Introduction: We describe the case of two brothers diagnosed with autism who both carry a paracentic inversion of the short arm of chromosome 4 (46,XY, inv(4)(p12–p15.3)). We have determined that this inversion is inherited from an apparently unaffected mother and unaffected maternal grandfather.
Methods/Results: Using fluorescence in situ hybridisation analysis and Southern blot hybridisation we identified the breakpoints. The proximal breakpoint (4p12) maps to a region containing a cluster of gamma-aminobutyric acid A (GABA(A)) receptor genes, and directly interrupts the GABRG1 gene, the distal-most gene of the cluster. We also identified an insertion/deletion polymorphism for a ∼2 kb LINE1 (L1) element that occurs within intron 7 of GABRG1. Our genotype analysis amongst autism families indicated that the L1 deletion allele did not show increased transmission to affected individuals. No linkage disequilibrium was evident between the L1 and single nucleotide polymorphisms in adjacent GABA(A) receptor genes on 4p, where a recent study has identified significant association with autism.
Discussion: Despite this, the identification of an inversion breakpoint disrupting GABRG1 provides solid support for the genetic involvement of the short arm of chromosome 4 in the genetic aetiology of autism, and for the hypothesis of disrupted GABA neurotransmission in autism.
Statistics from Altmetric.com
- ADI-R, Autism Diagnostic Interview-Revised
- ADOS, Autism Diagnostic Observation Schedule
- BAC, bacterial artificial chromosome
- CT, computed tomography
- EST, expressed sequence tag
- FISH, fluorescence in situ hybridisation
- GABA(A), gamma-aminobutyric acid A
- L1, LINE1
- LINE, long interspersed nucleotide element
- PPVT IIIA, Peabody Picture Vocabulary Test–3rd Edition
- SINE, short interspersed nucleotide element
- SNP, single nucleotide polymorphism
↵* These authors contributed equally to this work
Published Online First 23 March 2006
This work was supported by Genome Canada/Ontario Genomics Institute, the Howard Hughes Medical Institute (HHMI), the McLaughlin Centre for Molecular Medicine, and The Centre for Applied Genomics. SC received a Postdoctoral Fellowship, in part, through the Hospital for Sick Children Research Training Centre. JBV is a Seaver Foundation and National Alliance for Research into Schizophrenia and Depression (NARSAD) Young Investigator. ADP holds a Canada Research Chair in Genetics of Complex Diseases. SWS is a Scientist of the Canadian Institutes of Health Research and an International Scholar of the HHMI.
Competing interests: none declared
Ethics statement: the study was approved by the Research Ethics Board of The Hospital for Sick Children and CAMH, and informed, written consent was obtained from the participating families
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.