Frontiers in endocrinology · 2026
Functional and clinical evidence for two novel heterozygous BUB1B variants and their value in precision genetic counseling for recurrent pregnancy loss.
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Wei Tian-Ying, Kang Ming-Xian, Zhang Ge-Han, Zhang Jing, Liu Jia-En, Ma Jing, Tian Ya-Ping, Hu Hua-Ying
Аннотация
INTRODUCTION: Recurrent pregnancy loss (RPL) is a common reproductive disorder with largely unexplained etiology. Premature chromatid separation (PCS), a cytogenetic manifestation of chromosomal instability, is linked to spindle assembly checkpoint (SAC) dysfunction. While biallelic BUB1B mutations cause mosaic variegated aneuploidy syndrome, the contribution of heterozygous variants to RPL remains uncertain.
METHODS: Here, we investigated two unrelated families with unexplained RPL. Chromosomal microarray analysis of six miscarriage specimens revealed random aneuploidies. Whole-exome sequencing identified two novel heterozygous BUB1B variants-c.2164T>C (p.W722R) and c.2215G>T (p.A739S)-in the probands, confirmed by Sanger sequencing and segregation analysis. Agarose gel electrophoresis of RT-PCR products was performed to assess BUB1B mRNA expression, and Western blot was used to evaluate BUBR1 protein levels, in peripheral blood lymphocytes of both probands. Twenty healthy controls (10 male, 10 female) without history of pregnancy loss were enrolled for cytogenetic comparison. Cytogenetic analysis showed significantly elevated PCS rates in probands' lymphocytes compared to controls, as detected by G-banding and centromere-specific FISH.
RESULTS: Two novel heterozygous BUB1B missense variants (c.2164T>C [p.W722R] and c.2215G>T [p.A739S]) were identified in the two probands. Both variants were classified as variants of uncertain significance (VUS) per ACMG/AMP guidelines. Significantly elevated PCS rates were confirmed in peripheral blood lymphocytes of both probands by G-banding and centromere-specific PNA-FISH. Agarose gel electrophoresis and Western blot analyses revealed a trend toward reduced BUB1B mRNA and BUBR1 protein expression in both variant carriers, providing preliminary functional support for a haploinsufficiency mechanism.
DISCUSSION: These findings provide the first clinical evidence suggesting that heterozygous BUB1B variants may impair SAC fidelity, leading to somatic PCS and recurrent embryonic aneuploidy, thereby contributing to sporadic RPL. Our study highlights BUB1B as a candidate gene for genetic screening in idiopathic RPL and underscores the importance of SAC integrity in early embryogenesis.
METHODS: Here, we investigated two unrelated families with unexplained RPL. Chromosomal microarray analysis of six miscarriage specimens revealed random aneuploidies. Whole-exome sequencing identified two novel heterozygous BUB1B variants-c.2164T>C (p.W722R) and c.2215G>T (p.A739S)-in the probands, confirmed by Sanger sequencing and segregation analysis. Agarose gel electrophoresis of RT-PCR products was performed to assess BUB1B mRNA expression, and Western blot was used to evaluate BUBR1 protein levels, in peripheral blood lymphocytes of both probands. Twenty healthy controls (10 male, 10 female) without history of pregnancy loss were enrolled for cytogenetic comparison. Cytogenetic analysis showed significantly elevated PCS rates in probands' lymphocytes compared to controls, as detected by G-banding and centromere-specific FISH.
RESULTS: Two novel heterozygous BUB1B missense variants (c.2164T>C [p.W722R] and c.2215G>T [p.A739S]) were identified in the two probands. Both variants were classified as variants of uncertain significance (VUS) per ACMG/AMP guidelines. Significantly elevated PCS rates were confirmed in peripheral blood lymphocytes of both probands by G-banding and centromere-specific PNA-FISH. Agarose gel electrophoresis and Western blot analyses revealed a trend toward reduced BUB1B mRNA and BUBR1 protein expression in both variant carriers, providing preliminary functional support for a haploinsufficiency mechanism.
DISCUSSION: These findings provide the first clinical evidence suggesting that heterozygous BUB1B variants may impair SAC fidelity, leading to somatic PCS and recurrent embryonic aneuploidy, thereby contributing to sporadic RPL. Our study highlights BUB1B as a candidate gene for genetic screening in idiopathic RPL and underscores the importance of SAC integrity in early embryogenesis.