12 , 13 Most of identified mutations are family-specific and cannot account for the common causes of CHD, but it is possible that multiple variants may play a role in the disease development in a polygenic setting, although the interpretation of these variants can be very challenging and it is not always possible to establish their pathogenicity: these associations can be highly significant from a statistical and research perspective, but with low clinical relevance. 14 In many families and individuals with CHD, variations in genes expressed during heart formation are present with different profiles of inheritance, suggesting a continuum between Mendelian and complex forms of diseases
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38 Studies with next-generation sequencing have identified significant enrichment for mutations in genes involving histone modification in patients with CHD, especially H3K4 , H2K7 , H3K9 , and H3K27 , suggesting that histone modification may be significant in the pathology of isolated disease. 1 , 4 Investigation of chromatin remodeling in model organisms has shown that dynamic modification of chromatin structure plays an important role in the regulation of gene expression during heart development. 13 De novo mutations affecting chromatin regulation genes contribute to about 3% of the CHDs.