Pathogenic correlation between mosaic variegated aneuploidy 1 (MVA1) and a novel BUB1B variant: a reappraisal of a severe syndrome

Abstract

Background The BUB 1 mitotic checkpoint serine/threonine kinase B (BUB1B) gene encodes a key protein in the mitotic spindle checkpoint, which acts as a surveillance mechanism, crucial for the maintenance of the correct chromosome number during cell deviation. Mutations of BUB1B gene are linked to mosaic variegated aneuploidy 1 (MVA1) syndrome, a rare autosomal recessive disorder characterized by widespread mosaic aneuploidies, involving different chromosomes and tissues. MVA1 is clinically characterized by intrauterine growth restriction, post-natal growth retardation, and severe neurologic impairment including microcephaly, developmental delay/intellectual disability, epileptic seizures, and generalized hypotonia. Malignancies are also serious sequelae associated with the disorder. We reported on a case of two-year-old Italian girl with MVA1 who shows severe neurologic impairment, microcephaly and epileptic seizures. Materials and methods Clinical data collection and genetic diagnosis of the patient were assessed. Mutational analysis covers the chromosomal microarray analysis, the gene methylation pattern studied using the methylation-specific multiplex ligation-dependent probe amplification, and the family-based Whole Exome Sequencing (WES). A literature research based on reported cases of MVA and premature chromatid separation was also included. Results Karyotyping has revealed 12% of mosaics in the patient who carries a novel variant in BUB1B gene (c.2679A > T, p.Arg893Ser) detected by WES. Thirty-one cases of MVA1 including the present report, and four prenatally diagnosed cases with MVA1 were selected and inspected. Conclusion Clinical and genetic findings reported in the girl strongly suggest a new MVA1 genotype–phenotype correlation and lead to a reappraisal of a severe syndrome. Diagnosis and in-depth follow-up provided worthwhile data.

Sudden unexpected postnatal collapse and BUB1B mutation: first forensic case report

“…A published case report giving the clinical history of an Italian girl with a karyotype showing 12% mosaics with a new variant of the BUB1B gene (c.2679 A > T, p.Arg893Ser). The girl was two years old and presented with severe neurological disorders, microcephaly and epileptic seizures [35]. Another case report involved a child who, at 6 months of age, showed severe developmental delay, microcephaly, hypotonia, intractable seizures including infantile spasms with hypsarrhythmia, and Dandy-Walker malformation on MRI.…”

P53 independent pathogenic mechanisms contribute to BubR1 microcephaly

“…A well-characterized MVA causative gene, Budding Uninhibited by Benzimidazole 1B (BUB1B) encodes the BUB-related 1 (BubR1) protein (Bolanos-Garci and Blundell, 2011). Previous work in mice found that a BubR1 hypomorphic allele substantially reduces protein level presenting with premature aging, and tumor formation, but not microcephaly (Baker et al, 2004;Hanks et al, 2004;Matsuura et al, 2006;Frio et al, 2010;Suijkerbuijk et al, 2010;Miyamoto et al, 2011;Baker et al, 2012;Wijshake et al, 2012;Choi et al, 2016;Yang et al, 2017;Pavone et al, 2022). Successful…”

“…Mosaic variegated aneuploidy (MVA) is a rare autosomal recessive disorder characterized by growth retardation, predisposition to cancer, and microcephaly (Garcia-Castillo et al, 2008;Suijkerbuijk et al, 2010;Bianchi et al, 2018;Pavone et al, 2022). Premature chromatid separation resulting in cells with numerically abnormal chromosomes (aneuploidy) is a hallmark feature of MVA.…”