The findings are the culmination of an effort to find the genetic determinants of structural heart disease in the “Bench to Bassinet” program, launched six years ago by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health,
led at Pitt by principal investigator Cecilia Lo, Ph.D., professor and
chair of the Department of Developmental Biology, Pitt School of
Medicine.
“This project has given us new insights into the biological
pathways involved in development of the heart,” Dr. Lo said. “The genes
and pathways identified in our study will have clinical importance for
interrogating the genetic causes of congenital heart disease in
patients.”
For the study, Dr. Lo’s team mated mice exposed to chemicals that
could create random genetic mutations, resulting in 87,355 pregnancies.
They scanned each fetus using noninvasive ultrasound and recovered over
3,000 independent cases of congenital heart defects, all incompatible
with life. They sequenced the genes of mutant animals and compared them
to those of unaffected offspring to identify 91 recessive mutations in
61 genes.
“We were surprised to learn many of these genes were related to the
cilia, or cilia-transduced cell signaling,” Dr. Lo said. “These
findings suggest cilia play a central role in the regulation of heart
development, including patterning left-right asymmetry in the
cardiovascular system critical for efficient oxygenation of blood.”
She added that pathways recovered in the mouse study show overlap
with those associated with de novo, or spontaneous, mutations identified
in congenital heart disease patients. Co-investigators of the project
include other researchers from the University of Pittsburgh; the
University of Massachusetts Medical School; the Jackson Laboratory; and
Children’s National Medical Center.
The project was funded NHLBI grants HL098180 and HL098188; National
Institute of Mental Health grant MH094564; National Human Genome
Research Institute grant HG000330; and the University of Pittsburgh
School of Medicine.