Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients
Molecular definition of 22q11 deletions in 151 velo-cardio-facial syndrome patients
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DOI：
10.1086/515508
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发表时间：
1997-09-01
影响因子：
9.8
通讯作者：
Morrow, BE
中科院分区：
文献类型：
--
作者：
Carlson, C;Sirotkin, H;Morrow, BE
血管心面综合征(VCFS)是一种相对常见的发育障碍，以颅面畸形和圆锥干心脏缺陷为特征，许多VCFS患者存在22q11的Parr半合缺失，提示该区域的单倍体功能不全是其病因。由于大多数VCFS病例是散发性的，22q11的部分可能容易重排，为了了解染色体缺失的分子基础，我们定义了缺失的程度，通过对151例VCFS患者进行基因分型和对105例患者进行单倍型分析，在22q11连续使用15个多态标记，我们发现83%的VCFS患者存在缺失和>；其中90%的序列具有类似于3Mb的缺失，这表明共同断裂点两侧的序列容易重排。我们没有发现缺失的存在或大小与表型之间的相关性。为了进一步确定VCFS患者中的染色体断裂点，我们从一组VCFS患者中建立了体细胞杂交细胞系。构建了包含缺失断裂点的1,080kb区域的11kb分辨率物理图谱，结合杂交选择方法分离的基因和表达序列标签(EST)，利用有序标记检测体细胞杂交细胞系中分离的22号染色体的两个副本。在某些情况下，我们能够定位单个粘粒内的染色体断裂点，已经描绘出VCFS的一个480kb的临界区，包括GSCL、CTP、CLTD、HIRA和TMVCF基因，以及一些新的有序EST。
Velo-cardio-facial syndrome (VCFS) is a relatively common developmental disorder characterized by craniofacial anomalies and conotruncal heart defects, Many VCFS patients have hemizygous deletions for a parr of 22q11, suggesting that haploinsufficiency in this region is responsible for its etiology, Because most cases of VCFS are sporadic, portions of 22q11 may be prone to rearrangement, To understand the molecular basis for chromosomal deletions, we defined the extent of the deletion, by genotyping 151 VCFS patients and performing haplotype analysis on 105, using 15 consecutive polymorphic markers in 22q11, We found that 83% had a deletion and >90% of these had a similar similar to 3 Mb deletion, suggesting that sequences flanking the common breakpoints are susceptible to rearrangement. We found no correlation between the presence or size of the deletion and the phenotype. To further define the chromosomal breakpoints among the VCFS patients, we developed somatic hybrid cell lines from a set of VCFS patients. An 11-kb resolution physical map of a 1,080-kb region that includes deletion breakpoints was constructed, incorporating genes and expressed sequence tags (ESTs) isolated by the hybridization selection method, The ordered markers were used to examine the two separated copies of chromosome 22 in the somatic hybrid cell lines. Ln some cases, we were able to map the chromosome breakpoints within a single cosmid, A 480-kb critical region for VCFS has been delineated, including the genes for GSCL, CTP, CLTD, HIRA, and TMVCF, as well as a number of novel ordered ESTs.