Fieremans Nathalie, Van Esch Hilde, de Ravel Thomy, Van Driessche Jozef, Belet Stefanie, Bauters Marijke, Froyen Guy
Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium.
Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
Eur J Med Genet. 2015 May;58(5):324-7. doi: 10.1016/j.ejmg.2015.03.003. Epub 2015 Apr 7.
Intellectual disability (ID) is a very heterogeneous disorder with over 100 ID genes located on the X chromosome alone. Of these, KDM5C and IQSEC2 are located adjacent to each other at the Xp11.22 locus. While mutations in either of these genes are associated with severe ID in males, female carriers are mostly unaffected. Here, we report on a female patient with severe ID and autistic features carrying a de novo 0.4 Mb deletion containing six coding genes including KDM5C and IQSEC2. X-inactivation analysis revealed skewing in a lymphocyte-derived cell line from this patient with preferential inactivation of the mutant X chromosome. As the brain-expressed KDM5C and IQSEC2 genes escape X-inactivation, deletion of these alleles could still be detrimental despite skewing of X-inactivation. Indeed, mutations in either of both genes have been reported in a few female ID patients. Expression analysis in the patients' cell line revealed decreased KDM5C mRNA levels compared to female controls. IQSEC2 levels could not be compared due to very low expression in blood. Overall, our data suggest that heterozygous loss-of-function of the escape genes KDM5C and/or IQSEC2 can contribute to severe ID in female patients and should be taken into account in diagnostics.
智力障碍（ID）是一种非常异质性的疾病，仅X染色体上就有100多个与ID相关的基因。其中，KDM5C和IQSEC2在Xp11.22位点彼此相邻。虽然这两个基因中的任何一个发生突变都与男性的严重ID相关，但女性携带者大多不受影响。在此，我们报告一名患有严重ID和自闭症特征的女性患者，其携带一个从头发生的0.4 Mb缺失，该缺失包含六个编码基因，包括KDM5C和IQSEC2。X染色体失活分析显示，该患者淋巴细胞系中存在偏斜，突变的X染色体优先失活。由于在大脑中表达的KDM5C和IQSEC2基因逃避X染色体失活，尽管X染色体失活存在偏斜，但这些等位基因的缺失仍可能有害。事实上，已有少数女性ID患者报道了这两个基因中的任何一个发生突变。患者细胞系中的表达分析显示，与女性对照相比，KDM5C mRNA水平降低。由于在血液中表达极低，无法对IQSEC2水平进行比较。总体而言，我们的数据表明，逃避基因KDM5C和/或IQSEC2的杂合性功能丧失可能导致女性患者出现严重ID，在诊断中应予以考虑。
