Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant.
Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant.
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DOI：
10.1136/jmg.2007.055202
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发表时间：
2009-04
影响因子：
4
通讯作者：
Vermeesch JR
中科院分区：
文献类型：
--
作者：
Hannes FD;Sharp AJ;Mefford HC;de Ravel T;Ruivenkamp CA;Breuning MH;Fryns JP;Devriendt K;Van Buggenhout G;Vogels A;Stewart H;Hennekam RC;Cooper GM;Regan R;Knight SJ;Eichler EE;Vermeesch JR
基因组疾病通常是由片段重复之间的非等位基因同源重组引起的。染色体16特别富含染色体特异性低拷贝重复序列，称为LCR 16。采用细菌人工染色体（BAC）阵列比较基因组杂交（CGH）技术对1027例智力低下和/或多发性先天性畸形（MR/MCA）患者进行筛查。BAC阵列CGH筛选鉴定了5名缺失患者和5名具有覆盖1.65 Mb的16 p13的明显相互重复的患者，包括15个RefSeq基因。高分辨率寡核苷酸芯片的精细定位表明，这些缺失和重复是由不同LCR 16亚基之间的非等位基因同源重组（NAHR）引起的，序列同一性>99%。缺失和重复要么是新生的，要么是从未受影响的父母那里遗传的。为了确定这些不平衡是否与MR/MCA表型相关，或者它们是否可能是良性变异，筛选了2014名正常对照人群。对照人群中缺失的缺失表明16p13.11缺失与MR/MCA显著相关（p = 0.0048）。 尽管表型变异，共同的特点是确定：三个缺失的患者表现为MR，小头畸形和癫痫（其中两个也有身材矮小），和其他两个删除载体产前确定与唇裂和中线缺陷。与先前与自闭症的关联相反，重复似乎是人群中常见的变异（5/1682，0.29%）。这些发现表明，从临床正常的父母遗传的缺失可能是患者表型的原因，而重复（从头或遗传）在表型中的作用仍然不确定。关于缺失和重复的临床相关性的知识的这种差异导致（细胞）遗传咨询的范式转变。
Genomic disorders are often caused by non-allelic homologous recombination between segmental duplications. Chromosome 16 is especially rich in a chromosome-specific low copy repeat, termed LCR16. A bacterial artificial chromosome (BAC) array comparative genome hybridisation (CGH) screen of 1027 patients with mental retardation and/or multiple congenital anomalies (MR/MCA) was performed. The BAC array CGH screen identified five patients with deletions and five with apparently reciprocal duplications of 16p13 covering 1.65 Mb, including 15 RefSeq genes. In addition, three atypical rearrangements overlapping or flanking this region were found. Fine mapping by high-resolution oligonucleotide arrays suggests that these deletions and duplications result from non-allelic homologous recombination (NAHR) between distinct LCR16 subunits with >99% sequence identity. Deletions and duplications were either de novo or inherited from unaffected parents. To determine whether these imbalances are associated with the MR/MCA phenotype or whether they might be benign variants, a population of 2014 normal controls was screened. The absence of deletions in the control population showed that 16p13.11 deletions are significantly associated with MR/MCA (p = 0.0048). Despite phenotypic variability, common features were identified: three patients with deletions presented with MR, microcephaly and epilepsy (two of these had also short stature), and two other deletion carriers ascertained prenatally presented with cleft lip and midline defects. In contrast to its previous association with autism, the duplication seems to be a common variant in the population (5/1682, 0.29%). These findings indicate that deletions inherited from clinically normal parents are likely to be causal for the patients’ phenotype whereas the role of duplications (de novo or inherited) in the phenotype remains uncertain. This difference in knowledge regarding the clinical relevance of the deletion and the duplication causes a paradigm shift in (cyto)genetic counselling.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
影响因子：
30.8
作者：
Iafrate, AJ;Feuk, L;Lee, C
通讯作者：
Lee, C
影响因子：
56.9
作者：
Sebat, J;Lakshmi, B;Wigler, M
通讯作者：
Wigler, M
影响因子：
4
作者：
Menten, B.;Maas, N.;Vermeesch, J. R.
通讯作者：
Vermeesch, J. R.
影响因子：
56.9
作者：
Bailey, JA;Gu, ZP;Eichler, EE
通讯作者：
Eichler, EE