X-linked intellectual disability related genes disrupted by balanced X-autosome translocations.
Detailed molecular characterization of chromosomal rearrangements involving X-chromosome has been a key strategy in identifying X-linked intellectual disability-causing genes. We fine-mapped the breakpoints in four women with balanced X-autosome translocations and variable phenotypes, in order to investigate the corresponding genetic contribution to intellectual disability. We addressed the impact of the gene interruptions in transcription and discussed the consequences of their functional impairment in neurodevelopment. Three patients presented with cognitive impairment, reinforcing the association between the disrupted genes (TSPAN7-MRX58, KIAA2022-MRX98, and IL1RAPL1-MRX21/34) and intellectual disability. While gene expression analysis showed absence of TSPAN7 and KIAA2022 expression in the patients, the unexpected expression of IL1RAPL1 suggested a fusion transcript ZNF611-IL1RAPL1 under the control of the ZNF611 promoter, gene disrupted at the autosomal breakpoint. The X-chromosomal breakpoint definition in the fourth patient, a woman with normal intellectual abilities, revealed disruption of the ZDHHC15 gene (MRX91). The expression assays did not detect ZDHHC15 gene expression in the patient, thus questioning its involvement in intellectual disability. Revealing the disruption of an X-linked intellectual disability-related gene in patients with balanced X-autosome translocation is a useful tool for a better characterization of critical genes in neurodevelopment. © 2015 Wiley Periodicals, Inc.
Department of Morphology and Genetics, Genetics Division, Universidade Federal de São Paulo, São Paulo, Brazil.
Mariana
M
Moysés-Oliveira
Department of Morphology and Genetics, Genetics Division, Universidade Federal de São Paulo, São Paulo, Brazil.|Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Jena, Germany.
Roberta Santos
RS
Guilherme
Department of Morphology and Genetics, Genetics Division, Universidade Federal de São Paulo, São Paulo, Brazil.
Vera Ayres
VA
Meloni
Department of Morphology and Genetics, Genetics Division, Universidade Federal de São Paulo, São Paulo, Brazil.
Adriana
A
Di Battista
Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil.
Claudia Berlim
CB
de Mello
Department of Morphology and Genetics, Genetics Division, Universidade Federal de São Paulo, São Paulo, Brazil.
Silvia
S
Bragagnolo
Departament of Genetics, Instituto de Biocincias de Botucatu, Universidade Estadual de São Paulo, São Paulo, Brazil.
Danilo
D
Moretti-Ferreira
Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Jena, Germany.
Nadezda
N
Kosyakova
Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Jena, Germany.
Thomas
T
Liehr
Department of Morphology and Genetics, Genetics Division, Universidade Federal de São Paulo, São Paulo, Brazil.
Gianna Maria
GM
Carvalheira
Department of Morphology and Genetics, Genetics Division, Universidade Federal de São Paulo, São Paulo, Brazil.
Maria Isabel
MI
Melaragno
D000293:Adolescent; D000328:Adult; D002648:Child; D002874:Chromosome Mapping; D005260:Female; D050172:Genes, X-Linked; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D014178:Translocation, Genetic
IL1RAPL1; KIAA2022; TSPAN7; X-chromosome; ZDHHC15; intellectual disability