Nearly 10 percent of sudden infant death syndrome (SIDS) victims have mutations or variations in genes associated with potentially lethal heart rhythms (arrhythmias), according to two newly published studies involving Vanderbilt researchers.
The findings indicate that arrhythmia-susceptibility genes represent important genetic contributors to SIDS, said Alfred L. George Jr., M.D., senior author on one of the studies. The studies appear in the early online edition of the journal Circulation.
According to the Centers for Disease Control and Prevention, approximately 2,200 deaths each year in the United States are attributed to SIDS, making it the third leading cause of death among all infants, but the leading cause of mortality in infants age 1 month to 1 year. Several behavioral and environmental factors - such as prone (stomach) sleeping position and exposure to cigarette smoke - are known risk factors. Campaigns to educate parents about these potential dangers may explain the decrease in SIDS since the early 1990s.
However, SIDS continues to be a leading cause of infant mortality in developed countries, and the underlying basis of the condition remains unclear. A popular theory proposes that SIDS occurs because of a combination of risks including abnormal physiological state, environmental factors and developmental vulnerabilities. Genetic factors have also been proposed to be important.
"SIDS is not one disease," said George, the Grant W. Liddle Professor of Medicine and director of the Division of Genetic Medicine. "Multiple conditions can increase the risk of sudden death in an infant. Some have been identified, but many have not."
Anecdotal evidence previously suggested that some SIDS victims carry mutations in genes associated with conditions such as the long QT syndrome (LQTS) that predispose individuals to life-threatening arrhythmias and sudden death. But the proportion of SIDS cases that carry such mutations was not clear.
George's collaborators, Peter Schwartz, M.D., in Italy, and Torleiv Rognum, M.D., Ph.D., in Norway, led the efforts to screen seven arrhythmia-associated genes in 201 SIDS cases from Norway - the largest ever genetic survey of a SIDS cohort. The results showed that 9.5 percent of SIDS victims harbored mutations in genes associated with inherited forms of cardiac arrhythmia, such as LQTS.
The researchers identified mutations and variations in several genes, including the gene that encodes the cardiac sodium channel - a protein that regulates the electrical properties of heart cells. George's lab then performed studies to understand the physiological consequences of mutations in the cardiac sodium channel gene, called SCN5A, which has previously been associated with LQTS and several other conditions that cause unstable heart rhythms and sudden death.
"We observed a pattern of SCN5A dysfunction that is reminiscent of what's been observed in LQTS. That gives us confidence that the mutations observed in SIDS victims are not benign genetic variants - but rather could increase the risk of potentially lethal arrhythmias," he said. The researchers have similar evidence, to be published separately, demonstrating that mutations in heart potassium channels are also contributing factors in SIDS.
The findings also suggest that there may be strategies to identify whether infants are a carrier of one of these mutations before the tragic event of their death, George said.
"We are not recommending that a population-wide genetic screening be done, but there may be simpler, cost-effective measures that should be investigated further, perhaps performing ECG (electrocardiogram) screening of infants, although this idea is controversial."
Inherited arrhythmias are manageable conditions that can be treated with medications or implantable devices, George said.
"There's potentially an infant death every other day in the U.S. due to this problem (arrhythmias)," he said. "Exactly how best to identify this risk and prevent arrhythmia-related death during infancy needs to be determined."
George and colleagues are continuing to analyze other arrhythmia-linked genes identified in the Norwegian SIDS cohort. They are also planning studies to determine if the parents of SIDS victims carry the same mutations.
"This is critical because knowing how often mutations are transmitted from parents rather than occur spontaneously, will help establish the risk to siblings of SIDS victims," he said.
George hopes that eventually, all of the causes of SIDS - environmental, developmental and genetic factors - will be identified.
"Many years from now, 'SIDS' may not be a term we use anymore because we will understand all causes of sudden infant death," George said. "But right now, SIDS is a bona fide disease category, and we should strive to understand it fully."
The findings indicate that arrhythmia-susceptibility genes represent important genetic contributors to SIDS, said Alfred L. George Jr., M.D., senior author on one of the studies. The studies appear in the early online edition of the journal Circulation.
According to the Centers for Disease Control and Prevention, approximately 2,200 deaths each year in the United States are attributed to SIDS, making it the third leading cause of death among all infants, but the leading cause of mortality in infants age 1 month to 1 year. Several behavioral and environmental factors - such as prone (stomach) sleeping position and exposure to cigarette smoke - are known risk factors. Campaigns to educate parents about these potential dangers may explain the decrease in SIDS since the early 1990s.
However, SIDS continues to be a leading cause of infant mortality in developed countries, and the underlying basis of the condition remains unclear. A popular theory proposes that SIDS occurs because of a combination of risks including abnormal physiological state, environmental factors and developmental vulnerabilities. Genetic factors have also been proposed to be important.
"SIDS is not one disease," said George, the Grant W. Liddle Professor of Medicine and director of the Division of Genetic Medicine. "Multiple conditions can increase the risk of sudden death in an infant. Some have been identified, but many have not."
Anecdotal evidence previously suggested that some SIDS victims carry mutations in genes associated with conditions such as the long QT syndrome (LQTS) that predispose individuals to life-threatening arrhythmias and sudden death. But the proportion of SIDS cases that carry such mutations was not clear.
George's collaborators, Peter Schwartz, M.D., in Italy, and Torleiv Rognum, M.D., Ph.D., in Norway, led the efforts to screen seven arrhythmia-associated genes in 201 SIDS cases from Norway - the largest ever genetic survey of a SIDS cohort. The results showed that 9.5 percent of SIDS victims harbored mutations in genes associated with inherited forms of cardiac arrhythmia, such as LQTS.
The researchers identified mutations and variations in several genes, including the gene that encodes the cardiac sodium channel - a protein that regulates the electrical properties of heart cells. George's lab then performed studies to understand the physiological consequences of mutations in the cardiac sodium channel gene, called SCN5A, which has previously been associated with LQTS and several other conditions that cause unstable heart rhythms and sudden death.
"We observed a pattern of SCN5A dysfunction that is reminiscent of what's been observed in LQTS. That gives us confidence that the mutations observed in SIDS victims are not benign genetic variants - but rather could increase the risk of potentially lethal arrhythmias," he said. The researchers have similar evidence, to be published separately, demonstrating that mutations in heart potassium channels are also contributing factors in SIDS.
The findings also suggest that there may be strategies to identify whether infants are a carrier of one of these mutations before the tragic event of their death, George said.
"We are not recommending that a population-wide genetic screening be done, but there may be simpler, cost-effective measures that should be investigated further, perhaps performing ECG (electrocardiogram) screening of infants, although this idea is controversial."
Inherited arrhythmias are manageable conditions that can be treated with medications or implantable devices, George said.
"There's potentially an infant death every other day in the U.S. due to this problem (arrhythmias)," he said. "Exactly how best to identify this risk and prevent arrhythmia-related death during infancy needs to be determined."
George and colleagues are continuing to analyze other arrhythmia-linked genes identified in the Norwegian SIDS cohort. They are also planning studies to determine if the parents of SIDS victims carry the same mutations.
"This is critical because knowing how often mutations are transmitted from parents rather than occur spontaneously, will help establish the risk to siblings of SIDS victims," he said.
George hopes that eventually, all of the causes of SIDS - environmental, developmental and genetic factors - will be identified.
"Many years from now, 'SIDS' may not be a term we use anymore because we will understand all causes of sudden infant death," George said. "But right now, SIDS is a bona fide disease category, and we should strive to understand it fully."
Vanderbilt University Medical Center
http://www.brightsurf.com/news/
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