Steven Lipshultz.

Steven E. Lipshultz, MD, is senior author and principal investigator on a study that seeks to understand the genetic causes of pediatric cardiomyopathy.

Study Maps Genetic Causes of Pediatric Cardiomyopathy

Published March 28, 2022

story by dirk hoffman

A study led by Jacobs School of Medicine and Biomedical Sciences researchers sheds light on understanding the genetic causes of pediatric cardiomyopathy.

“This 10-year study is the tip of the iceberg in terms of understanding the genetic causes of primary cardiomyopathies presenting during childhood. ”
A. Conger Goodyear Professor and Chair of pediatrics, and senior author and principal investigator on the study

Published Feb. 3 in the American Journal of Human Genetics, the paper is titled “The Genetic Architecture of Pediatric Cardiomyopathy.”

It is the result of a National Institutes of Health-funded study begun in 2012 and led by Steven E. Lipshultz, MD, the study’s senior author and principal investigator and A. Conger Goodyear Professor and Chair of pediatrics.

“This 10-year study is the tip of the iceberg in terms of understanding the genetic causes of primary cardiomyopathies presenting during childhood,” Lipshultz says.

“This research by Dr. Lipshultz into the genetic causes of pediatric cardiomyopathy is truly groundbreaking,” says Allison Brashear, MD, UB’s vice president for health sciences and dean of the Jacobs School. “As principal investigator on this NIH-funded study, he is leading an international team of researchers whose work is at the forefront of aiding the development of novel therapies.”

14 Centers and 528 Children Involved in NHLBI Study

Cardiomyopathies are heart muscle disorders in which the heart muscle is structurally and functionally abnormal.

“Because more than 50 percent of children presenting with symptomatic cardiomyopathy, such as heart failure, fail medical management within two years after being diagnosed, resulting in a heart transplant or dying a cardiac death, and since cardiomyopathy is the leading cause for pediatric heart transplantation from 2-18 years of age, there is a critical need to determine the genetic causes of pediatric cardiomyopathies to tailor therapies and counsel accurately,” Lipshultz says.

“To understand the genetic contributions to primary pediatric cardiomyopathies, we performed gene exome sequencing in a large cohort of 528 children from 14 centers around the U.S. and Canada with cardiomyopathy,” Lipshultz says of the study funded by the National Heart, Lung and Blood Institute (NHLBI).

Lipshultz is an international leader whose research has led to major evidence-based improvements in the treatment of patients with pediatric cardiomyopathy and related diseases.

In addition to his role with the Jacobs School, Lipshultz serves as pediatric chief-of-service at Kaleida Health, medical director of pediatric services business development at Oishei Children’s Hospital, and president of UBMD Pediatrics.

First author on the paper is Stephanie M. Ware, MD, PhD, of the Indiana University School of Medicine, who also served as the lead genetics investigator.

Stimulating Further Novel Gene Discovery

Lipshultz says researchers found that 32 percent of children with cardiomyopathy had at least one genetic cause identified.

For 56 percent of these affected children, the genetic variants were known to be rare and damaging gene mutations, he notes.

“These rare and damaging gene mutations were significantly more common in children with cardiomyopathy than in children without cardiomyopathy,” Lipshultz says. “Many different gene mutations can result in cardiomyopathy. The gene mutations found in children with cardiomyopathy, although having some overlap with the gene mutations found in adults with cardiomyopathy, often were quite different and at times unique.”

Cardiomyopathy is rare in children compared with adults, occurring in 1 in 100,000, compared with 1 in 500.

Lipshultz says the results of the study should stimulate further novel gene discovery since there is “room for improvement.”

“For example, 36 percent of all patients in this study presented with primary cardiomyopathy during infancy (1 year of age or younger). Yet, a genetic diagnosis of cardiomyopathies being diagnosed during infancy was found in nearly 20 percent.

“In contrast, for children newly diagnosed with primary cardiomyopathies beyond infancy, 40 percent had a genetic mutation diagnosis,” Lipshultz says. “This suggests that there are likely many rare damaging or, at this time, novel unknown or undetected genetic mutations causing heart damage that results in infants presenting with primary cardiomyopathy that should be considered.”

Genetic Testing Seen to Have Clinical Value

Lipshultz says study researchers further found that for pediatric patients with primary cardiomyopathy the patient’s ancestry matters.

“Although there are some shared genetic causes of primary cardiomyopathy in children across ancestries, some common causal gene mutations may be ancestry specific,” he says.

“One example is the damaging gene mutation MYBPC3, which is a relatively common cause of primary cardiomyopathy in children of European ancestry, was absent among individuals of African American ancestry; that difference was statistically significant.”

Lipshultz says the work supports the use of genetic testing of all children with primary cardiomyopathy and suggests this will have clinical value.

“Such genetic screening may result in financial and emotional cost savings,” he says. “For example, based on the results of this study, now only asymptomatic family members of a child with primary cardiomyopathy with the same familial cardiomyopathy gene mutation may need to receive expensive serial cardiac surveillance studies to look for the development of cardiomyopathy instead of all first-degree asymptomatic family members who do not carry this cardiomyopathy gene mutation.”

Multiple Institutions Part of Genes Study

Lipshultz and his team, including senior research support specialists Miriam Mestre and Danielle Dauphin Megie and senior research coordinator Yvette Veira at the Jacobs School and its Child Health Research Institute, have led this study overall as the administrative coordinating center and principal investigator of this NHLBI “Pediatric Cardiomyopathy Genes” study.

Members of the NHLBI Pediatric Cardiomyopathy Genes Study where authors of this publication are at include:

  • Albert Einstein College of Medicine and Children’s Hospital at Montefiore
  • Ann & Robert H. Lurie Children’s Hospital of Chicago
  • Boston Children’s Hospital and Harvard Medical School
  • Children’s Hospital Colorado
  • Children’s Hospital Los Angeles
  • Children’s Hospital of Philadelphia
  • Cincinnati Children’s Hospital Medical Center
  • Columbia University Irving Medical Center
  • Indiana University School of Medicine
  • Jacobs School of Medicine and Biomedical Sciences
  • Monroe Carell Jr. Children’s Hospital at Vanderbilt
  • New England Research Institutes
  • Oishei Children’s Hospital
  • University of Miami Miller School of Medicine
  • University of Southern California Keck School of Medicine
  • University of Tabuk
  • University of Tennessee Heath Science Center and Le Bonheur Children’s Hospital, Memphis, Tennessee
  • University of Utah
  • Washington University, St Louis