First SIDS Gene Identified

The researchers first identified patients with SIDDT in a small Old Order Amish community in central Pennsylvania. Over two generations, nine families from this community had lost twenty-one infants to this sudden death syndrome. This familial clustering suggested a genetic basis for the syndrome. 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 (Nasdaq: AFFX) 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.