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A CGG‐Repeat Expansion Mutation in ZNF713 Causes FRA7A: Association with Autistic Spectrum Disorder in Two Families |
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| Authors: | Sofie Metsu Jacqueline K. Rainger Kim Debacker Birgitta Bernhard Liesbeth Rooms Daria Grafodatskaya Rosanna Weksberg Eric Fombonne Martin S. Taylor Stephen W. Scherer R. Frank Kooy David R. FitzPatrick |
| Affiliation: | 1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium;2. MRC Human Genetics Unit, MRC Institute of Genomic and Molecular Medicine, University of Edinburgh, Edinburgh, UK;3. South‐East Scotland Regional Genetics Services, Western General Hospital, Edinburgh, UK;4. Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada;5. Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada;6. Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada;7. Department of Psychiatry, Montreal Children's Hospital, Montréal, Quebec, Canada;8. McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada |
| Abstract: | We report de novo occurrence of the 7p11.2 folate‐sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG‐repeat expansion mutation (～450 repeats) in a 5′ intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband‐derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG‐repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed. |
| Keywords: | autism folate sensitive fragile site CGG repeat ZNF713 |