Pediatric Clinic, Department of Clinical and Experimental Medicine, University Hospital A.U.O. "Policlinico-Vittorio Emanuele, Catania, Italy.
National Council of Research, Institute for Biomedical Research and Innovation (IRIB), Unit of Catania, Catania, Italy.
Neurol Sci. 2022 Nov;43(11):6529-6538. doi: 10.1007/s10072-022-06247-w. Epub 2022 Jul 9.
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.
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.
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.
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.
BUB1 有丝分裂检查点丝氨酸/苏氨酸激酶 B（BUB1B）基因编码有丝分裂纺锤体检查点的关键蛋白，作为一种监测机制，对于在细胞偏离过程中维持正确的染色体数量至关重要。BUB1B 基因突变与镶嵌性不均一性 1 （MVA1）综合征有关，MVA1 综合征是一种罕见的常染色体隐性疾病，其特征为广泛的镶嵌性非整倍体，涉及不同的染色体和组织。MVA1 临床上表现为宫内生长受限、出生后生长迟缓以及严重的神经功能障碍，包括小头畸形、发育迟缓/智力残疾、癫痫发作和全身性肌张力低下。恶性肿瘤也是与该疾病相关的严重后遗症。我们报告了一例两岁意大利女孩患有 MVA1，表现为严重的神经功能障碍、小头畸形和癫痫发作。
对患者的临床数据收集和遗传诊断进行评估。突变分析包括染色体微阵列分析、使用甲基化特异性多重连接依赖性探针扩增研究的基因甲基化模式，以及基于家族的全外显子组测序（WES）。还包括基于已报道的 MVA 和过早染色单体分离病例的文献研究。
核型分析显示，患者的镶嵌率为 12%，携带 WES 检测到的 BUB1B 基因（c.2679A>T，p.Arg893Ser）的新型变异。选择并检查了包括本报告在内的 31 例 MVA1 病例和 4 例产前诊断为 MVA1 的病例。
该女孩的临床和遗传发现强烈提示存在新的 MVA1 基因型-表型相关性，并导致对严重综合征的重新评估。诊断和深入随访提供了有价值的数据。
