U.S. scientists have found the genetic basis for one form of sudden infant death syndrome

Jul 20 2004

U.S. scientists have found the genetic basis for one form of sudden infant death syndrome (SIDS).

Sudden infant death syndrome, also known as cot death and crib death, is defined as the death of an infant between the ages of one month and one year which remains unexplained after a thorough postmortem, investigation of the death scene and review of the clinical history.

Very little is known about the possible causes of SIDS. It is important to note that ruling a child's death to be a case of SIDS is not describing the cause of death, but in fact a statement that the cause of death remains unknown. Although there is no known way to prevent it, other research has provided several risk factors which are related to an increased incidence of the syndrome.

The scientists from the Translational Genomics Research Institute, Phoenix, Arizona, and the Clinic for Special Children, Strasburg, Pennsylvania, have released their findings in this weeks journal Proceeding of the National Academy of Sciences.

By discovering the newly described form, sudden infant death with dysgenesis of testes, or SIDDT, the research team led by Dr. Dietrich Stephan, have begun to expose the distinct genetic causes behind some 3,000 infant deaths a year in the US alone.

"This is one of the first genetic sub-classifications of SIDS," Dr. Stephan said. "And it's going to be helpful in offering parents answers for sudden infant deaths, recognizing predisposition early, and hopefully saving a number of these babies."

By identifying patients with SIDDT in an Amish community in central Pennsylvania, the team discovered that over two generations, nine families had lost twenty-one infants to this sudden death syndrome.

This familial clustering suggested a genetic basis for the syndrome and highlights the importance of genetic factors in relation to SIDS. All infants with SIDDT died before 12 months of age of abrupt cardiac and respiratory arrest. While many of these infants underwent testing at major medical centers, no abnormalities were found. Males with SIDDT may also have underdeveloped testes. Females appear to be normal and have normal female hormones in blood and urine. Despite these differences, male and female infants with SIDDT died suddenly at the same age.

The researchers analyzed the DNA from four of these infants, along with their parents, siblings, and extended family members. Using Affymetrix SNP* arrays* - which examine 11,555 single letter, or nucleotide, variations in the genome known as single nucleotide polymorphisms - the researchers narrowed the location of the disorder to a region on chromosome 6.

By correlating the genes known to reside in the region with their clinical understanding of the syndrome, the researchers believed a gene called TSPYL, which is expressed both in the brainstem and in testes, might be responsible for the sudden deaths in these infants. DNA sequencing of this gene in all four patients revealed a severe alteration. All affected infants were found to have two abnormal copies of the TSPYL gene and all parents were carriers of the alteration. Although several other genes are known to be associated with SIDS, this is the first gene identified which causes a primary form of SIDS.

"This study provides new insight into how the nervous system is regulated and highlights the benefits of close collaborations between researchers, physicians, and the patients they care for," said Dr. Erik G. Puffenberger, Laboratory Director at the Clinic for Special Children, the paper's first author.

The discovery also demonstrates the rapidly increasing speed of modern medical research. The mapping and identification of the gene was performed in less than two months from start to finish.

According to the physicians at the Clinic for Special Children, SIDDT is a new disease that has never been described before. The alteration in TSPYL can affect the neurological system and cause sudden death, and in males can also affect the reproductive system. According to Stephan, the relationship of TSPYL mutations or polymorphisms to SIDS in the general population will be studied next. Future work will examine the effects of this gene on the normal control of breathing and heart rate in otherwise normal, premature infants. The gene may be used as a diagnostic marker and to develop treatments.

"This collaboration between the Clinic for Special Children, Translational Genome Research Institute (TGEN), and Affymetrix is an important example of how modern genetic knowledge can, and should be, used to help solve medical problems," said Dr. D. Holmes Morton, Director of the Clinic for Special Children.

*A SNP (pronounced "snip") is a place in the genetic code where DNA differs from one person to the next by a single letter. These slight genetic variations between human beings may predispose some people to disease and explain why some respond better to certain drugs.

*Arrays are used to analyze large numbers of biological samples in an efficient (i.e. parallel) manner.