Autism-associated familial microdeletion of Xp11.22
Autism-associated familial microdeletion of Xp11.22
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DOI：
10.1111/j.1399-0004.2008.01028.x
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发表时间：
2008-08-01
影响因子：
3.5
通讯作者：
Lewis, M. E. S.
中科院分区：
文献类型：
--
作者：
Qiao, Y.;Liu, X.;Lewis, M. E. S.
通过使用1mb分辨率阵列比较基因组杂交技术筛选自闭症谱系障碍（asd）患者进行微缺失和重复，我们描述了患有自闭症、智力障碍（ID）和唇腭裂的两兄弟，他们检测到Xp11.22微缺失。通过荧光原位杂交/实时定量聚合酶链反应（RT-qPCR）证实了该缺失，并显示其遗传自未受影响的母亲，该母亲的异常染色体扭曲（100%）X失活。对del(X)（p11.22）区域（类似于53,887,000-54,359,000 bp）的RT-qPCR表征显示，植物同源结构域手指蛋白8 （PHF8）基因完全缺失，以及FAM120C和WNK赖氨酸缺陷蛋白激酶3 （WNK3）基因缺失，其明确的表型先前尚未表征。Xp11.2是几个神经发育障碍的关键连锁区间内的一个基因丰富区域。罕见的Xp11.22间质微缺失已被识别为ID，颅面畸形和/或唇腭裂以及该区域内PHF8基因的截断突变。尽管有证据表明Xp11.22中与语言和认知发育有关的基因可能导致ASD表型，但它们与自闭症的关系尚未得到系统的评估。在各自的ASD和对照队列中，481（319名男性/81名女性）和282条X染色体（90名男性/96名女性）的群体筛查未发现携带这种缺失的其他受试者。我们的研究结果表明，除了点突变外，PHF8基因的完全缺失与x连锁智力低下Siderius-Hamel综合征（OMIM 300263）有关，并进一步表明，包括FAM120C和WNK3基因在内的Xp11.22基因的较大缺失可能参与了自闭症的发病机制。
We describe two brothers with autistic disorder, intellectual disability (ID) and cleft lip/palate with a microdeletion of Xp11.22 detected through screening individuals with autism spectrum disorders (ASDs) for microdeletions and duplications using 1-Mb resolution array comparative genomic hybridization. The deletion was confirmed by fluorescence in situ hybridization/real-time quantitative polymerase chain reaction (RT-qPCR) and shown to be inherited from their unaffected mother who had skewed (100%) X inactivation of the aberrant chromosome. RT-qPCR characterization of the del(X)(p11.22) region (similar to 53,887,000-54,359,000 bp) revealed complete deletion of the plant homeodomain finger protein 8 (PHF8) gene as well as deletions of the FAM120C and WNK lysine-deficient protein kinase 3 (WNK3) genes, for which a definitive phenotype has not been previously characterized. Xp11.2 is a gene-rich region within the critical linkage interval for several neurodevelopmental disorders. Rare interstitial microdeletions of Xp11.22 have been recognized with ID, craniofacial dysmorphism and/or cleft lip/palate and truncating mutations of the PHF8 gene within this region. Despite evidence implicating genes within Xp11.22 with language and cognitive development that could contribute to an ASD phenotype, their involvement with autism has not been systematically evaluated. Population screening of 481 (319 males/81 females) and 282 X chromosomes (90 males/96 females) in respective ASD and control cohorts did not identify additional subjects carrying this deletion. Our findings show that in addition to point mutations, a complete deletion of the PHF8 gene is associated with the X-linked mental retardation Siderius-Hamel syndrome (OMIM 300263) and further suggest that the larger size of the Xp11.22 deletion including genes FAM120C and WNK3 may be involved in the pathogenesis of autism.