What Does an SRY-Negative 46,XX Testicular DSD Mean?

When genetic test results for 46,XX testicular difference of sex development (DSD) come back as SRY-negative, it means the SRY gene was not detected by the specific test used ^[1].

To break this down:

• 46,XX is the chromosome pattern typically associated with female development.
• Testicular DSD means that testicular tissue developed despite this chromosome pattern.
• SRY-negative means that the standard genetic “master switch” for testicular development (the SRY gene, normally found on the Y chromosome) was not found in the tested sample.

In about 80% of individuals with 46,XX testicular DSD, the SRY gene is present because a piece of the Y chromosome containing it has attached (translocated) to another chromosome ^[2]. However, studies estimate that about 20% of cases are SRY-negative ^[2]. In these instances, testicular tissue still formed, triggered by a different genetic variation—though the specific cause may remain unknown ^[1][3].

How Does Testicular Tissue Develop Without the SRY Gene?

Fetal sex development relies on a complex balance between a pathway that promotes testicular development and a pathway that promotes ovarian development ^[4]. If the SRY gene is missing, testicular tissue can still form if this balance shifts due to other genetic changes ^[4]. This can happen in several ways, though for many patients, the exact genetic cause is never found ^[3]. Known mechanisms include:

• Overactive Pro-Testis Genes: Other genes that promote male development may have extra copies (known as duplications). Well-established examples include the SOX9 and SOX3 genes. If regulatory regions for these genes are duplicated, they can independently trigger the body to form testicular tissue ^[5][6].
• Disrupted Pro-Ovarian Genes: Genes that normally promote ovarian development, such as RSPO1 or WNT4, may not function correctly. For example, specific mutations in RSPO1 are a rare cause of 46,XX testicular development and can also be associated with skin conditions like palmoplantar hyperkeratosis ^[7][8].
• Other Rare Variants: Specific variations in several other genes, including WT1 and NR5A1, have occasionally been linked to 46,XX testicular development in rare cases, though these do not always produce the same physical outcome ^[9].

How is SRY-Negative Different from SRY-Positive?

Knowing whether a patient is SRY-negative or SRY-positive is important because the two types tend to present differently, though these are general trends, not absolute rules:

• Time of Diagnosis: Because SRY-negative cases often involve more noticeable differences in genital development, they are frequently diagnosed during infancy ^[10][11]. For example, in one specific study cohort, 75% of SRY-negative patients were diagnosed in the neonatal period ^[11]. By contrast, SRY-positive individuals typically have typical male external genitalia and are often not diagnosed until adulthood during evaluations for infertility ^[12].
• Physical Characteristics: SRY-negative children tend to have more variable or atypical genital development (differences in genital appearance) compared to SRY-positive children ^[10]. However, some SRY-negative individuals are born with a typical male appearance and are diagnosed later in life ^[11].

What This Result Does Not Tell You

An SRY-negative result provides genetic context, but it does not dictate everything about a person’s life or body:

• Gender Identity: A genetic description of sex development does not determine a person’s gender identity, gender expression, or future identity.
• Hormone Function: SRY status alone cannot predict whether the body will produce enough testosterone for puberty. This depends on the specific amount and function of the testicular tissue present ^[13].
• Fertility Limits: Regardless of SRY status, the absence of a complete Y chromosome generally means that the capacity to produce sperm is severely limited or absent, so biological fertility usually requires specialized assisted reproductive technologies like donor sperm ^[13].

Next Steps and Care

A single negative SRY test is often just the beginning of the evaluation.

• Advanced Genetic Testing: Standard tests might miss the cause. Your doctor may recommend a microarray (which looks for extra or missing pieces of DNA, like SOX9 duplications) or exome sequencing (which looks closely at the spelling of specific genes) ^[14][15]. Because no single test catches everything, testing should be guided by a geneticist based on your specific clinical findings ^[16].
• Individualized, Multidisciplinary Care: Because SRY-negative 46,XX testicular DSD is complex and affects individuals differently, care is best managed by a specialized DSD team ^[17]. This team includes endocrinologists to monitor hormone function and puberty, urologists, geneticists, and psychosocial professionals who support informed, shared decision-making regarding any treatments or monitoring ^[17][18].