Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability

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Recently, the application of array-based comparative genomic hybridization (array CGH) has improved rates of detection of chromosomal imbalances in individuals with mental retardation and dysmorphic features1,2,3,4. Here, we describe three individuals with learning disability and a heterozygous deletion at chromosome 17q21.3, detected in each case by array CGH. FISH analysis demonstrated that the deletions occurred as de novo events in each individual and were between 500 kb and 650 kb in size. A recently described 900-kb inversion that suppresses recombination between ancestral H1 and H2 haplotypes5 encompasses the deletion. We show that, in each trio, the parent of origin of the deleted chromosome 17 carries at least one H2 chromosome. This region of 17q21.3 shows complex genomic architecture with well-described low-copy repeats (LCRs)5,6. The orientation of LCRs flanking the deleted segment in inversion heterozygotes is likely to facilitate the generation of this microdeletion by means of non-allelic homologous recombination.

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Figure 1: Clinical photographs of affected individuals.
Figure 2: MAPT haplotypes at 17q21.31.
Figure 3: Extended MAPT haplotypes in the three trios.


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This work was funded by the Wellcome Trust. A.P., R.d.S., and A.J.L. are funded by the Reta Lila Weston Trust for Medical Research. This work is also supported by a grant from the UK Medical Research Council (MRC) to R.d.S. The Brazilian authors are supported by the State of São Paulo Foundation for Research (FAPESP) and the Brazilian National Foundation for Research (CNPq). Arrays were printed by the Microarray Facility of the Wellcome Trust Sanger Institute. The authors thank L. Raymond for use of laboratory facilities, J. Cox for bioinformatics advice and G. Parkin and E. Kerr for technical support. The authors wish to thank the affected individuals and their families for contributing to this research study.

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Correspondence to Charles Shaw-Smith.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

FISH images for selected probes. (PDF 21 kb)

Supplementary Fig. 2

Depiction of possible nonallelic homologous recombination events in inversion heterozygote and homozygote parents. (PDF 20 kb)

Supplementary Table 1

FISH probes used to determine deletion size relative to fully sequenced tiling path clones. (PDF 16 kb)

Supplementary Table 2

Probes used to determine deletion size relative to H1 and H2 haplotypes in patients 1–3. (PDF 48 kb)

Supplementary Table 3

PCR primer sequences for genotyping SNPs and MAPT-repeat-t used in the haplotype analysis in the triads. (PDF 15 kb)

Supplementary Table 4

Genotype results of the SNPs, the H1/H2 insertion/deletion polymorphism and the tetranucleotide MAPT-repeat-t in the three trials. (PDF 30 kb)

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Shaw-Smith, C., Pittman, A., Willatt, L. et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet 38, 1032–1037 (2006) doi:10.1038/ng1858

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