Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome.
Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome.
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DOI：
10.1186/1471-2350-14-41
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发表时间：
2013-04-03
影响因子：
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通讯作者：
Finelli P
中科院分区：
文献类型：
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作者：
Gervasini C;Picinelli C;Azzollini J;Rusconi D;Masciadri M;Cereda A;Marzocchi C;Zampino G;Selicorni A;Tenconi R;Russo S;Larizza L;Finelli P
Cornelia de Lange 综合征 (CdLS) 是一种罕见的常染色体显性遗传疾病，其特征是面部畸形、生长和精神运动发育迟缓以及骨骼缺陷。迄今为止，NIPBL（粘连蛋白调节因子）和 SMC1A（粘连蛋白结构亚基）基因的致病突变分别占病例的 50% 和 6% 以上。我们招募了 50 名具有 CdLS 临床诊断或具有与 CdLS 重叠特征的患者，他们在分子筛查中 NIPBL 和 SMC1A 突变呈阴性。使用阵列比较基因组杂交（aCGH）筛选导致临床诊断的染色体重排。四名患者被证明携带不平衡，被认为在其临床表型中具有致病作用：患者 1 在染色体 20q11.2-q12 处有 4.2 Mb 的从头缺失；患者 2 在染色体 1p36.23-36.22 处有 4.8 Mb 的缺失；患者 3 携带不平衡易位 t(7;17)，染色体 17q24.2-25.3 出现 14 Mb 重复，染色体 7p22.3 出现 769 Kb 缺失；患者 4 的 19p13.3 号染色体有 880 Kb 的重复，他的母亲（具有轻度表型）也被证明是嵌合体。尽管包含四种不同不平衡的重排的大小和基因内容存在差异，但它们都映射到包含编码参与细胞周期进展或基因组稳定性的因子的基因的区域。已知的 CdLS 基因也表现出这些功能相似性，可以解释本研究中包括的患者与 CdLS 之间的表型重叠。我们的研究结果指出了 CdLS 临床诊断的复杂性，并证实了表型的存在，这是由影响多个基因组区域的不平衡引起的，包括本研究中 8% 的患者，他们在 NIPBL 和 SMC1A 上没有突变。我们的结果表明，应建议对具有无法解释的临床表型的 CdLS 谱病例进行 aCGH 分析，并将其纳入诊断具有 CdLS 谱临床评估病例的流程图中。
Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. To date, causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively. We recruited 50 patients with a CdLS clinical diagnosis or with features that overlap with CdLS, who were negative for mutations at NIPBL and SMC1A at molecular screening. Chromosomal rearrangements accounting for the clinical diagnosis were screened for using array Comparative Genomic Hybridisation (aCGH). Four patients were shown to carry imbalances considered to be candidates for having pathogenic roles in their clinical phenotypes: patient 1 had a 4.2 Mb de novo deletion at chromosome 20q11.2-q12; patient 2 had a 4.8 Mb deletion at chromosome 1p36.23-36.22; patient 3 carried an unbalanced translocation, t(7;17), with a 14 Mb duplication of chromosome 17q24.2-25.3 and a 769 Kb deletion at chromosome 7p22.3; patient 4 had an 880 Kb duplication of chromosome 19p13.3, for which his mother, who had a mild phenotype, was also shown to be a mosaic. Notwithstanding the variability in size and gene content of the rearrangements comprising the four different imbalances, they all map to regions containing genes encoding factors involved in cell cycle progression or genome stability. These functional similarities, also exhibited by the known CdLS genes, may explain the phenotypic overlap between the patients included in this study and CdLS. Our findings point to the complexity of the clinical diagnosis of CdLS and confirm the existence of phenocopies, caused by imbalances affecting multiple genomic regions, comprising 8% of patients included in this study, who did not have mutations at NIPBL and SMC1A. Our results suggests that analysis by aCGH should be recommended for CdLS spectrum cases with an unexplained clinical phenotype and included in the flow chart for diagnosis of cases with a clinical evaluation in the CdLS spectrum.