Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions
Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions
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DOI：
10.1136/jmedgenet-2011-100125
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发表时间：
2011-12-01
影响因子：
4
通讯作者：
Cheung, Sau Wai
中科院分区：
文献类型：
--
作者：
El-Hattab, Ayman W.;Fang, Ping;Cheung, Sau Wai
X连锁智力残疾（XLID）是常见的，估计患病率为1/1000。阵列比较基因组杂交（CGH）的扩大使用，导致了几个XLID相关的拷贝数variants.Methods阵列CGH分析进行染色体微阵列与类似的105 000寡核苷酸覆盖整个基因组的鉴定。随后进行了荧光原位杂交分析。染色体X失活（XCI）进行了评估，甲基化敏感的限制性内切酶消化，然后通过PCR amplified.Results一个新的类似0.5 Mb的重复Xq 28被确定在四个认知功能障碍的男性谁共享行为异常（多动和侵略性）和面部特征（高额头，上眼睑丰满，宽鼻梁和厚下唇）。这些重复遗传自XCI偏侧的母亲，并由低拷贝重复区域int 22 h-1和int 22 h-2之间的非等位基因同源重组介导，除了int 22 h-3之外，int 22 h-1和int 22 h-2也负责破坏血友病A中因子VIII基因的倒位。此外，我们已经确定了一个女孩和她的母亲，他们都表现出正常的认知和完全扭曲的XCI相互删除。母亲也有两个自然aborts.Conclusions int 22 h-1/int 22 h-2介导的Xq 28重复的受试者之间的表型相似性表明，这种重复是负责一种新的XLID综合征。由于XCI偏斜，相互缺失可能与携带者女性的临床表型无关，但对于子宫内的男性可能是致命的。阵列CGH技术的进步使得能够鉴定这种小的、临床相关的拷贝数变体。
Background X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants.Methods Array CGH analysis was performed using chromosomal microarray with similar to 105 000 oligonucleotides covering the entire genome. Confirmatory fluorescence in situ hybridisation analyses were subsequently performed. Chromosome X-inactivation (XCI) was assessed using methylation-sensitive restriction enzyme digestion followed by PCR amplification.Results A novel similar to 0.5 Mb duplication in Xq28 was identified in four cognitively impaired males who share behavioural abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip). These duplications were inherited from mothers with skewed XCI and are mediated by nonallelic homologous recombination between the low-copy repeat regions int22h-1 and int22h-2, which, in addition to int22h-3, are also responsible for inversions disrupting the factor VIII gene in haemophilia A. In addition, we have identified a reciprocal deletion in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions.Conclusions The phenotypic similarities among subjects with int22h-1/int22h-2-mediated Xq28 duplications suggest that such duplications are responsible for a novel XLID syndrome. The reciprocal deletion may not be associated with a clinical phenotype in carrier females due to skewed XCI, but may be lethal for males in utero. Advancements in array CGH technology have enabled the identification of such small, clinically relevant copy-number variants.