6615 Clinical features and genetic etiology of primary ovarian insufficiency in 46,XX children

Abstract Disclosure: F. Wang: None. X. Yin: None. X. Lan: None. P. Li: None. Purpose: The clinical features of primary ovarian insufficiency in 46,XX children were analyzed, the pathogenic genes of POI were screened, and the genetic etiology of primary ovarian insufficiency in children 46,XX was clarified. Method: The clinical data of 46,XX POI patients were collected, including uterine and ovarian ultrasound, serum follicle-stimulating hormone (FSH), estrogen, anti-mullerian hormone (AMH), chromosomal karyotype analysis, adrenal and thyroid function, and immune function. Whole exome sequencing (WES) and CNV were used to screen POI candidate genes. Novel mutations such as MCM8 gene were used to verify cell function. HE staining, immunohistochemistry, cell fluorescence, and Tunnel method were used to observe the changes in ovarian tissue structure. Construction overexpression plasmids of Mutant MCM8 gene in Hela cells. Result: 1. Clinical features of 46,XX POI: The age of onset of the children was 11.9∼16.1 years old. In addition to POI, the clinical phenotype showed height growth retardation. Among them, 4 cases were short stature, 3 cases were growth hormone deficiency, and 5 cases were backward in bone age. All of them showed elevated FSH (>25 IU/L), and 7 cases had low serum AMH (<0.5 ng/ml). 2.The Screening of POI candidate genes and pathogenicity analysis: 5 of the 10 children carried the mutations of the pathogenic genes with POI, that is, 2 cases (sisters of the same family) carried two novel heterozygous mutations of MCM8 gene, one infant carried two novel heterozygous mutations of CYP19A1 gene, and one case with delayed puberty carried one homozygous mutation of ZSW1M7 gene. 3.The MCM8 mutant were functionally validated: The sisters carried two novel mutations, namely p.C242R and p.S445*. The elder sister (the proband) showed POI, short stature and tumor susceptibility, while the younger sister showed a trend of gradual increase in FSH level and ovarian decline. The follicles of the proband disappeared and fibrous tissue proliferation, the MCM8 expression was lower, and the positive rate of cell apoptosis was higher than normal control. The downregulation of Bax and Capase3 expression in mutant MCM8 of Hela cell was delayed compared with wild type, indicating the persistence of apoptosis. Conclusion: 1. The clinical characteristics of 46,XX POI in children are ovarian hypoplasia, often combined with height growth retardation, biochemical manifestations of hypergonadotropic hypogonadism, decreased serum AMH, and karyotype 46,XX. 2.46,XX POI genetic etiology analysis found that five known POI-related pathogenic genes, namely CYP19A1, MCM8, and ZSW1M7, in which five novel mutations were identified.3.Mutant MCM8 promotes ovarian apoptosis by activating the Bcl-2/Bax/Caspase 3 pathway. Keywords: Primary ovarian insufficiency, short stature, apoptosis Presentation: 6/3/2024