Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: Delineation of clinical subtypes

Abstract

Mosaic variegated aneuploidy (MVA) is a rare autosomal recessive syndrome related to BUB1B gene mutations and characterized by multiple mosaic aneuploidies, cancer predisposition, and a distinct phenotype. We report on two mildly affected sibs with MVA syndrome but without BUB1B mutation. Both patients exhibited growth retardation, frontal bossing, triangular face and micrognathia but not microcephaly or cancer. Aneuploidies were assessed both in G-banded metaphases from lymphocyte cultures and in interphase nuclei from buccal cells by FISH. Screening of 23 exons and intron-exon boundaries of BUB1B was also carried out. These patients were then compared with other 19 MVA patients screened for BUB1B mutations. Around one half of the cultured lymphocytes from our patients had aneuploidies ranging from nullisomies to heptasomies; the most frequent abnormalities were trisomies (42%) and monosomies (28%). FISH results demonstrated more chromosomal losses than gains. Screening of BUB1B in our two patients failed to identify any mutation. A review of the 21/35 patients screened for BUB1B demonstrated three clinical pictures. Patients with monoallelic BUB1B mutations were severely affected with Dandy-Walker complex (7/8), cataracts (6/6), and Wilms' tumor (7/8); premature chromatid separation (PCS) was observed in 8/8 propositi and 7/7 carrier parents. Patients without BUB1B mutations were mildly affected with no evidence of cancer, Dandy-Walker malformation or cataract, and rarely (1/7) showed PCS. Finally, patients with biallelic BUB1B mutations showed a moderate phenotype. The distinct MVA clinical groups delineated here point to involvement of at least another mitotic spindle checkpoint gene in addition to the BUB1B gene.

TALEN-mediated single-base-pair editing identification of an intergenic mutation upstream of BUB1B as causative of PCS (MVA) syndrome

“…PCS (MVA) syndrome is characterized by PCS in >50% metaphase cells and a variety of mosaic aneuploidies (1,2). Patient clinical findings include Dandy-Walker complex, postcerebellar cysts, hypoplasia of the cerebellar vermis, lissencephaly, cataracts, uncontrollable clonic seizures, polycystic kidneys, infantile obesity, and a high risk of malignancy including Wilms' tumor and rhabdomyosarcoma (3).…”

Germline mutation contribution to chromosomal instability

“…The authors followed up by screening a larger population of 208 young (aged <40 years) patients with familial or early-onset colorectal cancer and found that germline mutations in BUB1 and BUB3 were associated with 2.9% of these patients, some of them who demonstrated variegated aneuploidies (de Voer et al 2013). However, this was contradicted by findings in a study screening 192 patients with early-onset (<50 years) colorectal cancer, which showed that BUB1B germline mutation is not enriched in these patients thus is unlikely to have a major role in predisposition to colorectal cancer, although it was acknowledged that the sample size was too small to conclusively determine the role of BUB1B in colorectal risk and that germline mutations in BUB1B are associated with a variable phenotype (García-Castillo et al 2008) made complex by other risk factors such as environmental influence as well as other genetic modifiers (Hahn et al 2016).…”

Gradual reduction of BUBR1 protein levels results in premature sister-chromatid separation then in aneuploidy

“…Initially described in 1986 by Scheres et al (1986), the association of microcephaly, mental retardation, and mosaic trisomy was subsequently designated as MVA in 1991 by Warburton et al (1991). The 29 MVA cases described so far conWrmed that the phenotype includes severe intrauterine growth retardation, severe microcephaly, mental retardation, occasional seizures, Dandy-Walker malformation; this condition is associated with a high risk of malignancy, mostly rhabdomyosarcoma, Wilms tumor, and leukemia (Callier et al 2005;Garcia-Castillo et al 2008;Hanks et al 2004;Jacquemont et al 2002;Matsuura et al 2006;Micale et al 2007). In approximately two-third of the cases, MVA is associated to premature chromatid separation (PCS; OMIM 176430) (Callier et al 2005;Jacquemont et al 2002) suggesting that two types of MVA may be distinguished, depending on presence or absence of PCS.…”

“…Among the Wve MVA families with biallelic BUB1B mutations, three had previously been analyzed for PCS and in each one PCS was present (Limwongse et al 1999;Plaja et al 2001); among the three families without BUB1B mutations, only one had previously been analyzed for PCS and had been found negative for this phenotype (Tolmie et al 1988). Recently, Garcia-Castillo et al (2008) reviewed the MVA cases analyzed for the BUB1B gene and observed that none of the patients without BUB1B mutations showed the PCS phenotype. These Wndings indicate a relationship between BUB1B alterations and the PCS phenotype.…”