Systematic assessment of atypical deletions reveals genotype-phenotype correlation in 22q11.2
Systematic assessment of atypical deletions reveals genotype-phenotype correlation in 22q11.2
复制标题
DOI：
10.1136/jmg.2004.030619
复制
发表时间：
2005-11-01
影响因子：
4
通讯作者：
Hofbeck, M
中科院分区：
文献类型：
--
作者：
Rauch, A;Zink, S;Hofbeck, M
前言：与常见的22q11.2微缺失相关的临床变异是众所周知的，并已导致FISH诊断的广泛应用，其探针为TUPLE1或D22S75(N25)，尽管很少报道与相同表型谱相关的非典型缺失，但这些探针不会发现这些缺失。由于大多数类型的22q11.2缺失发生在区域内的低拷贝重复之间(LCR22)，我们假设非典型缺失应该比已报道的更常见。为了解决这个问题，以及与缺失大小相关的基因型-表型相关性的可能性，我们系统地评估了大量患者中典型和非典型22q11.2缺失的频率。方法：我们使用了一组10个荧光原位杂交(FISH)DNA探针，能够检测LCR22之间所有已报道的和假设的缺失，并分析了350名患者。通过使用进一步的FISH探针确定非典型缺失中的缺失大小。结果：圆锥干心脏缺陷(CtCHD)和典型VCFS表型患者存在常见的3Mb或嵌套式1.5Mb缺失(分别为18.5%和78.6%)，但无非典型缺失；而轻度提示、不典型表型的患者中有5%(3/63)出现不典型的远端缺失，这在原因不明的智力低下患者和健康对照组中未发现。讨论：这些差异表明22q11.2远端非典型缺失在ctCHD患者中非常罕见而不典型的先天性心脏缺陷和轻度畸形是非典型远端缺失的可识别特征。进一步的表型-基因分析显示，显著的发育迟缓与共同缺失区的远端部分有关，后鼻孔闭锁和不典型先心病与邻近的远端缺失区相关。
Introduction: Clinical variability associated with the common 22q11.2 microdeletion is well known, and has led to a broad application of FISH diagnostics with probes for loci TUPLE1 or D22S75 (N25), although, rarely reported atypical deletions associated with the same phenotypic spectrum would not be discovered by these probes. As most types of 22q11.2 deletions occur between low copy repeats within the region (LCR22), we assumed that atypical deletions should be more common than has been reported. To address this question and the possibility of a deletion size related genotype-phenotype correlation, we systematically assessed the frequency of typical and atypical 22q11.2 deletions in a large cohort of patients.Methods: We used a set of 10 fluorescent in situ hybridisation (FISH) DNA probes, capable of detecting all reported and hypothetical deletions between the LCR22, and analysed 350 patients. Deletion sizes in atypical deletions were established by use of further FISH probes. Frequency of certain atypical deletions was analysed in controls by FISH and quantitative PCR.Results: Patients with conotruncal heart defects (ctCHD) and with typical VCFS phenotype showed the common 3 Mb or nested 1.5 Mb deletions (in 18.5% and 78.6%, respectively), but no atypical deletion, while 5% (3/63) of patients with a mildly suggestive, atypical phenotype showed atypical distal deletions, which were not detected in patients with mental retardation of unknown origin or in healthy controls.Discussion: These statistically significant differences demonstrate that atypical distal 22q11.2 deletions are very uncommon in patients with ctCHDs, while atypical congenital heart defects and mild dysmorphism are recognisable feature of atypical distal deletions. Further phenotype-genotype analysis disclosed association of significant developmental delay with the distal part of the common deletion region, and choanal atresia and atypical CHDs with the adjacent distal deletion region.