"This gene, ISL1, plays a key role in regulating early cardiac development, so there is a compelling biological reason for investigating it as a genetic risk factor for CHD," said study leader Peter J. Gruber, M.D., Ph.D., a paediatric cardiothoracic surgeon at The Children's Hospital of Philadelphia. Gruber collaborated with his brother, Stephen B. Gruber, M.D., Ph.D., a geneticist at the University of Michigan Medical School.
CHD affects at least one in 100 live births. It ranges widely in severity, from tiny holes between heart chambers that close naturally, to life-threatening abnormal structures such as hypoplastic left-heart syndrome that require a series of complicated surgeries. CHD can affect a variety of different structures in the heart, but the researchers decided to focus on the earliest period of the organ's development. "Instead of assuming separate genes would govern each specific defect, we formed the hypothesis that a common gene variant operates early in the biological pathway of heart formation, thus affecting multiple subtypes of congenital heart disease," said Peter Gruber.
In Peter Gruber's previous research in human cardiac stem cells, he found that a gene called ISL1 was crucial in regulating the development of early cardiac progenitor cells. Suspecting that ISL1 was a candidate gene involved in human CHD, he designed a study in collaboration with two genetics teams. Gruber collected DNA samples from 300 children with CHD and from 2,200 healthy children. Another team did the initial genotyping—looking for gene variants (mutations) in the DNA of genes in or near the ISL1 gene. When combined with results from the genetics team, the researchers found eight of these alternative spellings in DNA bases raised the risk of CHD.
Stephen Gruber and colleagues performed second-stage studies on the initial data, analyzing specific DNA sequences and performing "fine mapping" research—focusing in sharper detail on the gene regions of interest. "It was challenging to analyze how genetic variation contributes to complex congenital heart disease," Stephen Gruber said. "We combined expertise in cardiology, epidemiology, genetics and developmental biology that led to an interesting discovery."
MEDICA.de; Source:The Children's Hospital of Philadelphia