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
