SNP Shot: Genomic Insights

Swyer syndrome is a condition that disrupts typical sex development. Usually, sex development follows a path determined by a person's chromosomes. However, in Swyer syndrome, this process deviates from what would be expected based on the affected individual's chromosomal makeup.

Chromosomes are structures that carry the body's genetic instructions, guiding development and function. Humans typically have 46 chromosomes in each cell, with two of these, the X and Y chromosomes, being the sex chromosomes. These chromosomes play a crucial role in determining the development of male or female reproductive organs. Typically, females have two X chromosomes (designated as 46,XX), while males possess one X and one Y chromosome (designated as 46,XY). Individuals with Swyer syndrome have the 46,XY chromosome pattern, usually associated with males, but develop female reproductive structures.

Individuals with Swyer syndrome exhibit female external genitalia and some female internal reproductive organs, generally including a uterus and fallopian tubes. However, their gonads (ovaries or testes) are non-functional. Instead, they have underdeveloped, small gonads containing minimal gonadal tissue, referred to as streak gonads. Due to the risk of cancer developing in this tissue, which is often difficult to detect, surgical removal is usually recommended. Swyer syndrome is also known as 46,XY complete gonadal dysgenesis, with "dysgenesis" indicating abnormal development.

Because they physically appear female, infants with Swyer syndrome are typically raised as girls and develop a female gender identity (their personal sense of being male, female, both, or neither). Swyer syndrome can be diagnosed before birth, at birth, or later if puberty does not occur as expected. Since their ovaries do not produce hormones, affected individuals often begin hormone replacement therapy in early adolescence to induce puberty. This therapy stimulates breast and uterine growth and eventually leads to menstruation. Hormone replacement is also vital for maintaining bone health, reducing the risk of osteopenia (low bone density) and osteoporosis (fragile bones). While women with Swyer syndrome do not produce eggs (ova), they may be able to achieve pregnancy using a donated egg or embryo if they have a uterus.

Inheritance:

Most cases of Swyer syndrome are not hereditary, arising in individuals with no family history of the condition. These cases are often the result of new (de novo) changes in a gene occurring during the formation of eggs or sperm or in early embryonic development. Occasionally, non-inherited cases can stem from non-genetic factors. SRY-related Swyer syndrome is typically caused by a new, non-inherited variant. However, in some instances, an individual with Swyer syndrome inherits an altered SRY gene from an unaffected father who is mosaic for the variant. Mosaicism signifies the presence of the variant in some, but not all, of the individual's cells, including potentially some reproductive cells. Because the father has some cells without the variant, he remains unaffected and can have children, to whom he may pass on the variant. Rarely, a father might carry the variant in all cells of his body but also have other genetic variations that prevent him from being affected. Since the SRY gene is located on the Y chromosome, Swyer syndrome resulting from SRY gene variants is described as having a Y-linked inheritance pattern. When Swyer syndrome is associated with a variant in the MAP3K1 or NR5A1 gene, it is also frequently due to a new, non-inherited variant. In rare inherited cases, the variant can be inherited from either parent, as these genes are not on the Y chromosome; however, only individuals with an XY chromosome pattern are affected (the condition is considered sex-limited). In inherited cases, the condition follows an autosomal dominant inheritance pattern, meaning that only one copy of the altered gene in each cell is enough to cause the condition. However, the parent carrying the variant typically does not exhibit any signs or symptoms. Swyer syndrome caused by variants in the DHH gene is inherited in a sex-limited autosomal recessive pattern, meaning that both copies of the gene in each cell must have variants, and only individuals with an XY chromosome pattern are affected. In autosomal recessive conditions, each parent of the affected individual carries one copy of the altered gene but typically does not exhibit any signs or symptoms of the condition.