Complete Androgen Insensitivity Syndrome (CAIS) Genetic Counseling: Navigating Germline Mosaicism Concerns

Area of Science:

• Genetics
• Endocrinology
• Reproductive Medicine

Background:

• Complete Androgen Insensitivity Syndrome (CAIS) typically results from X-linked recessive inheritance of pathogenic variants in the androgen receptor (AR) gene.
• CAIS leads to a female appearance in individuals with XY chromosomes.
• The condition is usually inherited, with de novo variants being less common.

Purpose of the Study:

• To report a rare instance of germline mosaicism in Complete Androgen Insensitivity Syndrome (CAIS).
• To highlight the implications of germline mosaicism for genetic counseling in CAIS.
• To present a case of two sisters with identical pathogenic AR variants but different clinical outcomes.

Main Methods:

• Clinical evaluation of two sisters presenting with CAIS.
• Androgen receptor (AR) gene sequencing in the affected sisters and their mother.
• Analysis of inheritance patterns and variant identification.

Main Results:

• Identical hemizygous pathogenic variants in the AR gene were identified in both sisters.
• The pathogenic variants were absent in the mother, indicating germline mosaicism.
• The sisters exhibited distinct clinical presentations despite the shared genetic mutation.

Conclusions:

• Germline mosaicism is a rare but possible cause of CAIS, even with identical variants in siblings.
• The identification of de novo AR gene variants should prompt consideration of germline mosaicism.
• Genetic counseling is crucial for families to understand recurrence risks and reproductive options.