Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is a rare condition that is fatal in the first year of life; its major features include abnormalities of the reproductive system in males, feeding difficulties, and breathing problems.

Infants with SIDDT who are genetically male, with one X chromosome and one Y chromosome in each cell, have underdeveloped or abnormal testes. They may also have external genitalia that appear female-typical or that do not look clearly male or clearly female. In affected infants who are genetically female, with two X chromosomes in each cell, development of the internal and external reproductive organs is normal.

SIDDT is associated with abnormal development of the brain, particularly the brainstem, which is the part of the brain that is connected to the spinal cord. The brainstem regulates many basic body functions, including heart rate, breathing, eating, and sleeping. It also relays information about movement and the senses between the brain and the rest of the body. Many features of SIDDT appear to be related to brainstem malfunction, including a slow or uneven heart rate, abnormal breathing patterns, difficulty controlling body temperature, unusual tongue and eye movements, an exaggerated startle reflex to sudden lights or loud noises, and feeding difficulties. Affected infants also have an unusual cry that has been described as similar to the bleating of a goat, which is probably a result of abnormal nerve connections between the brain and the voicebox (larynx).

The brainstem abnormalities lead to death in the first year of life, when affected infants suddenly stop breathing or their heart stops beating (cardiorespiratory arrest).

A single mutation in the TSPYL1 gene has caused all identified cases of SIDDT. This gene provides instructions for making a protein called TSPY-like 1, whose function is unknown. Based on its role in SIDDT, researchers propose that TSPY-like 1 is involved in the development of the male reproductive system and the brain.

The TSPYL1 gene mutation that causes SIDDT eliminates the function of TSPY-like 1. The loss of this protein's function appears to cause the major features of the disorder by disrupting the normal development of the male reproductive system and the brain, particularly the brainstem.

Research findings suggest that mutations in the TSPYL1 gene are not associated with sudden infant death syndrome (SIDS) in the general population. SIDS is a major cause of death in children younger than 1 year.

Normal Function

The TSPYL1 gene provides instructions for making a protein called TSPY-like 1. This protein is active in the brain, testes (in males), and other tissues, although its function is not well understood. TSPY-like 1 contains a region called a nucleosome assembly protein (NAP) domain, which is found in other proteins that help control cell division, copy (replicate) DNA, and regulate the activity of various genes. It is unknown whether TSPY-like 1 also has these functions.

Based on its role in a condition called sudden infant death with dysgenesis of the testes syndrome, researchers propose that TSPY-like 1 is involved in the development of the male reproductive system and the brain, including the brainstem. The brainstem is a part of the brain that is connected to the spinal cord. It regulates many basic body functions, including heart rate, breathing, eating, and sleeping. It also relays information about movement and the senses between the brain and the rest of the body.

Health Conditions Related to Genetic Changes

Sudden infant death with dysgenesis of the testes syndrome

A single mutation in the TSPYL1 gene has caused all identified cases of sudden infant death with dysgenesis of the testes syndrome (SIDDT), a condition that has been reported in an Old Order Amish community in Pennsylvania. The condition is fatal in the first year of life; its major features include abnormalities of the reproductive system in males, breathing problems, a slow or uneven heart rate, and feeding difficulties.

The mutation that causes SIDDT inserts a single DNA building block (nucleotide) into the TSPYL1 gene. This mutation is written as 457_458insG. The extra nucleotide alters how the gene's instructions are used to make TSPY-like 1, which results in the production of an abnormally short, nonfunctional protein. A loss of TSPY-like 1 function appears to disrupt the normal development of the male reproductive system and the brain, including the brainstem. Abnormalities of brainstem function, particularly involving breathing and heart rate, are likely the cause of sudden death in affected infants.

Research findings suggest that mutations in the TSPYL1 gene are not associated with sudden infant death syndrome (SIDS) in the general population. SIDS is a major cause of death in children younger than 1 year.

Other disorders

Changes in the TSPYL1 gene have been studied as a potential cause of infertility, which is the inability to have biological children. Variations in the gene have been identified in several infertile men and in at least one person who was genetically male (with one X chromosome and one Y chromosome in each cell) but had external genitalia that appeared female. However, it is unclear whether the TSPYL1 gene variations were related to these abnormalities or occurred by coincidence. Changes in the TSPYL1 gene are not thought to be a major cause of infertility.

Other Names for This Gene

• testis-specific Y-encoded-like protein 1
• TSPY-like 1
• TSPY-like protein 1
• TSPYL

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

SIDDT has been diagnosed in more than 20 infants from a single Old Order Amish community in Pennsylvania. The condition has not been reported outside this community.