Trisomy 15 (T15) is a rare and severe chromosomal condition where an individual has three copies of chromosome 15 instead of the usual two. Chromosomes contain the genetic blueprints for development, and having an extra copy of this particular chromosome severely disrupts the body’s normal instructions. This genomic imbalance leads to a condition known as aneuploidy. T15 is overwhelmingly associated with spontaneous miscarriage, making it one of the most common trisomies found in pregnancy loss. The condition’s impact depends significantly on whether the extra chromosome is present in all cells or only some, and whether the entire chromosome or just a segment is involved.
How Chromosomal Errors Occur
The presence of an extra chromosome 15 most often arises from an error during the formation of reproductive cells, the egg and sperm, a process called meiosis. Normal meiosis ensures that each resulting gamete receives exactly one copy of each chromosome, so that upon fertilization, the offspring has the correct total of 46 chromosomes.
The failure of chromosome separation is known as nondisjunction, which can occur in two main stages of meiosis. If the error happens during Meiosis I, the pair of homologous chromosomes fails to separate, leading to a gamete with two copies of chromosome 15. The second possibility is an error in Meiosis II, where the sister chromatids fail to separate, also resulting in an egg or sperm cell carrying an extra chromosome 15.
For Trisomy 15, errors during maternal meiosis I are thought to be the cause in the vast majority of cases where the extra chromosome is of maternal origin. Nondisjunction results in a gamete containing 24 chromosomes, including two copies of chromosome 15, instead of the normal 23. When this abnormal gamete combines with a normal gamete, the resulting fertilized egg, or zygote, possesses three copies of chromosome 15, leading to Trisomy 15.
The likelihood of this separation error is linked to advanced maternal age, which is the only well-documented risk factor for meiotic nondisjunction in general. The extra chromosome can also arise from a postzygotic error, a nondisjunction event that happens after fertilization during the initial cell divisions of the embryo, which is thought to account for a smaller percentage of Trisomy 15 cases.
Clinical Manifestations of Trisomy 15
The clinical impact of Trisomy 15 is highly variable and depends on the specific chromosomal makeup of the cells.
Full Trisomy 15
The most severe and common presentation is Full Trisomy 15, where every cell in the body contains the extra chromosome. This full form is considered a lethal condition, typically resulting in spontaneous miscarriage early in pregnancy. Some newborns with multiple congenital anomalies have been reported who experience neonatal death.
Mosaic Trisomy 15
A less severe form is Mosaic Trisomy 15, which occurs when the extra chromosome is present in only a fraction of the body’s cells. The outcomes for individuals with mosaic T15 are highly unpredictable, ranging from relatively mild symptoms to serious medical problems, depending on the proportion of trisomic cells and which tissues are affected.
Common features reported in individuals with mosaic T15 often include:
- Intrauterine growth restriction.
- Heart defects such as ventricular and atrial septal defects.
- Distinct craniofacial characteristics like a wide nasal bridge and widely spaced eyes.
- Abnormalities of the brain, such as an underdeveloped cerebellum.
- Renal and genital anomalies.
The variability in mosaic T15 is also complicated by confined placental mosaicism, where the trisomic cells are limited to the placenta and not the developing fetus.
Partial Trisomy 15
Partial Trisomy 15 involves a duplication of only a segment of chromosome 15. The severity of this partial form depends entirely on the size and location of the duplicated segment, with specific duplications of the long arm (15q) resulting in developmental delay and specific facial features.
Understanding Familial Risk and Inheritance
The question of whether Trisomy 15 is inherited is complex, as the majority of cases occur sporadically rather than being passed down through a family. The most common cause, nondisjunction during egg or sperm formation, is a random biological event with a recurrence risk typically not much higher than the general population’s baseline risk. This means that T15 is usually a new error in the child, not a condition inherited from a parent.
However, Trisomy 15 can be familial when a parent carries a balanced chromosomal rearrangement, such as a translocation. A balanced translocation involves a rearrangement of genetic material where the parent is healthy because they have the correct total amount of chromosomal material, just in the wrong order. When the carrier parent produces gametes, the rearranged chromosomes can segregate incorrectly, resulting in an unbalanced gamete. This can lead to a partial trisomy or a full trisomy of chromosome 15 upon fertilization.
The presence of a parental balanced translocation significantly increases the risk for future pregnancies. For families who have experienced T15, karyotyping of both parents is a necessary step to check for such a balanced translocation. Genetic counseling is highly recommended to accurately assess their specific recurrence risk and discuss options for future pregnancy planning, including prenatal testing.