Dr Paul van der Zwaag MD, PhD

MSc & MD: 2008, University of Groningen, the Netherlands
PhD: 2012, University of Groningen. Thesis entitled Genetic and clinical characterisation of arrhythmogenic cardiomyopathy

Clinical geneticist registered in 2017

Research focus: Genotypic and phenotypic variability of inherited cardiomyopathies, especially caused by the (phospholamban) PLN p.Arg14del founder mutation

Keywords: Cardiomyopathy, modifiers, gene identification, phospholamban

Publications PubMed ; GoogleScholar

E-mail

Research interests

My research work focuses on the genetic and clinical heterogeneity of inherited cardiomyopathies. Cardiomyopathies are diseases of the heart muscle and they are characterized by a large clinical variability and age-dependent penetrance. The monogenic background of cardiomyopathies is increasingly elucidated since the identification of the first genes in the early 1990’s. During my PhD, I identified the phospholamban (PLN) p.Arg14del founder mutation as the most common cause of dilated and arrhythmogenic cardiomyopathies in the Netherlands. Currently, over 1,000 mutation carriers have been identified, a spectacular number for a single mutation in the field of cardiogenetics.

The PLN p.Arg14del mutation is related to a high rate of sudden cardiac death and heart failure and an implantable cardioverter defibrillator (ICD) is advised early. On the other hand, 30% of mutation carriers are asymptomatic at age 60. This large phenotypic spectrum is typical of cardiomyopathies, but not well understood. Additional genetic factors (modifiers) and lifestyle factors are suspected to influence the individual phenotype.

With the identification of protective genetic and lifestyle factors, unnecessary and expensive evaluations and treatments such as ICD-implantations could be avoided. I am convinced that studying asymptomatic PLN p.Arg14del carriers from the general population, enrolled in Lifelines, as well as mutation carriers identified after a clinical diagnosis or cascade family screening will identify these protective factors.

These results will be the foundation on which we can build personalised medical care for PLN p.Arg14del carriers. Essential insights into the pathophysiology of cardiomyopathy caused by PLN p.Arg14del will be obtained and these could be a starting point for novel pharmaceutical and lifestyle interventions. If successful, this strategy can be applied to other founder mutations causing cardiac or other diseases. This comprehensive collection of ACM genetic data represents a valuable source of information on the spectrum of ACM-associated genes and aims to facilitate the interpretation of genetic data and genetic counselling.

See also www.arvcdatabase.info and Cardiogenetics research

Selected papers

• Te Rijdt WP, van der Klooster ZJ, Hoorntje ET, Jongbloed JDH, van der Zwaag PA, Asselbergs FW, Dooijes D, de Boer RA, van Tintelen JP, van den Berg MP, Vink A, Suurmeijer AJH. Phospholamban immunostaining is a highly sensitive and specific method for diagnosing phospholamban p.Arg14del cardiomyopathy. Cardiovasc Pathol. 2017;30:23-26 https://www.ncbi.nlm.nih.gov/pubmed/28759816
• Almomani R, Verhagen JM, Herkert JC, Brosens E, van Spaendonck-Zwarts KY, Asimaki A, van der Zwaag PA, Frohn-Mulder IM, Bertoli-Avella AM, Boven LG, van Slegtenhorst MA, van der Smagt JJ, van IJcken WF, Timmer B, van Stuijvenberg M, Verdijk RM, Saffitz JE, du Plessis FA, Michels M, Hofstra RM, Sinke RJ, van Tintelen JP, Wessels MW, Jongbloed JD, van de Laar IM. Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy. J Am Coll Cardiol. 2016;67:515-25 https://www.ncbi.nlm.nih.gov/pubmed/26846950
• Lazzarini E, Jongbloed JD, Pilichou K, Thiene G, Basso C, Bikker H, Charbon B, Swertz M, van Tintelen JP, van der Zwaag PA. The ARVD/C genetic variants database: 2014 update. Hum Mutat. 2015;36:403-10 https://www.ncbi.nlm.nih.gov/pubmed/25676813
• van Rijsingen IA, van der Zwaag PA, Groeneweg JA, Nannenberg EA, Jongbloed JD, Zwinderman AH, Pinto YM, Dit Deprez RH, Post JG, Tan HL, de Boer RA, Hauer RN, Christiaans I, van den Berg MP, van Tintelen JP, Wilde AA. Outcome in phospholamban R14del carriers: results of a large multicentre cohort study. Circ Cardiovasc Genet. 2014;7:455-65 https://www.ncbi.nlm.nih.gov/pubmed/24909667
• Van der Zwaag PA, van Rijsingen IA, Asimaki A, Jongbloed JD, van Veldhuisen DJ, Wiesfeld AC, Cox MG, van Lochem LT, de Boer RA, Hofstra RM, Christiaans I, van Spaendonck-Zwarts KY, Lekanne dit Deprez RH, Judge DP, Calkins H, Suurmeijer AJ, Hauer RN, Saffitz JE, Wilde AA, van den Berg MP, van Tintelen JP. Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail. 2012;14:1199-207 https://www.ncbi.nlm.nih.gov/pubmed/22820313
• Cox MG, van der Zwaag PA, van der Werf C, van der Smagt JJ, Noorman M, Bhuiyan ZA, Wiesfeld AC, Volders PG, van Langen IM, Atsma DE, Dooijes D, van den Wijngaard A, Houweling AC, Jongbloed JD, Jordaens L, Cramer MJ, Doevendans PA, de Bakker JM, Wilde AA, van Tintelen JP, Hauer RN. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/ cardiomyopathy genotype-phenotype follow-up study. Circulation. 2011;123:2690-700 https://www.ncbi.nlm.nih.gov/pubmed/21606396
• Van der Zwaag PA, Jongbloed JD, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H, Hofstra RM, van Tintelen JP. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat. 2009;30:1278-83 https://www.ncbi.nlm.nih.gov/pubmed/19569224