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A Rare Cause of Syncope: Naxos Disease Caused by Novel Homozygous Deletion in the JUP Gene

2021; Lippincott Williams & Wilkins; Volume: 14; Issue: 10 Linguagem: Inglês

10.1161/circimaging.121.013059

1942-0080

Mehmet Rasih Sonsöz, Ezgi Gökpınar İli, Alper Gezdirici, Çağdaş Topel, Gökhan Kahveci, Helen Bornaun,

Cardiomyopathy and Myosin Studies

HomeCirculation: Cardiovascular ImagingVol. 14, No. 10A Rare Cause of Syncope: Naxos Disease Caused by Novel Homozygous Deletion in the JUP Gene Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessCase ReportPDF/EPUBA Rare Cause of Syncope: Naxos Disease Caused by Novel Homozygous Deletion in the JUP Gene Mehmet Rasih Sonsöz, MD, Ezgi Gökpinar İli, MD, Alper Gezdirici, MD, Cagdas Topel, MD, Gökhan Kahveci, MD and Helen Bornaun, MD Mehmet Rasih SonsözMehmet Rasih Sonsöz Correspondence to: Mehmet Rasih Sonsöz, MD, Department of Cardiology, Basaksehir Cam & Sakura City Hospital, Basaksehir Olimpiyat Blvd, Istanbul 34480, Turkey. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1535-5168 Department of Cardiology (M.R.S., G.K.), Basaksehir Cam & Sakura City Hospital, Istanbul, Turkey. , Ezgi Gökpinar İliEzgi Gökpinar İli https://orcid.org/0000-0002-2234-3536 Department of Medical Genetics (E.G.İ., A.G.), Basaksehir Cam & Sakura City Hospital, Istanbul, Turkey. , Alper GezdiriciAlper Gezdirici Department of Medical Genetics (E.G.İ., A.G.), Basaksehir Cam & Sakura City Hospital, Istanbul, Turkey. , Cagdas TopelCagdas Topel Department of Radiology, Mehmet Akif Ersoy Cardiothoracic and Vascular Surgery Research Hospital, Istanbul, Turkey (C.T.). , Gökhan KahveciGökhan Kahveci Department of Cardiology (M.R.S., G.K.), Basaksehir Cam & Sakura City Hospital, Istanbul, Turkey. and Helen BornaunHelen Bornaun https://orcid.org/0000-0001-9431-2256 Department of Pediatric Cardiology, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, Turkey (H.B.). Originally published30 Sep 2021https://doi.org/10.1161/CIRCIMAGING.121.013059Circulation: Cardiovascular Imaging. 2021;14:e013059Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 30, 2021: Ahead of Print A 19-year-old woman born to third-degree consanguineous parents was admitted to our cardiology department with a history of syncope during exertion. Her medical history was unremarkable.Examination revealed overall good health, woolly hair, sparse eyebrows, and tachycardia (110 beats/minute). An ECG showed extreme right-axis deviation, incomplete right bundle brunch block, and precordial negative T waves (Figure 1A and 1B).Download figureDownload PowerPointFigure 1. Characteristics of the Naxos disease. A, Patient has woolly hair. B, ECG shows extreme right axis, incomplete right bundle brunch block, and precordial negative T waves. C, Transthoracic echocardiogram in parasternal short-axis view shows dilatation in both ventricles. Note the hyperechogenic layer in the left ventricular (LV) myocardium. D, Modified apical 4-chamber view shows marked dilatation in the right ventricle (RV) and aneurysm in the free wall. E, Cardiac magnetic resonance in short-axis image shows subepicardial fatty replacement of the LV wall. F, Late gadolinium–enhanced image of RV inflow and outflow tract shows fibrosis in the RV wall.An echocardiogram disclosed dilatation in all chambers, severely reduced biventricular systolic function, global left ventricular hypokinesis, and hypokinesis of the right ventricular free wall (Figure 1C and 1D; Movies I and II in the Data Supplement). Cardiac magnetic resonance imaging confirmed dilatation in all chambers, severe left ventricular hypokinesia (ejection fraction, 21%), and severe dyskinesia on the anterior, apical, and inferior walls of the right ventricle (Movies III and IV in the Data Supplement). Late gadolinium–enhanced images revealed subepicardial fibrofatty replacement in the left ventricular wall and an enhanced right ventricular wall (Figure 1E and 1F). To avoid the risk of sudden cardiac death, a cardioverter defibrillator was implanted. One month later, the device administered appropriate shocks for ventricular fibrillation. Pharmacotherapy with angiotensin-converting enzyme inhibitors and β-blockers stabilized her.With informed consent, high-throughput sequencing was performed for 172 cardiovascular disease–related genes, including JUP, DSP, and DSC2. A previously unreported homozygous c.901_903delGAG (p.Glu301del) mutation was found in the JUP gene. Sanger sequencing found the mutation to be heterozygous in her healthy father and homozygous in her 15-year-old brother who did not have the cardiac phenotype (Figure 2). He had woolly hair, sparse woolly eyebrows, dry skin, and nail dysplasia in the left fifth toe. His echocardiogram and cardiac magnetic resonance imaging were normal. Neither of the siblings had palmoplantar keratoderma. Their mother and maternal aunt, whose parents were also consanguineous, had palpitations and woolly hair but refused further evaluation (Figure 3).Download figureDownload PowerPointFigure 2. Sanger sequencing chromatograms. Homozygous c.901_903delGAG JUP mutation in the proband (V.1-top), and her brother (V.3-middle); heterozygous c.901_903delGAG JUP mutation in the father (IV.5; bottom) were found.Download figureDownload PowerPointFigure 3. Pedigree of the family. The proband (V.1) and proband's brother (V.3) are homozygous for c.901_903delGAG JUP mutation while their father (IV.5) is heterozygous. The proband's mother (IV.6) has woolly hair, her maternal aunt (IV.8) has woolly hair and palpitations, and her paternal uncle (IV.2) had woolly hair who died due to cardiac disease.This case illustrates the Naxos disease caused by a novel homozygous deletion in the JUP gene, which encodes plakoglobin—a submembranous cytoplasmic protein found in desmosomes.1Biallelic pathogenic variants of JUP cause autosomal recessive Naxos disease—a cardiocutaneous syndrome characterized by woolly hair, palmoplantar keratoses, arrhythmogenic right ventricular cardiomyopathy, and commonly, left ventricular involvement.2 Mutations in the plakoglobin protein disrupt the desmosomal cutaneous links with keratin. Defective cell adhesions caused by plakoglobin mutations also reduce connexin-43—a major gap junction protein. This in turn causes myocardial gap junction remodeling, contributing to the arrhythmogenic substrate of the Naxos disease.2 Our patient had biventricular systolic dysfunction, dilatation of all heart chambers, and a regional right ventricular aneurysm, all consistent with arrhythmogenic right ventricular cardiomyopathy with left ventricular involvement. High-throughput sequencing revealed the homozygous c.901_903delGAG (p.Glu301del) mutation, and to our best knowledge, this mutation has not previously been reported.Our patient's brother was also homozygous for the mutation. Although he also had woolly hair, he lacked the cardiac phenotype. At the age of only 15 years, his cardiomyopathy might be forthcoming. Protonotarios et al3 conducted a genotype-phenotype correlation study of 78 participants from 12 families and suggested that arrhythmogenic right ventricular cardiomyopathy is fully penetrant by adolescence when JUP mutations are homozygous. Mean age at diagnosis was 36 (17) years; 1 patient lacked arrhythmogenic right ventricular cardiomyopathy upon initial evaluation at the age of 7 years but developed the cardiac phenotype at the age of 18 years. On the contrary, Cabral et al4 reported 3 unrelated patients and 2 siblings with 5′ region JUP mutations. All these patients, the oldest aged 14 years, had normal echocardiograms and electrocardiograms. Therefore, it is important to follow younger patients for cardiac manifestations. The lack of cardiac findings in the brother of our patient and in the patients studied by Cabral et al might be a result of the phenotypic variability of the disease. Long-term follow-up and further studies with larger patient groups are needed to confirm the phenotypic variability.This case report demonstrates the clinical manifestation of Naxos disease caused by the novel homozygous c.901_903delGAG (p.Glu301del) mutation in the JUP gene.AcknowledgmentsWe all provided care for the patient and reviewed the case. Dr Sonsöz produced the initial draft of this article. Drs İli and Gezdirici revised the initial draft. Drs Tobel, Kahveci, and Bornaun revised the final draft. All authors approved the final version. The authors certify that they have obtained all appropriate patient consent forms.Sources of FundingNone.DisclosuresNone.Supplemental MaterialsSupplemental Movies I–IVFootnotesThe Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.121.013059.For Sources of Funding and Disclosures, see page 1001.Correspondence to: Mehmet Rasih Sonsöz, MD, Department of Cardiology, Basaksehir Cam & Sakura City Hospital, Basaksehir Olimpiyat Blvd, Istanbul 34480, Turkey. Email [email protected]comReferences1. Mathur M, Goodwin L, Cowin P. Interactions of the cytoplasmic domain of the desmosomal cadherin Dsg1 with plakoglobin.J Biol Chem. 1994; 269:14075–14080.CrossrefMedlineGoogle Scholar2. Leopoulou M, Mattsson G, LeQuang JA, Pergolizzi JV, Varrassi G, Wallhagen M, Magnusson P. Naxos disease - a narrative review.Expert Rev Cardiovasc Ther. 2020; 18:801–808. doi: 10.1080/14779072.2020.1828064CrossrefMedlineGoogle Scholar3. Protonotarios N, Tsatsopoulou A, Anastasakis A, Sevdalis E, McKoy G, Stratos K, Gatzoulis K, Tentolouris K, Spiliopoulou C, Panagiotakos D, et al.. Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin.J Am Coll Cardiol. 2001; 38:1477–1484. doi: 10.1016/s0735-1097(01)01568-6CrossrefMedlineGoogle Scholar4. Cabral RM, Liu L, Hogan C, Dopping-Hepenstal PJ, Winik BC, Asial RA, Dobson R, Mein CA, Baselaga PA, Mellerio JE, et al.. Homozygous mutations in the 5' region of the JUP gene result in cutaneous disease but normal heart development in children.J Invest Dermatol. 2010; 130:1543–1550. doi: 10.1038/jid.2010.7CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails October 2021Vol 14, Issue 10 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCIMAGING.121.013059PMID: 34587761 Originally publishedSeptember 30, 2021 Keywordsmutationmagnetic resonance imaginggamma cateninechocardiographyNaxos diseasearrhythmogenic right ventricular dysplasiaPDF download Advertisement SubjectsCardiomyopathyEchocardiographyGeneticsHeart FailureMagnetic Resonance Imaging (MRI)