{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:37:22Z","timestamp":1793039842046,"version":"4.5.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","license":[{"start":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T00:00:00Z","timestamp":1793059200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2026,10,27]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Disruption of\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      precursor mRNA splicing is a frequent genetic cause of hypertrophic cardiomyopathy (HCM). Most often, it reflects changes at canonical sites or the creation of novel splice sites. Prediction tools usually prioritize splice variants with lower efficiency when they are distant from canonical sites. These elusive variants may explain HCM in patients considered genotype-negative after DNA testing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Massively parallel sequencing identified the previously unreported deep-intronic variant\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      c.2308+227G&gt;A in a cohort of genotype-negative patients with HCM from Salamanca, Spain. SpliceAI predicted a benign effect (\u0394 score, 0.03). However, its recurrent detection prompted us to conduct extensive analyses to investigate its pathogenicity, including genetic testing, clinical assessment, family studies, splicing assays, and haplotype reconstruction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We identified 35 unrelated HCM probands carrying c.2308+227G&gt;A, plus 46 relatives from 27 families, yielding 81 confirmed carriers. Of these, 56 (69%) met diagnostic criteria for HCM (66% male; mean age, 53\u00b115 years). By age 60 years, cumulative penetrance was estimated to be 81% in women and 96% in men. The combined logarithm of the odds score of 5.51 across 20 informative families provided strong evidence of cosegregation. During follow-up of probands, no significant differences were observed in heart failure, arrhythmic events, atrial fibrillation, or mortality when compared with cohorts carrying other pathogenic\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      variants. Blood splicing assays, confirmed in cardiac tissue, showed that c.2308+227G&gt;A disrupts splicing by the use of pre-existing cryptic donor (c.2308+299) and acceptor (c.2309\u2212580) splice sites, generating 2 misspliced mRNAs with partial intron retention or cryptic exon inclusion, which encode truncated proteins. These cryptic sites are the leading natural, unannotated missplicing events in intron 23, and some of the most frequent across the whole\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      precursor mRNA, as revealed by SpliceVault analysis of RNA sequencing databases. This deep-intronic variant does not alter essential splice motifs but promotes the use of pre-existing cryptic sites, likely through gain of splicing regulatory enhancer elements. The identification of a shared haplotype among HCM probands carrying this variant explains its recurrent detection, consistent with an ancient founder effect.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      c.2308+227G&gt;A is a pathogenic splice-altering variant that causes HCM by amplifying natural missplicing events. These background splicing errors help explain how this elusive variant disrupts splicing without creating novel essential splice sites, thereby expanding the known mechanisms by which deep-intronic variants alter\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      splicing and ultimately contribute to HCM pathogenesis. Elusive\n                      <jats:italic toggle=\"yes\">MYBPC3<\/jats:italic>\n                      splice-altering variants should be considered in HCM patients with an unresolved genetic origin of disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.125.078812","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:02:08Z","timestamp":1789462928000},"page":"1700-1717","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Missplicing Events Amplified by an Elusive Deep-Intronic\n                    <i>MYBPC3<\/i>\n                    Variant Cause Hypertrophic Cardiomyopathy"],"prefix":"10.1161","volume":"154","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0726-9646","authenticated-orcid":true,"given":"Mar\u00eda","family":"Gallego-Delgado","sequence":"first","affiliation":[{"name":"Department of Cardiology (M.G.-D., S.R.-D., M.G.M., L.M.R., C.A.M., E.D.-P., I.C.-G., P.L.S., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (M.G.-D., L.M.R., I.C.-G., P.L.S., J.P.O., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1685-4315","authenticated-orcid":true,"given":"Sandra Milagros","family":"Lorenzo Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Clinical Laboratory Department (S.M.L.H., D.H.H.-J., B.G.-B., M.J.G.-S., M.I.-G.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Reference Unit for Rare Diseases (S.M.L.H., D.H.H.-J., B.G.-B., M.J.G.-S., M.I.-G.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2547-685X","authenticated-orcid":true,"given":"Soledad","family":"Garc\u00eda Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Health in Code S.L., A Coru\u00f1a, Spain (S.G.H., E.M.P., M.P.-B., J.P.O.)."},{"name":"Inherited Cardiac Diseases Unit, San Cecilio Hospital, Granada, Spain (S.G.H.)."},{"name":"Universidade da Coru\u00f1a, Cardiovascular Research Group, Spain (S.G.H., M.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Rodr\u00edguez-Diego","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.G.-D., S.R.-D., M.G.M., L.M.R., C.A.M., E.D.-P., I.C.-G., P.L.S., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-9319","authenticated-orcid":true,"given":"David Hansoe","family":"Heredero-Jung","sequence":"additional","affiliation":[{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Clinical Laboratory Department (S.M.L.H., D.H.H.-J., B.G.-B., M.J.G.-S., M.I.-G.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Reference Unit for Rare Diseases (S.M.L.H., D.H.H.-J., B.G.-B., M.J.G.-S., M.I.-G.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Maneiro Pamp\u00edn","sequence":"additional","affiliation":[{"name":"Health in Code S.L., A Coru\u00f1a, Spain (S.G.H., E.M.P., M.P.-B., J.P.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"P\u00e9rez-Barbeito","sequence":"additional","affiliation":[{"name":"Health in Code S.L., A Coru\u00f1a, Spain (S.G.H., E.M.P., M.P.-B., J.P.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3061-8568","authenticated-orcid":true,"given":"M\u00f3nica","family":"Garc\u00eda Monsalvo","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.G.-D., S.R.-D., M.G.M., L.M.R., C.A.M., E.D.-P., I.C.-G., P.L.S., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1397-9508","authenticated-orcid":true,"given":"Bel\u00e9n","family":"Garc\u00eda-Berrocal","sequence":"additional","affiliation":[{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Clinical Laboratory Department (S.M.L.H., D.H.H.-J., B.G.-B., M.J.G.-S., M.I.-G.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Reference Unit for Rare Diseases (S.M.L.H., D.H.H.-J., B.G.-B., M.J.G.-S., M.I.-G.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1819-5742","authenticated-orcid":true,"given":"Luis M.","family":"Rinc\u00f3n","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.G.-D., S.R.-D., M.G.M., L.M.R., C.A.M., E.D.-P., I.C.-G., P.L.S., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (M.G.-D., L.M.R., I.C.-G., P.L.S., J.P.O., E.V.)."},{"name":"Department of Medicine, University of Salamanca, Spain (L.M.R., I.C.-G., P.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jes\u00fas","family":"Garc\u00eda-Salgado","sequence":"additional","affiliation":[{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Clinical Laboratory Department (S.M.L.H., D.H.H.-J., B.G.-B., M.J.G.-S., M.I.-G.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Reference Unit for Rare Diseases (S.M.L.H., D.H.H.-J., B.G.-B., M.J.G.-S., M.I.-G.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5151-7235","authenticated-orcid":true,"given":"Mar\u00eda Elena","family":"Arn\u00e1iz-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Department of Cardiac Surgery (M.E.A.-G., R.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"\u00c1lvarez Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.G.-D., S.R.-D., M.G.M., L.M.R., C.A.M., E.D.-P., I.C.-G., P.L.S., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4411-5144","authenticated-orcid":true,"given":"Elena","family":"D\u00edaz-Pel\u00e1ez","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.G.-D., S.R.-D., M.G.M., L.M.R., C.A.M., E.D.-P., I.C.-G., P.L.S., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Reference Unit for Inherited Cardiac Diseases (M.G.-D., S.M.L.H., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."},{"name":"Institute of Biomedical Research of Salamanca, Spain (M.G.-D., S.R.-D., D.H.H.-J., M.G.M., B.G.-B., L.M.R., M.J.G.-S., M.E.A.-G., C.A.M., E.D.-P., R.V., I.C.-G., P.L.S., M.I.-G., E.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mar\u00eda","family":"Merino","sequence":"additional","affiliation":[{"name":"University Hospital of Salamanca, Department of Cardiology, University Hospital of Burgos (A.M.M., A.R.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3513-1193","authenticated-orcid":true,"given":"\u00c1lvaro","family":"Rold\u00e1n","sequence":"additional","affiliation":[{"name":"University Hospital of Salamanca, Department of Cardiology, University Hospital of Burgos (A.M.M., A.R.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Mayorga","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital de El Bierzo (A.M., E.M.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7826-0598","authenticated-orcid":true,"given":"Emilse","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital de El Bierzo (A.M., E.M.), Gerencia Regional de Salud de Castilla y Le\u00f3n, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1974-5243","authenticated-orcid":true,"given":"Mar\u00eda Jos\u00e9","family":"Ruiz Olgado","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital Virgen de la Concha, Gerencia Regional de Salud de Castilla y Le\u00f3n, Zamora, Spain (M.J.R.O., L.R.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5493-9754","authenticated-orcid":true,"given":"Luc\u00eda","family":"Rodr\u00edguez Est\u00e9vez","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital Virgen de la Concha, Gerencia Regional de Salud de Castilla y Le\u00f3n, Zamora, Spain (M.J.R.O., L.R.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro D.","family":"Perdiguero","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Hospital Nuestra Se\u00f1ora de Sonsoles, Gerencia Regional de Salud de Castilla y Le\u00f3n, \u00c1vila, Spain (P.D.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2814-9045","authenticated-orcid":true,"given":"Roberto","family":"Voces","sequence":"additional","affiliation":[{"name":"Reference Unit for Inherited Cardiac Diseases 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