Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome
Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome
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DOI：
10.1086/302343
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发表时间：
1999-04-01
影响因子：
9.8
通讯作者：
Morrow, BE
中科院分区：
文献类型：
--
作者：
Edelmann, L;Pandita, RK;Morrow, BE
Velo-cardio-facial syndrome（VCFS）是人类最常见的微缺失综合征。据估计，其发生率为每4 000名活产婴儿中有1人。大多数病例是偶发性的，表明这种缺失在人群中是经常发生的。超过90%的VCFS和22 q11缺失的患者具有类似的3-Mb半合子缺失，这表明断点处的序列赋予重排的易感性。为了确定包含染色体断裂点的区域，我们构建了一个8 kb分辨率的物理图谱。我们在两个断点附近发现了一个低拷贝重复序列。将一组遗传标记整合到物理图谱中以确定缺失是否发生在重复序列内。单倍型分析与侧翼的重复序列的遗传标记表明，大多数患者与VCFS的重复缺失断点。在重复序列内是200-kb的序列重复，包括围绕断点的基因/假基因的串联重复。重复序列中的基因是GGT、BCRL、V7-rel、POM 121-like和GGT-rel。物理作图和基因组指纹分析表明，在200-kb区域内重复序列几乎相同，表明缺失是通过同源重组介导的。对两个三代家系的检测表明，减数分裂染色体内重组介导了缺失。
Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans. It occurs with an estimated frequency of 1 in 4,000 live births. Most cases occur sporadically, indicating that the deletion is recurrent in the population. More than 90% of patients with VCFS and a 22q11 deletion have a similar 3-Mb hemizygous deletion, suggesting that sequences at the breakpoints confer susceptibility to rearrangements. To define the region containing the chromosome breakpoints, we constructed an 8-kb-resolution physical map. We identified a low-copy repeat in the vicinity of both breakpoints. A set of genetic markers were integrated into the physical map to determine whether the deletions occur within the repeat. Haplotype analysis with genetic markers that flank the repeats showed that most patients with VCFS had deletion breakpoints in the repeat. Within the repeat is a 200-kb duplication of sequences, including a tandem repeat of genes/pseudogenes, surrounding the breakpoints. The genes in the repeat are GGT, BCRL, V7-rel, POM121-like, and GGT-rel. Physical mapping and genomic fingerprint analysis showed that the repeats are virtually identical in the 200-kb region, suggesting that the deletion is mediated,by homologous recombination.,Examination of two three-generation families showed that meiotic intrachromosomal recombination mediated the deletion.