Abstract
PURPOSE: Our study aimed to identify the genetic causes of non-syndromic primary ovarian insufficiency (POI) in female patients. METHODS: We performed whole exome sequencing in females suffering from isolated POI and in their available family members. Copy number variations were validated by long-range PCR and Sanger sequencing, and conservation analysis was used to evaluate the impact of sequence variants on protein composition. RESULTS: We detected two pathogenic TP63 heterozygous deleterious single nucleotide variants and a novel TP63 intragenic copy number alteration in three unrelated women with isolated POI. Two of these genetic variants are predicted to result in loss of transactivation inhibition of p63, whereas the third one affects the first exon of the ΔNp63 isoforms. CONCLUSION: Our results broaden the spectrum of TP63-related disorders, which now includes sporadic and familial, isolated, and syndromic POI. Genomic variants that impair the transactivation inhibitory domain of the TAp63α isoform are the cause of non-syndromic POI. Additionally, variants affecting only the ΔNp63 isoforms may result in isolated POI. In patients with isolated POI, careful evaluation of genomic variants in pleiotropic genes such as TP63 will be essential to establish a full clinical spectrum and atypical presentation of a disorder.