Editorial comment
The challenge of assessing variant pathogenicity in candidate Z-disc genes: The example of TCAP in hypertrophic cardiomyopathy
O desafio de avaliar a patogenicidade nos genes candidatos do disco Z: o exemplo de TCAP na miocardiopatia hipertrófica
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A: DNA sequencing electropherograms demonstrating heterozygosity for the detected mutation c.171C>G in individuals II-1 and II-2. The missense mutation is shown as two overlapping peaks (marked with an arrow). Individual II-3 exhibits a normal electropherogram (homozygous C). Codons are marked with gray blocks and the respective amino acid is shown below. B: Pedigree of the identified family. Squares represent males; circles females. Open symbols indicate unaffected individuals and solid symbols affected individuals; question marks, individuals with unknown status (without clinical data), and slanted bar, a deceased individual. The presence or absence of the mutation p.C57W is indicated by a plus and minus symbol, respectively. An arrow denotes the proband. C: Alignment of orthologs from eleven different species demonstrating high conservation in mammals (from chimp to dolphin) but no conservation in distantly related species such as fish. The mutated residue in the human sequence is underlined.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Alexandra Toste, Andreas Perrot, Cemil Özcelik, Nuno Cardim" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Alexandra" "apellidos" => "Toste" ] 1 => array:2 [ "nombre" => "Andreas" "apellidos" => "Perrot" ] 2 => array:2 [ "nombre" => "Cemil" "apellidos" => "Özcelik" ] 3 => array:2 [ "nombre" => "Nuno" "apellidos" => "Cardim" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204920302543?idApp=UINPBA00004E" "url" => "/21742049/0000003900000006/v1_202012131841/S2174204920302543/v1_202012131841/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial comment</span>" "titulo" => "The challenge of assessing variant pathogenicity in candidate Z-disc genes: The example of <span class="elsevierStyleItalic">TCAP</span> in hypertrophic cardiomyopathy" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "329" "paginaFinal" => "330" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Luís R. Lopes" "autores" => array:1 [ 0 => array:4 [ "nombre" => "Luís R." "apellidos" => "Lopes" "email" => array:1 [ 0 => "luis.lopes.10@ucl.ac.uk" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Barts Heart Centre, St. Bartholomew's Hospital, London, UK" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Centro Cardiovascular da Universidade de Lisboa, Lisboa, Portugal" "etiqueta" => "c" "identificador" => "aff0015" ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "O desafio de avaliar a patogenicidade nos genes candidatos do disco Z: o exemplo de TCAP na miocardiopatia hipertrófica" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in genes encoding sarcomere proteins, inherited as an autosomal dominant phenotype and detected in 50% of the patients.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> This incomplete yield of genetic testing is not ideal; establishing a genetic cause enables confirmation of the diagnosis in a proband/family and the planning of more informed screening and surveillance for relatives.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The remaining 50% of genotype-negative cases are likely to be explained by a mixture of novel genes. Examples of this include: formin homology 2 domain containing 3 (<span class="elsevierStyleItalic">FHOD3</span>),<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> rarer mutational mechanisms, such as copy number variation,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> cryptic or deep-intronic variation, particularly relevant for <span class="elsevierStyleItalic">MYBPC3</span>,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> and oligo/polygenic mechanisms, which defy classical Mendelian concepts and have been described for other inherited cardiac conditions, including channelopathies.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Recent classification efforts, which take advantage of the growing availability of control genomes,<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 (<span class="elsevierStyleItalic">MYBPC3, MYH7, TNNT2, TNNI3, MYL2, MYL3, ACTC1, TPM1</span>) are still the most strongly associated with HCM.<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.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> For other candidate genes, including the ones encoding Z-disc and cytoskeleton proteins, the level of evidence is weaker.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,9</span></a> However, this field is always changing and co-segregation studies, sometimes in conjunction with functional research, have established causality for some of the candidate genes encoding non-contractile proteins, including junctophilin (<span class="elsevierStyleItalic">JPH</span>)<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">10</span></a> and alpha-actinin (<span class="elsevierStyleItalic">ACNT2</span>).<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Titin cap-telethonin, encoded by <span class="elsevierStyleItalic">TCAP</span>, mediates the assembly of the N-terminal domain of two adjacent titin molecules and interacts with other relevant Z-disc, ion channel and sarcomere-cytoskeleton components.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a> Due to this interaction, it has long been added to the list of possible candidate cardiomyopathy genes, and a small number of <span class="elsevierStyleItalic">TCAP</span> variants have been described in patients with HCM and dilated cardiomyopathy (DCM). However, while for DCM a significant excess of cases <span class="elsevierStyleItalic">vs</span> controls has been described, this does not seem to be the case for HCM. Additionally, co-segregation or functional data are nearly all absent.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">7,9</span></a> It is therefore extremely challenging to attribute pathogenicity to a variant identified in this gene. Pathogenicity prediction for variants where familial linkage or convincing functional data are unavailable can be quite difficult, even for established causal genes. For candidate genes where evidence of causality is scarce, this task is even more difficult. 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. A possible explanation could be its poor tolerance of variation (functional constraint)<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> but the constraint metrics available in the GnomAD browser (<a href="https://gnomad.broadinstitute.org/gene/ENSG00000173991?dataset=gnomad_r2_1">https://gnomad.broadinstitute.org/gene/ENSG00000173991?dataset=gnomad_r2_1</a>)<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> appear to indicate otherwise.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In the case report by Toste et al., published in the current issue of the journal, the authors describe a small HCM family where the <span class="elsevierStyleItalic">TCAP</span> variant p.C57W was detected. No pathogenic variants in established causal genes were found. The authors describe this variant as likely pathogenic for HCM. The phenotype of the two affected members is not dissimilar to that commonly described in sarcomere HCM, including in the Portuguese population.<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, it is well preserved across mammal species and causes a significant biochemical shift, which is reflected in the almost consensual in silico predictions of pathogenicity. Another feature supporting causality is the very low minor allele frequency in GnomAD v2.1.1<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> (four alleles, 0.0000166). In the reported family, the variant segregates with the phenotype, but a definitive co-segregation conclusion is limited by the small size (two affected and one non-affected siblings).</p><p id="par0030" class="elsevierStylePara elsevierViewall">If applying strict American College of Medical Genetics criteria (PM2, PP3),<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> the variant would be classified as a variant of uncertain significance, but this would change in the presence of functional data, which would upgrade the variant to likely pathogenic. At its current status, it is advisable to be very careful; this variant should not be used for predictive testing, although further segregation efforts are certainly desirable.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Despite these challenges, interesting observations such as those made in the case reported by the authors should be shared. Other authors may encounter the same or neighboring variants in larger families or be interested in exploring functional data in collaboration. These joint curation efforts can potentially contribute to clarifying the role of candidate Z-disc genes, such as <span class="elsevierStyleItalic">TCAP,</span> in the genetic architecture of HCM and other cardiomyopathies, leading to an increase in the yield of genetic testing.</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.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluating the clinical validity of hypertrophic cardiomyopathy genes" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 4 | 10 |
| 2024 October | 37 | 36 | 73 |
| 2024 September | 53 | 28 | 81 |
| 2024 August | 40 | 23 | 63 |
| 2024 July | 38 | 32 | 70 |
| 2024 June | 35 | 28 | 63 |
| 2024 May | 38 | 20 | 58 |
| 2024 April | 25 | 29 | 54 |
| 2024 March | 31 | 28 | 59 |
| 2024 February | 25 | 28 | 53 |
| 2024 January | 24 | 22 | 46 |
| 2023 December | 26 | 33 | 59 |
| 2023 November | 30 | 27 | 57 |
| 2023 October | 14 | 18 | 32 |
| 2023 September | 17 | 22 | 39 |
| 2023 August | 18 | 15 | 33 |
| 2023 July | 14 | 11 | 25 |
| 2023 June | 24 | 11 | 35 |
| 2023 May | 38 | 24 | 62 |
| 2023 April | 22 | 3 | 25 |
| 2023 March | 47 | 18 | 65 |
| 2023 February | 29 | 14 | 43 |
| 2023 January | 14 | 14 | 28 |
| 2022 December | 41 | 19 | 60 |
| 2022 November | 46 | 26 | 72 |
| 2022 October | 44 | 22 | 66 |
| 2022 September | 17 | 31 | 48 |
| 2022 August | 32 | 16 | 48 |
| 2022 July | 26 | 38 | 64 |
| 2022 June | 19 | 25 | 44 |
| 2022 May | 19 | 32 | 51 |
| 2022 April | 25 | 23 | 48 |
| 2022 March | 19 | 42 | 61 |
| 2022 February | 25 | 39 | 64 |
| 2022 January | 14 | 21 | 35 |
| 2021 December | 18 | 27 | 45 |
| 2021 November | 21 | 31 | 52 |
| 2021 October | 70 | 38 | 108 |
| 2021 September | 45 | 33 | 78 |
| 2021 August | 42 | 29 | 71 |
| 2021 July | 26 | 20 | 46 |
| 2021 June | 25 | 26 | 51 |
| 2021 May | 17 | 39 | 56 |
| 2021 April | 24 | 31 | 55 |
| 2021 March | 28 | 19 | 47 |
| 2021 February | 20 | 7 | 27 |
| 2021 January | 20 | 22 | 42 |
| 2020 December | 19 | 9 | 28 |
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