García-Castillo Herbert, Vásquez-Velásquez Ana Isabel, Rivera Horacio, Barros-Núñez Patricio
División de Genética, Centro de Investigación Biomédica de Occidente, IMSS. Guadalajara, Mexico.
Am J Med Genet A. 2008 Jul 1;146A(13):1687-95. doi: 10.1002/ajmg.a.32315.
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.
镶嵌杂合非整倍体（MVA）是一种罕见的常染色体隐性综合征，与BUB1B基因突变相关，其特征为多种镶嵌非整倍体、癌症易感性和独特的表型。我们报告了两名患有MVA综合征但无BUB1B突变的轻度受累同胞。两名患者均表现出生长发育迟缓、额部突出、三角形脸和小颌畸形，但无小头畸形或癌症。通过淋巴细胞培养的G带中期染色体和颊细胞间期核的荧光原位杂交（FISH）评估非整倍体情况。还对BUB1B的23个外显子和内含子-外显子边界进行了筛查。然后将这些患者与其他19名筛查BUB1B突变的MVA患者进行比较。我们患者约一半的培养淋巴细胞存在从缺体到七体的非整倍体；最常见的异常是三体（42%）和单体（28%）。FISH结果显示染色体丢失多于增加。对我们两名患者的BUB1B筛查未发现任何突变。对21/35名筛查BUB1B的患者进行回顾显示出三种临床情况。单等位基因BUB1B突变的患者受到严重影响，患有丹迪-沃克综合征（7/8）、白内障（6/6）和威尔姆斯瘤（7/8）；在8/8先证者和7/7携带者父母中观察到早发性染色单体分离（PCS）。无BUB1B突变的患者受到轻度影响，无癌症、丹迪-沃克畸形或白内障的证据，很少（1/7）表现出PCS。最后，双等位基因BUB1B突变的患者表现出中度表型。这里描绘的不同MVA临床组表明，除了BUB1B基因外，至少还有另一个有丝分裂纺锤体检查点基因参与其中。
