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.
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Data availability
Some or all datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.
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Acknowledgements
We are grateful to the patients and their families for participating in this study as well as Jessica Settino for a technical assistance.
Funding
This work was supported by the National Institute of Child Health and Human Development (R01HD070647 and R21HD074278, to AR) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5T32HD007263-38 to MR-E).
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SHC, SAY, and AR collected the clinical information; SAY and AR conceived the experiments; RKV, MRE, SAY, and AR analyzed experimental data; MRE and AJB performed conservation analysis and in silico modeling. The manuscript was written by RKV, MRE, and SAY; reviewed by AJB, SHC, and AR. All authors read and approved the final manuscript.
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Vanderschelden, R.K., Rodriguez-Escriba, M., Chan, S.H. et al. Heterozygous TP63 pathogenic variants in isolated primary ovarian insufficiency. J Assist Reprod Genet 40, 2211–2218 (2023). https://doi.org/10.1007/s10815-023-02886-w
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DOI: https://doi.org/10.1007/s10815-023-02886-w