{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:17:46Z","timestamp":1789521466833,"version":"build-2803163510"},"reference-count":12,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: PLACK syndrome is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in CAST, which encodes calpastatin, an endogenous inhibitor of calpains. The syndrome is classically defined by peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads. Although the phenotype has been largely restricted to dermatological manifestations, emerging reports suggest dilated cardiomyopathy (DCM) as a systemic complication. Methods: We investigated five affected children from three sibships of an extended consanguineous family. Clinical evaluation and genome sequencing (GS) followed by segregation analysis of the targeted mutation test (TMT) were performed. Histopathological examination of an explanted heart was conducted in one child who underwent heart transplantation. Results: All affected children exhibited typical dermatological features of PLACK syndrome. Four developed severe DCM, two of whom required orthotopic heart transplantation. GS, performed in three affected children, identified a novel homozygous frameshift variant in CAST (NM_001750.7:c.1177dup, p.Arg393Profs*4), which segregated with the disease within the family. No additional plausible variants in known cardiomyopathy-associated genes were detected. Histopathological examination of the explanted heart demonstrated hypertrophied cardiomyocytes with nuclear enlargement, hyperchromasia, and fibrosis. Conclusions: Our findings expand the phenotypic spectrum of PLACK syndrome to include severe DCM and suggest CAST deficiency as a novel cause of recessively inherited cardiomyopathy. The favorable short-term outcome following transplantation highlights a potential therapeutic option. Given the possibility of age-dependent penetrance, lifelong cardiac surveillance is for the affected individuals suggested. To emphasize cardiomyopathy as a critical and underrecognized component of the syndrome, we propose the consideration of modifying the acronym to PLACK-C.<\/jats:p>","DOI":"10.3390\/genes16111292","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:23:59Z","timestamp":1761873839000},"page":"1292","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Severe Dilated Cardiomyopathy with PLACK Syndrome Caused by a Novel Truncating Variant in the CAST Gene"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2506-9384","authenticated-orcid":false,"given":"Maarab","family":"Alkorashy","sequence":"first","affiliation":[{"name":"Department of Translational Genomics, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital & Research Centre, Takhassusi Street, P.O. BOX 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9670-2087","authenticated-orcid":false,"given":"Hamzah","family":"Naji","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital & Research Centre, Takhassusi Street, P.O. BOX 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadiah","family":"ALRuwaili","sequence":"additional","affiliation":[{"name":"Heart Center of Excellence, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimpna","family":"Albert","sequence":"additional","affiliation":[{"name":"Heart Center of Excellence, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saud","family":"Takroni","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital & Research Centre, Takhassusi Street, P.O. BOX 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamayel","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Takhassusi Street, P.O. BOX 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadeel","family":"Binomar","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital & Research Centre, Takhassusi Street, P.O. BOX 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0801-6295","authenticated-orcid":false,"given":"Aisha","family":"ALqahtani","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital & Research Centre, Takhassusi Street, P.O. BOX 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuhair","family":"Al-Hassnan","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital & Research Centre, Takhassusi Street, P.O. BOX 3354, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.ajhg.2014.12.026","article-title":"Loss-of-function mutations in CAST cause peeling skin, leukonychia, acral punctate keratoses, cheilitis, and knuckle pads","volume":"96","author":"Lin","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nature07451","article-title":"Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin","volume":"456","author":"Hanna","year":"2008","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/0300-9084(92)90120-4","article-title":"The calpain-calpastatin system in mammalian cells: Properties and possible functions","volume":"74","author":"Melloni","year":"1992","journal-title":"Biochimie"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Haxho, F., Haber, R.M., Mohamad, J., Sarig, O., Sprecher, E., Perrier, R., Boctor, D., and Ramien, M. (Pediatr. Dermatol., 2025). Peeling Skin, Leukonychia, Acral Punctate Keratoses, Cheilitis and Knuckle Pads (PLACK) Syndrome: An Updated Review of Cases and Identification of a Recurrent CAST Variant in Two Patients, Pediatr. Dermatol., in press.","DOI":"10.1111\/pde.15987"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1111\/pde.15823","article-title":"PLACK Syndrome in Two Unrelated Indian Children Caused by Novel Pathogenic Variants in the CAST Gene","volume":"42","author":"Srinivas","year":"2025","journal-title":"Pediatr. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1111\/ijd.16760","article-title":"Novel nonsense CAST mutation in two siblings with PLACK syndrome","volume":"62","author":"Durmaz","year":"2023","journal-title":"Int. J. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1093\/ced\/llad185","article-title":"A patient with PLACK syndrome with a novel splicing mutation in CAST: The evidence for a loss-of-function mechanism through mis-splicing","volume":"48","author":"Mamivand","year":"2023","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1111\/pde.15671","article-title":"CASTing the net wider: A case report of PLACK syndrome associated with dilated cardiomyopathy","volume":"41","author":"Nguyen","year":"2024","journal-title":"Pediatr. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1093\/cvr\/cvs099","article-title":"The role of calpains in myocardial remodelling and heart failure","volume":"96","author":"Letavernier","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00395-019-0726-1","article-title":"Increased calpain-1 in mitochondria induces dilated heart failure in mice: Role of mitochondrial superoxide anion","volume":"114","author":"Cao","year":"2019","journal-title":"Basic Res. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1038\/s41401-022-00965-9","article-title":"Sustained over-expression of calpain-2 induces age-dependent dilated cardiomyopathy in mice through aberrant autophagy","volume":"43","author":"Ji","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1161\/01.RES.0000261938.28365.11","article-title":"Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis","volume":"100","author":"Galvez","year":"2007","journal-title":"Circ. Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/11\/1292\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:37:31Z","timestamp":1761874651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/11\/1292"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,30]]},"references-count":12,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["genes16111292"],"URL":"https:\/\/doi.org\/10.3390\/genes16111292","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,30]]}}}