Androgen insensitivity and the evolving genetic heterogeneity.

Area of Science:

• Endocrinology
• Genetics
• Developmental Biology

Background:

• Androgen Insensitivity Syndrome (AIS) is a 46,XY difference of sex development (DSD).
• It is classically linked to androgen receptor (AR) gene mutations, causing varied androgen resistance and phenotypes.
• Phenotypic variability exists even with identical AR mutations, suggesting complex genetic underpinnings.

Purpose of the Study:

• To review the current understanding of AIS aetiology, diagnostics, and therapeutic strategies.
• To highlight emerging genetic factors contributing to AIS beyond AR mutations.
• To discuss advancements in molecular diagnostics and patient-derived models.

Main Methods:

• Review of current literature on AIS genetics and molecular diagnostics.
• Analysis of emerging evidence implicating non-coding variants, intronic mutations, and co-regulator dysfunction.
• Discussion of diagnostic workflows including AR sequencing and whole-exome sequencing.
• Evaluation of biochemical and functional assays.
• Exploration of patient-derived hiPSC and testicular organoid models.

Main Results:

• While AR gene mutations are classical causes, non-coding regulatory variants, deep intronic mutations, AR co-regulator dysfunction, and oligogenic inheritance are implicated in AIS aetiology.
• Molecular diagnostics should integrate targeted AR sequencing or whole-exome sequencing.
• Biochemical and functional assays are valuable for variants of unknown significance (VUS) or when AR variants are undetected.
• Patient-derived hiPSC and testicular organoid models offer novel insights into AR function and therapeutic approaches.

Conclusions:

• AIS aetiology is more complex than initially thought, involving multiple genetic and epigenetic factors.
• Refined molecular diagnostic strategies are crucial for accurate diagnosis.
• Advanced research models are paving the way for personalized care and improved patient outcomes in AIS.