title: Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.
abstract: High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed.
authors.affiliation: Inserm, UMR_S 910, Marseille, France; Aix Marseille Université, GMGF, Marseille, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Mignon-Ravix
authors.forename: Pierre
authors.initials: P
authors.lastname: Cacciagli
authors.forename: Nancy
authors.initials: N
authors.lastname: Choucair
authors.forename: Cornel
authors.initials: C
authors.lastname: Popovici
authors.forename: Chantal
authors.initials: C
authors.lastname: Missirian
authors.forename: Mathieu
authors.initials: M
authors.lastname: Milh
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Tiffany
authors.initials: T
authors.lastname: Busa
authors.forename: Sophie
authors.initials: S
authors.lastname: Julia
authors.forename: Nadine
authors.initials: N
authors.lastname: Girard
authors.forename: Catherine
authors.initials: C
authors.lastname: Badens
authors.forename: Sabine
authors.initials: S
authors.lastname: Sigaudy
authors.forename: Nicole
authors.initials: N
authors.lastname: Philip
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
mesh_terms: D002675:Child, Preschool; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D017353:Gene Deletion; D050172:Genes, X-Linked; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D050052:TRPC Cation Channels / Q000235:genetics; D014178:Translocation, Genetic; D049951:X Chromosome Inactivation
chemical_list: C503716:KLHL15 protein, human; D008840:Microfilament Proteins; D050052:TRPC Cation Channels; C491780:TRPC5 protein, human
keywords: KLHL15; TRPC5; X-linked intellectual disability; array CGH