title: Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features.
abstract: 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.
authors: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors: Nathalie
authors: N
authors: Fieremans
authors: Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors: Hilde
authors: H
authors: Van Esch
authors: Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors: Thomy
authors: T
authors: de Ravel
authors: Marie-Marguerite Delacroix Foundation, Tienen, Belgium.
authors: Jozef
authors: J
authors: Van Driessche
authors: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors: Stefanie
authors: S
authors: Belet
authors: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium; Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors: Marijke
authors: M
authors: Bauters
authors: Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium. Electronic address: guy.froyen@med.kuleuven.be.
authors: Guy
authors: G
authors: Froyen
mesh_terms: D001321:Autistic Disorder / Q000175:diagnosis* / Q000235:genetics; D002872:Chromosome Deletion; D005260:Female; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics; D055815:Young Adult
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C550083:IQSEC2 protein, human; D056466:Histone Demethylases; C086877:KDM5C protein, human
keywords: IQSEC2; Intellectual disability; KDM5C; Skewing of X-inactivation; Xp11.22 deletion