Abstract
Recurrent pregnancy loss (RPL) is a severe reproductive pathology with a significant component of unexplained etiology. Extended homozygous regions as a possible etiological factor for RPL were sought in the genomes of embryos. Twenty-two paired first-trimester spontaneously aborted embryos from eleven women with recurrent miscarriage were analyzed. All embryos had normal karyotypes according to metaphase karyotyping and conventional comparative genomic hybridization. SurePrint G3 Human CGH + SNP 4 × 180K microarrays (Agilent Technologies) were used to search for homozygous regions. As a result, 39 runs of homozygosity (ROH) were identified in extraembryonic tissues of 15 abortuses. Verification of recurrent homozygous regions was performed by Sanger sequencing. The presence of occasional heterozygous SNPs was shown in 25 extended ROHs, which may indicate that they did not arise de novo but were inherited from parents. In the course of inheritance in a series of generations, they may accumulate mutations, leading to heterozygosity for several sites in the initially homozygous population-specific regions. Homozygotization of recessive mutations is one of the putative mechanisms of the influence of such inherited ROHs on RPL development. The high frequency of extended ROHs detected in the present study may point to a role of inbreeding in RPL etiology. Homozygous regions may also occur due to uniparental disomy, and abnormalities of genomic imprinting may be another mechanism responsible for the pathological manifestation of ROHs in embryogenesis. Indeed, five predicted imprinted genes were identified within ROHs according to the Geneimprint database: OBSCN, HIST3H2BB, LMX1B, CELF4, and FAM59A. This work reports the first finding of a high frequency of extended ROHs in spontaneously aborted embryos with normal karyotypes from families with RPL.
Highlights
Spontaneous abortions occur in approximately 15 % of pregnancies in different populations; in some families, pregnancy loss occurs more than once (Nikitina et al, 2016)
It was shown that extended runs of homozygosity (ROH) (>2.5 Mb) are not typical for unrelated individuals and for populations with low levels of inbreeding. (About 20 % of samples had extended ROHs.) In contrast, isolated endogamous populations had a high frequency of extended ROHs (~80 %) (McQuillan et al, 2008)
Multiple extended ROHs were detected in 40 % of the samples (9/22)
Summary
Spontaneous abortions occur in approximately 15 % of pregnancies in different populations; in some families, pregnancy loss occurs more than once (Nikitina et al, 2016). According to the guidelines of the European Society of Human Reproduction and Embryology, a diagnosis of recurrent pregnancy loss (RPL) should be considered after the loss of two or more pregnancies (Goddijn, 2017). Recurrent pregnancy loss may be caused by uterine abnormalities, parental chromosomal aberrations, antiphospholipid antibodies, polycystic ovarian syndrome, diabetes mellitus, and hyperthyroidism. In about half of all cases, the RPL cause remains unexplained (Nikitina et al, 2016). Homozygotization of recessive mutations due to runs of homozygosity (ROH) or uniparental disomy (UPD) may be one of the causes (Robberecht et al, 2012; Niida et al, 2018). This approach to the search for pathological mutations made it possible to map genes associated with many recessive Mendelian diseases (Botstein, Risch, 2003)
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