Identification and characterization of a novel homozygous splice site variant of PATL2 causing female infertility due to oocyte germinal vesicle arrest

Liwei Sun; Keya Tong; Weiwei Liu; Yin Tian; Sheng Yang; Danni Zhou; Dongyun Liu; Guoning Huang; Jingyu Li

doi:10.3389/fgene.2022.967288

Identification and characterization of a novel homozygous splice site variant of PATL2 causing female infertility due to oocyte germinal vesicle arrest

Front Genet. 2022 Aug 22:13:967288. doi: 10.3389/fgene.2022.967288. eCollection 2022.

Authors

Liwei Sun^{1

2}, Keya Tong^{1

2}, Weiwei Liu^{1

2}, Yin Tian^{1

2}, Sheng Yang^{1

2}, Danni Zhou^{1

2}, Dongyun Liu^{1

2}, Guoning Huang^{1

2}, Jingyu Li^{1

2}

Affiliations

¹ Chongqing Key Laboratory of Human Embryo Engineering, Center for Reproductive Medicine, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
² Chongqing Clinical Research Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Chongqing, China.

Abstract

Background: This study aims to describe clinical and diagnostic phenotype and identify pathogenic variants of a female with unknown causes of infertility. Methods: Clinical assessment was performed for the phenotype diagnosis. Whole-exome sequencing (WES) and the followed cDNA-PCR sequencing were applied to identify the pathogenic variant and investigate the potentially aberrant mRNA splicing event. The pathogenicity of the variant was analysed using multiple in silico prediction tools, including the 3D protein remodelling. Quantitative RT-PCR (qRT-PCR) was performed to measure PATL2 mRNA expression in the peripheral blood leukocytes of the proband and controls. Results: The proband was diagnosed with the female infertility due to oocyte germinal vesicle (GV) arrest. A novel homozygous splice site variant of PATL2 (NM_001145112.2, c.871-1G>A), inherited from her asymptomatic heterozygous parents, was detected by WES. Sequencing of cDNA amplification products demonstrated that this variant resulted in the exon 10 skipping and in-frame loss of 54 nucleotides in the PATL2 transcript. Quantitative RT-PCR suggested that the mutant transcript escape the mRNA degradation. Conclusion: We identified a novel pathogenic homozygous splice site of PATL2 (c.871-1G>A) underlying the oocyte GV arrest phenotype and elucidated its molecular mechanism. This study expands the variant spectrum of PATL2 and benefits our understanding of its genotype-phenotype correlations.

Keywords: PATL2; aberrant splicing; female infertility; germinal vesicle arrest; novel variant.