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A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures


We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4–BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes.

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Figure 1: High-resolution oligonucleotide array mapping of 15q12–q13.3 rearrangements (chr15:25700000–31400000).
Figure 2: Pedigrees and photographs of individuals with 15q13 deletions.
Figure 3: Duplication architecture of 15q13 breakpoint regions.
Figure 4: Duplications identified in two of 960 normal control samples using the Illumina HumanHap300 Genotyping BeadChip.
Figure 5: Identification of a common inversion polymorphism in 15q13.3.

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We are grateful to R. Krauss and the PARC project for the use and analysis of Illumina SNP genotyping data, funded by US National Institutes of Health (NIH) grant U01 HL069757. This work was supported in part by grants from the NIH (HD043569, E.E.E.), the South Carolina Department of Disabilities and Special Needs (C.S., R.E.S., R.J.S. and C.E.S.), Oxford Genetics Knowledge Park and the Oxford National Institute for Health Research (NIHR) Biomedical Research Centre (R.R. and S.J.L.K.), Fondazione Mariani, CARIPLO and PRIN 2005 (O.Z.), and the Italian Ministry of Health (C.R., P.F., L.C. and M.F.). EEE is an Investigator of the Howard Hughes Medical Institute.

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A.J.S., H.C.M. and E.E.E. contributed to the writing of this paper. The study was coordinated by A.J.S., H.C.M., S.J.L.K., C.R., O.Z., C.C., C.E.S. and E.E.E.; experimental work was done by A.J.S., H.C.M., K.L., C. Baker, F.N., M.D.G., R.C., A.B., G.G., R.R., M.F., L.C., P.F. and M.V.; clinical work was done by R.E.S., R.J.S., B.D.B., C.T., R.G., V.M., S.M., C.S. and C.R.; computational analysis was performed by Y.W., C.X., C. Barbacioru, Z.J., I.C. and G.M.C.

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Correspondence to Evan E Eichler.

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Competing interests

K. Li, A.J. Broomer, Y.Wang, C. Xiao, C. Barbacioru and C. Chen are employees of Applied Biosystems, Inc. and have stock options in the company.

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Sharp, A., Mefford, H., Li, K. et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40, 322–328 (2008).

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