Jacobsen Syndrome (JS) is a rare congenital disorder impacting multiple organ systems, with a reported incidence of approximately one in 100,000 newborns. This condition is characterized by a wide spectrum of physical and developmental challenges, including congenital heart defects, intellectual disability, and the bleeding disorder Paris-Trousseau syndrome. JS is a chromosomal disorder caused by a specific alteration in the body’s genetics, rather than a single-gene defect. Understanding the precise genetic mechanism by which this syndrome is acquired is important for families seeking to understand the risk and for genetic counseling.
The Chromosomal Basis of Jacobsen Syndrome
Jacobsen Syndrome is fundamentally a contiguous gene deletion disorder caused by the loss of genetic material from the long arm of chromosome 11. In JS, one copy of chromosome 11 is missing a segment at its very end, known as the terminal deletion. The deletion always involves the distal portion of the long arm, referred to as 11q, with the breakpoint typically occurring within or beyond subband 11q23.3.
The size of the missing segment can vary significantly between affected individuals, usually ranging from 7 to 16 million base pairs (Mb) of DNA. This deletion results in the loss of a large number of genes, potentially between 170 to over 340, which are responsible for the development of the brain, heart, and facial features. The extent of the deletion directly influences the severity and range of symptoms; a larger deletion generally leads to a more severe clinical presentation. For example, the loss of a gene called FLI1 in this region is linked to the bleeding disorder Paris-Trousseau syndrome, which affects nearly all patients with JS.
Primary Inheritance Patterns
The genetic error that causes Jacobsen Syndrome occurs through two distinct pathways: spontaneous occurrence or inheritance. The vast majority of cases, estimated to be between 85% and 90%, are classified as de novo deletions. This means the deletion is a new, random event that occurs either during the formation of the egg or sperm cells or very early in embryonic development after conception.
In these de novo cases, the parents have completely normal chromosomes, and the deletion is present for the first time in their child. The spontaneous nature of this event is why most affected individuals do not have a family history of the disorder. The recurrence risk for parents of a child with a de novo deletion is considered extremely low, although it is not zero due to the small possibility of parental germline mosaicism.
A smaller percentage of cases, ranging from 10% to 15%, are inherited from an unaffected parent. This inheritance occurs when one parent carries a specific type of chromosomal rearrangement called a balanced translocation involving chromosome 11 and another chromosome. A balanced translocation is generally harmless to the parent because no genetic material has been lost or gained, only rearranged, and the parent is therefore healthy.
However, when this parent produces reproductive cells, the rearranged chromosomes may be passed on in an unbalanced form. This imbalance results in the child receiving the necessary deletion on chromosome 11, leading to Jacobsen Syndrome. This mechanism highlights that the condition can be inherited even if the parent has no symptoms.
Genetic Testing and Recurrence Risk
Confirming a diagnosis of Jacobsen Syndrome and determining the inheritance pattern requires specialized genetic testing methods that can detect the chromosomal deletion. Traditional Karyotyping, which involves viewing chromosomes under a microscope, can often detect the large terminal deletion on chromosome 11. More detailed techniques, such as Fluorescence In Situ Hybridization (FISH) and Chromosomal Microarray (CMA), are employed to precisely determine the size and location of the deletion.
CMA is particularly effective because it can identify microscopic losses of DNA that might be too small to be seen with standard Karyotyping, providing a highly accurate map of the deleted segment. Parental testing is essential to distinguish between a de novo occurrence and an inherited case. This involves analyzing the parents’ chromosomes to see if either one carries a balanced translocation.
If the deletion is confirmed to be de novo, the recurrence risk for future pregnancies is typically cited as less than one percent. Conversely, if a parental balanced translocation is identified, the risk of having another child with Jacobsen Syndrome is substantially higher, although the exact percentage depends on the specific chromosomes involved in the rearrangement. In such cases, genetic counseling helps the family understand the specific risks for future pregnancies and explore options like prenatal diagnosis.