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Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome)

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Abstract

We performed a prospective analysis on 14 11q- patients to determine the relationship between the degree of cognitive impairment and relative deletion size. Seventeen measures of cognitive function were assessed. All nine patients with a deletion of at least 12.1 Mb had severe global cognitive impairment, with full-scale IQ <50, whereas all five patients with smaller deletions, ≤11.8 Mb, demonstrated mild cognitive impairment, with a full-scale IQ of 63 or higher (p < 0.001). Among these five patients, the two patients with the larger deletions (11.4, 11.8 Mb) had a selective impairment in freedom from distractability compared to the three patients with smaller deletions (≤9.1 Mb). We propose the presence of a proximal critical region that contains a gene for global cognitive function and a distal critical region that contains a gene essential for auditory attention, which may be necessary for optimizing intellectual function. The proximal critical region is 300 kb and contains three annotated genes. One of these genes, BSX, encodes a brain-specific homeobox protein that in gene-targeted mice has been shown previously to have a role in regulating locomotory behavior via BSX-expressing neurons in the hypothalamus. The distal critical region, ∼2.2 Mb, contains 18 annotated genes. One gene in this region, Neurogranin, has been demonstrated previously in mice to be critical for synapse plasticity and long-term potentiation. Taken together, our results implicate the presence of at least two loci in distal 11q that when deleted, cause global and selective deficits in neurocognitive function. These findings have important implications for genetic counseling and potential gene-specific therapies.

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Acknowledgments

The authors would like to thank all of the 11q- patients and their families for their participation in this study. This work was supported by PRIN 2005 and 2006 (OZ and ER), Fondazione Mariani and Fondazione CARIPLO (OZ), The Carson Foundation (CC, DI), NIH/NHLBI SCCOR P50 HL084923 (CC, DI), and grant #MO1-RR00827 for the General Clinical Research Center at UCSD from the NCRR of the NIH (PS).

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Authors and Affiliations

  1. Department of Pulmonary Medicine, University of Colorado Health Sciences Center, Denver, CO, USA

    C. D. Coldren & S. C. Glidewell

  2. San Diego, CA, USA

    Z. Lai

  3. Department of Medicine, UCSD School of Medicine, La Jolla, CA, USA

    P. Shragg

  4. Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy

    E. Rossi & O. Zuffardi

  5. Department of Medical Genetics, University of Catania, Catania, Italy

    T. Mattina

  6. Division of Pediatric Cardiology, The Children’s Hospital, Denver, CO, USA

    D. D. Ivy

  7. Department of Clinical Genetics, Academic Hospital Maastricht, Maastricht, The Netherlands

    L. M. Curfs

  8. Department of Psychology, Center for Behavioral Teratology, San Diego State University, San Diego, CA, USA

    S. N. Mattson & E. P. Riley

  9. Developmental Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany

    M. Treier

  10. Division of Cardiology, Department of Pediatrics, UCSD School of Medicine, La Jolla, CA, USA

    P. D. Grossfeld

  11. Division of Pediatric Cardiology, 3020 Children’s Way, San Diego, CA, 92123, USA

    P. D. Grossfeld

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  1. C. D. Coldren
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  2. Z. Lai
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  4. E. Rossi
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  6. O. Zuffardi
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  7. T. Mattina
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  9. L. M. Curfs
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  10. S. N. Mattson
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  11. E. P. Riley
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  12. M. Treier
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  13. P. D. Grossfeld
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Corresponding author

Correspondence to P. D. Grossfeld.

Additional information

C. D. Coldren and Z. Lai contributed equally to this work.

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Supplemental Table 1

Deletion breakpoints on 14 patients determined by chromosomal microarray analysis, listed in descending order of deletion size. Patient JS14 has an interstitial deletion; the other 13 patients have terminal deletions. The numbers correspond to the map position in 11q from NCBI Build 36.1. (DOC 23.5 KB)

Supplemental Table 2

Student independent group t test comparing patients with large (≥12.1 Mb) deletions to those with smaller (≤11.8 Mb) deletions. For each variable, the top row represents the patient group with the smallest deletions, and the bottom row represents the patients with the largest deletions, as well as the one patient with an interstitial deletion. Not all variables were able to be assessed on all patients. Abbreviations: See legend to Table 1. (PDF 147 KB)

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Coldren, C.D., Lai, Z., Shragg, P. et al. Chromosomal microarray mapping suggests a role for BSX and Neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome). Neurogenetics 10, 89–95 (2009). https://doi.org/10.1007/s10048-008-0157-x

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  • DOI: https://doi.org/10.1007/s10048-008-0157-x

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