CGB8 – Habitual Spontaneous Abortion

Multiple independent studies in European populations have identified an association between variants in the CGB8 gene (HGNC:16453) and habitual spontaneous abortion (MONDO_0006774). In a case‑control study involving 184 recurrent miscarriage patients and 195 fertile controls (PMID:18782867), resequencing of chorionic gonadotropin beta‑subunit genes revealed a number of novel variants that appear to modulate the risk of miscarriage. A meta‑analysis including thousands of subjects further confirmed that specific single nucleotide polymorphisms in CGB genes are associated with a reduced risk of recurrent miscarriage (PMID:23499152).

Genetic evidence supports an autosomal dominant contribution in that affected individuals often carry heterozygous variants, including rare missense changes. Notably, the variant c.218C>G (p.Pro73Arg) in CGB8 was detected in multiple RM cases, with segregation analysis revealing its transmission in affected families (PMID:22554618). Additional affected relatives with co‑segregating variants were documented, reinforcing the link between CGB8 variation and the phenotype.

The variant spectrum in these studies encompassed both intronic and coding changes, but the emphasis has been on missense mutations that alter protein conformation. The reported c.218C>G (p.Pro73Arg) variant, for instance, is associated with an alternative conformation of secreted beta‑subunits. Although some studies noted that this change does not compromise biological activity, the observed alteration in dimer formation and receptor binding kinetics suggests a nuanced impact on the function of hCG, which is critical during early pregnancy.

Functional assessments employing in silico structure analysis, molecular dynamics, and in vitro bioassays have provided moderate experimental evidence supporting a pathogenic mechanism. These studies demonstrated that the p.Pro73Arg variant leads to impaired assembly of the hCG heterodimer, which is postulated to affect hormonal signaling during the first trimester and thereby contribute to habitual spontaneous abortion (PMID:22554618; PMID:18782867).

Despite some variability in the functional consequences likely due to the mild impact of most variants, a consistent theme emerges: genetic variation in CGB8 modulates hCG levels and activity. This integrated evidence from genetic association and functional studies consolidates the correlation between CGB8 variants and the risk of habitual spontaneous abortion, even though some promoter polymorphisms appear protective. Minor conflicting findings prompt further exploration; however, the preponderance of multi‑population data supports a strong association.

In conclusion, cumulative genetic and experimental evidence confirm that CGB8 is a critical contributor to the risk of habitual spontaneous abortion. The demonstrated association and functional impact of variants such as c.218C>G (p.Pro73Arg) underscore the potential utility of CGB8 screening in the diagnostic evaluation and genetic counseling of recurrent miscarriage cases.

Key take‑home sentence: CGB8 variant analysis provides clinically actionable insights into the risk and management of habitual spontaneous abortion.

References

• The Journal of clinical endocrinology and metabolism • 2008 • Chorionic gonadotropin beta-gene variants are associated with recurrent miscarriage in two European populations PMID:18782867
• Molecular human reproduction • 2012 • Structural and functional analysis of rare missense mutations in human chorionic gonadotrophin β‑subunit PMID:22554618
• Fertility and sterility • 2013 • A modest but significant effect of CGB5 gene promoter polymorphisms in modulating the risk of recurrent miscarriage PMID:23499152
• Glycoconjugate journal • 2020 • N- and O-glycosylation patterns and functional testing of CGB7 versus CGB3/5/8 variants of the human chorionic gonadotropin β subunit PMID:32767150

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