Scientists find that a variant of the synaptonemal complex protein SYCE2 increases the risk of miscarriage

Although it is well established that chromosomal abnormalities are a major cause of miscarriages, the biology behind miscarriages with or without chromosomal errors is not well understood. More than 114,000 women from Iceland, Denmark, the United Kingdom, the United States and Finland who had suffered a miscarriage participated in a genome-wide association study, testing 50 million variants of sequence. A low-frequency missense variant in the SYCE2 gene increases the risk of miscarriage by 22%.

Scientists from deCODE Genetics, a subsidiary of Amgen, and collaborators from Iceland, Denmark and the United States published a study in Nature Structural and molecular biology titled “A variant of the synaptonemal complex protein SYCE2 is associated with miscarriage through effects on recombination.”

In a previous report from deCODE scientists, this missense variant was shown to be associated with recombination phenotypes in maternally passed chromosomes.

Recombination between homologous chromosomes is an essential part of meiosis, the generation of the human egg and sperm. The product of SYCE2 is part of a protein complex essential for the alignment of homologous chromosomes for recombination, and the missense variant associated with miscarriage and recombination is expected to affect the stability of this protein complex.

Closer inspection of the variant’s effect on recombination revealed an effect on crossover positioning proportional to chromosome length: the longer the chromosome, the greater the effect. The effect on recombination is measured in individuals born alive.

The authors suggest that this effect may be more extreme in lost pregnancies and could contribute to miscarriage. The association with miscarriage does not account for embryos lost early in gestation before pregnancy is detected, so the effect of the variant on pregnancy success may be underestimated.

The results reported in this study demonstrate that a variant with a substantial effect on recombinations can be maintained in the population despite increased risk of miscarriage.

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