NDIAG • Education • Advocacy • Support
Remember the Girls
Awareness for females affected by X-linked AVPR2-related NDI and the role of variable/skewed X-inactivation.
X-linked AVPR2 NDI
NDI does not only affect boys.
Females who carry an AVPR2 pathogenic variant can have no symptoms, mild symptoms, or significant NDI. GeneReviews specifically notes variable polyuria and polydipsia in heterozygous females and says some can be as severely affected as males.
One proposed explanation is skewed X-chromosome inactivation—sometimes called Lyonization—where the X chromosome carrying the working copy is inactivated more often in relevant cells, leaving the X chromosome with the AVPR2 variant more active.
What is Lyonization?
People with two X chromosomes normally have one X chromosome largely inactivated in each cell. This process helps balance gene expression between XX and XY individuals. The pattern is not necessarily perfectly even. When inactivation is skewed, a female carrying an X-linked variant may have more cells expressing the altered copy in a tissue that matters for the condition.
That is one reason a girl or woman with an AVPR2 variant may not fit the stereotype of an “unaffected carrier.”
Why Remember the Girls matters
- Girls can be missed because NDI is often thought of as an X-linked condition affecting boys.
- Symptoms can be variable, including partial or significant disease.
- A family history may be absent or not recognized.
- Genetic testing can be important when symptoms suggest NDI.
- Female relatives may need evaluation based on family history and clinical findings.
Awareness helps families and clinicians consider the diagnosis instead of assuming that an affected girl cannot have X-linked NDI.