Heterozygous TP63 pathogenic variants in isolated primary ovarian insufficiency

Area of Science:

• Genetics
• Reproductive Biology
• Molecular Biology

Background:

• Primary ovarian insufficiency (POI) affects women of reproductive age.
• The genetic underpinnings of non-syndromic POI remain incompletely understood.
• TP63 gene variants have been linked to syndromic forms of ovarian insufficiency.

Purpose of the Study:

• To identify the genetic etiology of non-syndromic primary ovarian insufficiency (POI).
• To investigate the role of the TP63 gene in isolated POI.
• To expand the clinical spectrum of TP63-related disorders.

Main Methods:

• Whole exome sequencing was performed on female patients with isolated POI and their families.
• Copy number variations were validated using long-range PCR and Sanger sequencing.
• Conservation analysis assessed the impact of identified sequence variants on protein function.

Main Results:

• Three unrelated women with isolated POI harbored pathogenic heterozygous TP63 variants.
• Two variants led to loss of transactivation inhibition of p63.
• A novel intragenic copy number alteration affected the ΔNp63 isoforms.

Conclusions:

• TP63 variants are a cause of non-syndromic POI, broadening the spectrum of TP63-related disorders.
• Impairment of the TAp63α isoform's transactivation inhibitory domain causes non-syndromic POI.
• Variants affecting only ΔNp63 isoforms can lead to isolated POI, necessitating evaluation of TP63 in such cases.