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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Hypertrophic cardiomyopathy &#40;HCM&#41; is primarily caused by mutations in genes encoding sarcomere proteins&#44; inherited as an autosomal dominant phenotype and detected in 50&#37; of the patients&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> This incomplete yield of genetic testing is not ideal&#59; establishing a genetic cause enables confirmation of the diagnosis in a proband&#47;family and the planning of more informed screening and surveillance for relatives&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The remaining 50&#37; of genotype-negative cases are likely to be explained by a mixture of novel genes&#46; &#40;one recent example is FHOD3&#41;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> rarer mutational mechanisms&#44; such as copy number variation&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> cryptic or deep-intronic variation&#44; particularly relevant for <span class="elsevierStyleItalic">MYBPC3</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> and oligo&#47;polygenic mechanisms&#44; which defy classical Mendelian concepts and have been described for other inherited cardiac conditions&#44; including channelopathies&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Recent classification efforts&#44; which take advantage of the growing availability of control genomes&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> have repeatedly highlighted that the core group of initially described eight causal sarcomere genes &#40;<span class="elsevierStyleItalic">MYBPC3&#44; MYH7&#44; TNNT2&#44; TNNI3&#44; MYL2&#44; MYL3&#44; ACTC1&#44; TPM1</span>&#41; are still the most strongly associated with HCM&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a> The recently published genetic architecture of the large population recruited to the Portuguese Registry of HCM reflects this&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> For other candidate genes&#44; including the ones encoding Z-disc and cytoskeleton proteins&#44; the level of evidence is weaker&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1&#44;9</span></a> However&#44; this field is always changing and co-segregation studies&#44; sometimes in conjunction with functional research&#44; have established causality for some of the candidate genes encoding non-contractile proteins&#44; including junctophilin &#40;<span class="elsevierStyleItalic">JPH</span>&#41;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> and alpha-actinin &#40;<span class="elsevierStyleItalic">ACNT2</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Titin cap-telethonin&#44; encoded by <span class="elsevierStyleItalic">TCAP</span>&#44; mediates the assembly of the N-terminal domain of two adjacent titin molecules and interacts with other relevant Z-disc&#44; ion channel and sarcomere-cytoskeleton components&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a> Due to this interaction&#44; it has long been added to the list of possible candidate cardiomyopathy genes&#44; and a small number of <span class="elsevierStyleItalic">TCAP</span> variants have been described in patients with HCM and dilated cardiomyopathy &#40;DCM&#41;&#46; However&#44; while for DCM a significant excess of cases <span class="elsevierStyleItalic">vs</span> controls has been described&#44; this does not seem to be the case for HCM&#46; Additionally&#44; co-segregation or functional data are nearly all absent&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">7&#44;9</span></a> It is therefore extremely challenging to attribute pathogenicity to a variant identified in this gene&#46; Pathogenicity prediction for variants where familial linkage or convincing functional data are unavailable can be quite difficult&#44; even for established causal genes&#46; For candidate genes where evidence of causality is scarce&#44; this task is even more difficult&#46; Why a gene with such extensive interaction with major components of the sarcomere and related cardiomyocyte biology does not harbor more obvious causal variation is perhaps puzzling&#46; A possible explanation could be its poor tolerance of variation &#40;functional constraint&#41;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> but the constraint metrics available in the GnomAD browser &#40;<a href="https://gnomad.broadinstitute.org/gene/ENSG00000173991?dataset=gnomad_r2_1">https&#58;&#47;&#47;gnomad&#46;broadinstitute&#46;org&#47;gene&#47;ENSG00000173991&#63;dataset&#61;gnomad&#95;r2&#95;1</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> appear to indicate otherwise&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In the case report by Toste et al&#46;&#44; published in the current issue of the journal&#44; the authors describe a small HCM family where the <span class="elsevierStyleItalic">TCAP</span> variant p&#46;C57W was detected&#46; No pathogenic variants in established causal genes were found&#46; The authors describe this variant as likely pathogenic for HCM&#46; The phenotype of the two affected members is not dissimilar to that commonly described in sarcomere HCM&#44; including in the Portuguese population&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a> The variant is located in a region of the protein that interacts with muscle LIM protein and titin&#44; it is well preserved across mammal species and causes a significant biochemical shift&#44; which is reflected in the almost consensual in silico predictions of pathogenicity&#46; Another feature supporting causality is the very low minor allele frequency in GnomAD v2&#46;1&#46;1<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> &#40;four alleles&#44; 0&#46;0000166&#41;&#46; In the reported family&#44; the variant segregates with the phenotype&#44; but a definitive co-segregation conclusion is limited by the small size &#40;two affected and one non-affected siblings&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">If applying strict American College of Medical Genetics criteria &#40;PM2&#44; PP3&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> the variant would be classified as a variant of uncertain significance&#44; but this would change in the presence of functional data&#44; which would upgrade the variant to likely pathogenic&#46; At its current status&#44; it is advisable to be very careful&#59; this variant should not be used for predictive testing&#44; although further segregation efforts are certainly desirable&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Despite these challenges&#44; interesting observations such as those made in the case reported by the authors should be shared&#46; Other authors may encounter the same or neighboring variants in larger families or be interested in exploring functional data in collaboration&#46; These joint curation efforts can potentially contribute to clarifying the role of candidate Z-disc genes&#44; such as <span class="elsevierStyleItalic">TCAP&#44;</span> in the genetic architecture of HCM and other cardiomyopathies&#44; leading to an increase in the yield of genetic testing&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">The author has no conflicts of interest to declare&#46;</p></span></span>"
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