CGB5 – Habitual Spontaneous Abortion

Human chorionic gonadotropin (hCG) is critical for sustaining early pregnancy, and altered levels are a recognized risk factor for habitual spontaneous abortion. Several independent studies have analyzed CGB5 variants in European cohorts, uncovering significant associations between specific gene promoter polymorphisms and reduced risk of recurrent miscarriage (PMID:23499152).

Case‑control analyses conducted in Estonia, Finland, and Denmark have compared RM patients (up to 184 individuals in one study) with fertile controls, demonstrating that particular CGB5 alleles exhibit statistically significant protective effects against miscarriage (PMID:18782867). Although segregation data remain limited, familial clustering hints at a genetic component further supporting a role for CGB5 in the disorder.

In addition to association studies, rare nonsynonymous variants in CGB5 have been identified among RM patients. For instance, a heterozygous variant resulting in a p.Val56Leu substitution was reported, suggesting that even single‐allele alterations could perturb hCG assembly and function (PMID:22554618). While a formally validated HGVS coding change for this variant is not provided in the current evidence, it reinforces the notion that CGB5 genetic variation contributes to disease risk.

Functional assessments using in vitro approaches have demonstrated that CGB5 variant-induced changes can impair hCG heterodimer formation and alter receptor signaling. These experimental results are concordant with the genetic findings and suggest that modulation of CGB5 expression or function may have direct clinical consequences in the context of recurrent pregnancy loss (PMID:22554618).

Although the precise mode of inheritance is not classically Mendelian, the detection of heterozygous effects in association studies supports a model consistent with an autosomal dominant contribution in a multifactorial context. The convergent genetic and functional evidence, despite some limitations regarding familial segregation numbers, provides a robust argument for the involvement of CGB5 in habitual spontaneous abortion.

Key take‑home: The robust integration of population-based genetic data and functional assays supports the clinical utility of evaluating CGB5 variants in diagnostic settings for recurrent miscarriage.

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 beta-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

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