Functional and clinical evidence for two novel heterozygous BUB1B variants and their value in precision genetic counseling for recurrent pregnancy loss - Summary - MDSpire
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Functional and clinical evidence for two novel heterozygous BUB1B variants and their value in precision genetic counseling for recurrent pregnancy loss
To investigate the role of heterozygous BUB1B variants in recurrent pregnancy loss (RPL) and their implications for genetic counseling.
Approach:
Genetic Analysis: Chromosomal microarray analysis and whole-exome sequencing were performed on two families with unexplained RPL to identify pathogenic variants.
Functional Assessment: BUB1B mRNA expression and BUBR1 protein levels were evaluated using RT-PCR and Western blot in peripheral blood lymphocytes.
Cytogenetic Comparison: Cytogenetic analysis was conducted to compare PCS rates between probands and healthy controls.
Key Findings:
Two novel heterozygous BUB1B missense variants (c.2164T>C [p.W722R] and c.2215G>T [p.A739S]) were identified.
Both variants were classified as variants of uncertain significance (VUS) according to ACMG/AMP guidelines.
Significantly elevated PCS rates were confirmed in probands' lymphocytes compared to controls, as detected by G-banding and centromere-specific PNA-FISH.
A trend toward reduced BUB1B mRNA and BUBR1 protein expression was noted in both variant carriers.
Interpretation:
Heterozygous BUB1B variants may impair spindle assembly checkpoint fidelity, contributing to recurrent embryonic aneuploidy and RPL.
Limitations:
The study is limited to two families, which may not represent the broader population.
The clinical significance of the identified variants remains uncertain as they are classified as VUS.
Conclusion:
This study highlights BUB1B as a candidate gene for genetic screening in idiopathic RPL.
