235
JO - Gene
JF - Gene
SN - 0378-1119
IS - 2
ER -