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Brief Report
January 13, 2021

Identification of Cardiac Fibrosis in Young Adults With a Homozygous Frameshift Variant in SERPINE1

Author Affiliations
  • 1Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 3Associate Editor, JAMA Cardiology
  • 4Department of Medicine and Cardiovascular Center, Medical College of Wisconsin, Milwaukee
  • 5Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 6Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 7Department of Radiology, Northwestern University, Chicago, Illinois
  • 8Indiana Hemophilia and Thrombosis Center, Indianapolis
JAMA Cardiol. Published online January 13, 2021. doi:10.1001/jamacardio.2020.6909
Key Points

Question  What is the genetic cause of cardiac fibrosis observed in young adults from 3 related Amish families?

Findings  In this study, cardiovascular phenotyping and genotyping of 17 participants (mean age, 24 years) was performed, including cardiovascular imaging, whole-exome sequencing, and examination of stem cell–derived cardiomyocytes. An autosomal recessive phenotype of cardiac fibrosis in individuals homozygous for a frameshift variant in SERPINE1, the gene that codes for plasminogen activator inhibitor-1 (PAI-1), was identified.

Meaning  In this study, genetic deficiency of PAI-1 was associated with early-onset cardiac fibrosis, suggesting an optimal range of PAI-1 is needed for cardiac homeostasis in humans.

Abstract

Importance  Cardiac fibrosis is exceedingly rare in young adults. Identification of genetic variants that cause early-onset cardiomyopathy may inform novel biological pathways. Experimental models and a single case report have linked genetic deficiency of plasminogen activator inhibitor-1 (PAI-1), a downstream target of cardiac transforming growth factor β, with cardiac fibrosis.

Objective  To perform detailed cardiovascular phenotyping and genotyping in young adults from an Amish family with a frameshift variant (c.699_700dupTA) in SERPINE1, the gene that codes for PAI-1.

Design, Setting, and Participants  This observational study included participants from 3 related nuclear families from an Amish community in the primary analysis and participants from the extended family in the secondary analysis. Participants were recruited from May 2015 to December 2016, and analysis took place from June 2015 to June 2020.

Main Outcomes and Measures  (1) Multimodality cardiovascular imaging (transthoracic echocardiography and cardiac magnetic resonance imaging), (2) whole-exome sequencing, and (3) induced pluripotent stem cell–derived cardiomyocytes.

Results  Among 17 participants included in the primary analysis, the mean (interquartile range) age was 23.7 (20.9-29.9) years and 9 individuals (52.9%) were confirmed to be homozygous for the SERPINE1 c.699_700dupTA variant. Late gadolinium enhancement was present in 6 of 9 homozygous participants (67%) with absolute PAI-1 deficiency vs 0 of 8 in the control group (P = .001). Late gadolinium enhancement patterns tended to be dense and linear, usually subepicardial but also midmyocardial and transmural with noncoronary distributions. Targeted whole-exome sequencing analysis identified that homozygosity for c.699_700dupTA SERPINE1 was the only shared pathogenic variant or variant of uncertain significance after examination of cardiomyopathy genes among those with late gadolinium enhancement. Induced pluripotent stem cell–derived cardiomyocytes from participants homozygous for the SERPINE1 c.699_700dupTA variant exhibited susceptibility to cardiomyocyte injury in response to angiotensin II (increased transforming growth factor β1 secretion and release of lactate dehydrogenase) compared with control induced pluripotent stem cell–derived cardiomyocytes. In a secondary analysis based on echocardiography in 155 individuals across 3 generations in the extended family, no difference in global longitudinal strain was observed in carriers for the SERPINE1 c.699_700dupTA variant compared with wild-type participants, supporting an autosomal recessive inheritance pattern.

Conclusions and Relevance  In this study, a highly penetrant, autosomal recessive, cardiac fibrosis phenotype among young adults with homozygous frameshift variant for SERPINE1 was identified, suggesting an optimal range of PAI-1 levels are needed for cardiac homeostasis.

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