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Exome sequencing allowed scientists to find the genetic causes of recurrent pregnancy loss

27.08.2019

According to the World Health Organization, 211 million pregnancies occur annually. Pregnancy loss before week 20 occurs in approximately 15–25% of all cases. About 50% of losses are secondary to chromosomal abnormalities, including monosomy and trisomy. In many cases, these errors are episodic in nature and do not imply future pregnancy losses. Habitual miscarriage (NSP) is defined as the loss of two or more pregnancies before the 20th week of pregnancy. The incidence of PNB is approximately 1 in 100 pregnancies. Several studies have already attempted to identify genes in which mutations can lead to embryo death. However, their results rarely indicated the same genes. Researchers from Baltimore (USA) evaluated the known genetic causes of PNB identified by exome sequencing and showed what the candidate genes are responsible for.

Known risk factors for PNS are maternal endocrine or anatomical abnormalities, hereditary maternal thrombophilia, and parental genetic abnormalities. The American Society for Reproductive Medicine recommends testing for PNS after a second clinically recognized miscarriage. The examination includes determination of the maternal and paternal karyotype, tests for lupus anticoagulant, antiphospholipid antibodies, prolactin levels, hemoglobin A1c and a sonohistogram to assess uterine anatomy. In addition, chromosome microarray analysis is recommended. According to recent estimates, the cause of 95% of NSP can be identified using such an examination. Consequently, 5% of NSPs, or the causes of approximately 100,000 cases of pregnancy loss per year worldwide, remain unclear.

American scientists reviewed current literature describing the use of exome sequencing to diagnose causes of abortion.

A total of 19 studies reported 19 candidate genes, with 3 studies reporting 2 or more different candidate genes in 2 different families with similar function. All these 19 genes have well-known functions, most of which are combined into 4 categories: development, expression and regulation of genes, immunity and inflammation, as well as cell cycle processes.

- Genes encoding proteins that are already known to be involved or necessary for intrauterine development of vertebrates, such as APAF1, CASP9, CSPP1, IFT122, NLRP5 and PADI6, were damaged in fetuses that showed neural tube defects, including including craniorachisis and abnormalities of vertebral segmentation. In addition, normal mitotic function is important for the developing embryo, as evidenced by the participation of DYNC2H1 and STIL. Starting with a unicellular fertilized egg, embryo growth depends on normal mitosis. A genetic variant of the loss of function in STIL, a central centrosome protein necessary for maintaining the mitotic spindle, leading to PNB with all fruits showing microcephaly, is described. Finally, an effective immune response, controlled by FOXP3, IDO2, NLRP2, NLRP5 and NLRP7, is necessary to fight the infection in the fetus and to prevent fetal rejection by the maternal immune system, the authors of the article write.

Thus, the 4 gene groups identified in these studies are promising candidates for further observation and research in other cases of PNB. However, scientists draw attention to the fact that the use of other sequencing technologies together with exogenous should improve understanding of the causes of miscarriage.

The study is published in the journal Journal of Assisted Reproduction and Genetics.

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