{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:03:40Z","timestamp":1789376620429,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"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: Infantile dilated cardiomyopathy (DCM) is uncommon but carries substantial mortality, particularly when accompanied by neurological, ocular, or metabolic abnormalities. Long\u2013Olsen\u2013Distelmaier syndrome is a rare mTORopathy caused by heterozygous gain-of-function variants in RRAGC and may include cortical malformations, congenital cataracts, mineral disturbances, and early-onset DCM. Case Summary: We describe a term male infant born to consanguineous parents with hypocalcemia and hyperphosphatemia, bilateral frontoparietal polymicrogyria, bilateral congenital lamellar cataracts, small patent ductus arteriosus and ventricular septal defect, and initially preserved biventricular function. At 53 days of age, he developed cardiogenic shock, severe lactic acidosis, and hyperkalemia during a rhinovirus\/enterovirus-positive respiratory illness. Echocardiography showed severe DCM with marked left ventricular dilatation and an ejection fraction of 27%. Despite multi-agent inotropic support, ventricular function did not recover, and he died at approximately two months. Accordingly, the contemporaneous clinical WES record documented a heterozygous RRAGC c.343T&gt;C, p.(Trp115Arg) variant, reported by the diagnostic laboratory as likely pathogenic. The variant was subsequently standardized in this manuscript as NM_022157.4:c.343T&gt;C, and an independent manuscript-level ACMG\/AMP reassessment was concordant. Conclusions: Because p.(Trp115Arg) was previously reported, the principal contribution is detailed documentation of rapid progression from preserved neonatal ventricular function to fatal infantile DCM, while extending the clinical and geographic spectrum of RRAGC-related Long\u2013Olsen\u2013Distelmaier syndrome. Respiratory viral detection should be interpreted cautiously because myocarditis was not established; early exome-based testing should be considered in infants with cardiomyopathy and multisystem abnormalities.<\/jats:p>","DOI":"10.3390\/genes17091106","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:10:23Z","timestamp":1789373423000},"page":"1106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rapidly Progressive Infantile Dilated Cardiomyopathy in Long\u2013Olsen\u2013Distelmaier Syndrome Associated with RRAGC NM_022157.4:c.343T&gt;C, p.(Trp115Arg): A Case Report"],"prefix":"10.3390","volume":"17","author":[{"given":"Mohammed Shahab","family":"Uddin","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Ministry of National Guard Health Affairs, Dammam 31412, Saudi Arabia"},{"name":"King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia"},{"name":"Faculty of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fayez","family":"AlShammari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ministry of National Guard Health Affairs, Dammam 31412, Saudi Arabia"},{"name":"King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia"},{"name":"Faculty of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr","family":"Esmail","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ministry of National Guard Health Affairs, Dammam 31412, Saudi Arabia"},{"name":"King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia"},{"name":"Faculty of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6784-8067","authenticated-orcid":false,"given":"Khaled","family":"Shafeen","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahad","family":"Alnajim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ministry of National Guard Health Affairs, Dammam 31412, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danah","family":"AlMohaimeed","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ministry of National Guard Health Affairs, Dammam 31412, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nujud","family":"Alessa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ministry of National Guard Health Affairs, Dammam 31412, Saudi 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Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6952-8654","authenticated-orcid":false,"given":"Maryam","family":"AlQannas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ministry of National Guard Health Affairs, Dammam 31412, Saudi Arabia"},{"name":"King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia"},{"name":"Faculty of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1001\/jama.296.15.1867","article-title":"Incidence, Causes, and Outcomes of Dilated Cardiomyopathy in Children","volume":"296","author":"Towbin","year":"2006","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E9","DOI":"10.1161\/CIR.0000000000000682","article-title":"Cardiomyopathy in Children: Classification and Diagnosis: A Scientific Statement From the American Heart Association","volume":"140","author":"Lipshultz","year":"2019","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2671","DOI":"10.1161\/CIRCULATIONAHA.106.635128","article-title":"National Australian Childhood Cardiomyopathy Study. Clinical features and outcomes of childhood dilated cardiomyopathy: Results from a national population-based study","volume":"114","author":"Daubeney","year":"2006","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2039","DOI":"10.1161\/CIRCULATIONAHA.113.002767","article-title":"Long-term outcomes of dilated cardiomyopathy diagnosed during childhood: Results from a national population-based study of childhood cardiomyopathy","volume":"128","author":"Alexander","year":"2013","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1161\/CIRCULATIONAHA.110.973826","article-title":"Competing risks for death and cardiac transplantation in children with dilated cardiomyopathy: Results from the pediatric cardiomyopathy registry","volume":"124","author":"Alvarez","year":"2011","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.4330\/wjc.v6.i11.1156","article-title":"Importance of genetic evaluation and testing in pediatric cardiomyopathy","volume":"6","author":"Tariq","year":"2014","journal-title":"World J. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1016\/j.jacc.2018.08.2171","article-title":"Genetic Basis of Severe Childhood-Onset Cardiomyopathies","volume":"72","author":"Vasilescu","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"E003686","DOI":"10.1161\/CIRCGEN.121.003686","article-title":"Genetic Basis of Childhood Cardiomyopathy","volume":"15","author":"Bagnall","year":"2022","journal-title":"Circ. Genom. Precis Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1097\/MOP.0000000000000533","article-title":"Genetics of paediatric cardiomyopathies","volume":"29","author":"Ware","year":"2017","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1016\/j.jacc.2018.09.009","article-title":"Cardiomyopathy in Children: Identifying the Causes","volume":"72","author":"Ware","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1161\/CIRCRESAHA.121.318157","article-title":"The Complex and Diverse Genetic Architecture of Dilated Cardiomyopathy","volume":"128","author":"Hershberger","year":"2021","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1161\/CIRCULATIONAHA.120.053033","article-title":"Evidence-Based Assessment of Genes in Dilated Cardiomyopathy","volume":"144","author":"Jordan","year":"2021","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100200","DOI":"10.1016\/j.shj.2023.100200","article-title":"The Genetic Evaluation of Dilated Cardiomyopathy","volume":"7","author":"Bui","year":"2023","journal-title":"Struct. Heart"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e017731","DOI":"10.1161\/JAHA.120.017731","article-title":"Genetic causes of cardiomyopathy in children: First results from the pediatric cardiomyopathy genes study","volume":"10","author":"Ware","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s13073-024-01390-9","article-title":"Cardiomyopathies in 100,000 genomes project: Interval evaluation improves diagnostic yield and informs strategies for ongoing gene discovery","volume":"16","author":"Josephs","year":"2024","journal-title":"Genome Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"i1","DOI":"10.1093\/eurheartjsupp\/suae002","article-title":"The new 2023 ESC guidelines for the management of cardiomyopathies: A guiding path for cardiologist decisions","volume":"26","author":"Grasso","year":"2024","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1093\/eurheartj\/ehad194","article-title":"2023 ESC Guidelines for the management of cardiomyopathies: Developed by the task force on the management of cardiomyopathies of the European Society of Cardiology (ESC)","volume":"44","author":"Arbelo","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1055\/s-0044-1779469","article-title":"Exploring Health Care Disparities in Genetic Testing and Research for Hereditary Cardiomyopathy: Current State and Future Perspectives","volume":"11","author":"Huang","year":"2024","journal-title":"Glob. Med. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5812","DOI":"10.1038\/s41467-024-50034-4","article-title":"Ragopathies and the rising influence of RagGTPases on human diseases","volume":"15","author":"Sambri","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s00439-016-1685-3","article-title":"De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy","volume":"135","author":"Long","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kim, M., Lu, L., Dvornikov, A.V., Ma, X., Ding, Y., Zhu, P., Olson, T.M., Lin, X., and Xu, X. (2021). Tfeb overexpression, not mtor inhibition, ameliorates ragcs75y cardiomyopathy. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115494"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"H1187","DOI":"10.1152\/ajpheart.00705.2023","article-title":"RRAGD variants cause cardiac dysfunction in a zebrafish model","volume":"327","author":"Adella","year":"2024","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100838","DOI":"10.1016\/j.gim.2023.100838","article-title":"De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood","volume":"25","author":"Reijnders","year":"2023","journal-title":"Genet Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/j.ajhg.2022.10.013","article-title":"Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3\/BP4 criteria","volume":"109","author":"Pejaver","year":"2022","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13073-019-0690-2","article-title":"Recommendations for application of the functional evidence PS3\/BS3 criterion using the ACMG\/AMP sequence variant interpretation framework","volume":"12","author":"Brnich","year":"2020","journal-title":"Genome Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1002\/humu.24088","article-title":"Fitting a naturally scaled point system to the ACMG\/AMP variant classification guidelines","volume":"41","author":"Tavtigian","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Long, P.A., Evans, J.M., and Olson, T.M. (2017). Diagnostic yield of whole exome sequencing in pediatric dilated cardiomyopathy. J. Cardiovasc Dev. Dis., 4.","DOI":"10.3390\/jcdd4030011"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/j.jacc.2022.07.023","article-title":"Natural history of MYH7-related dilated cardiomyopathy","volume":"80","author":"Ochoa","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1016\/j.jacc.2016.09.927","article-title":"Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies","volume":"68","author":"Cuenca","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1016\/j.jacc.2016.08.079","article-title":"Clinical and mechanistic insights into the genetics of cardiomyopathy","volume":"68","author":"Burke","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1161\/CIRCULATIONAHA.119.037661","article-title":"Reevaluating the genetic contribution of monogenic dilated cardiomyopathy","volume":"141","author":"Mazzarotto","year":"2020","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1038\/s41436-021-01255-1","article-title":"Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy","volume":"23","author":"Stroeks","year":"2021","journal-title":"Genet Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e000067","DOI":"10.1161\/HCG.0000000000000067","article-title":"Genetic testing for inherited cardiovascular diseases: A scientific statement from the American Heart Association","volume":"13","author":"Musunuru","year":"2020","journal-title":"Circ. Genom. Precis Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2885","DOI":"10.1681\/ASN.2021030333","article-title":"mTOR-activating mutations in RRAGD are causative for kidney tubulopathy and cardiomyopathy","volume":"32","author":"Schlingmann","year":"2021","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1038\/s41467-023-38428-2","article-title":"RagD auto-activating mutations impair MiT\/TFE activity in kidney tubulopathy and cardiomyopathy syndrome","volume":"14","author":"Sambri","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1159\/000539889","article-title":"RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD): A review on the clinical manifestations and therapeutic options","volume":"49","author":"Trepiccione","year":"2024","journal-title":"Kidney Blood Press Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.cell.2025.01.011","article-title":"Advances in the study and treatment of genetic cardiomyopathies","volume":"188","author":"Parikh","year":"2025","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e72070","DOI":"10.1096\/fj.202501099RR","article-title":"RRAGD p. (Ser76Leu) variant causes dysregulated expression of muscle development and cytoskeleton genes in cardiomyocytes","volume":"40","author":"Adella","year":"2026","journal-title":"FASEB J."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1106\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:17:41Z","timestamp":1789373861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,12]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091106"],"URL":"https:\/\/doi.org\/10.3390\/genes17091106","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,12]]}}}