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Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome

(2009) JOURNAL OF MEDICAL GENETICS. 46(8). p.511-523
Author
Organization
Abstract
Background: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy. Methods: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region. Results: The 15q13.3 microdeletion in our series was associated with a highly variable intra-and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients. Conclusions: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.
Keywords
LINKAGE DISEQUILIBRIUM, CHROMOSOME 22Q11, PRADER-WILLI, MENTAL-RETARDATION, SEGMENTAL DUPLICATIONS, MOLECULAR CHARACTERIZATION, ARRAY-CGH, ABSENT-RADIUS SYNDROME, HUMAN GENOME, COPY-NUMBER VARIATION

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MLA
van Bon, BWM et al. “Further Delineation of the 15q13 Microdeletion and Duplication Syndromes: a Clinical Spectrum Varying from Non-pathogenic to a Severe Outcome.” JOURNAL OF MEDICAL GENETICS 46.8 (2009): 511–523. Print.
APA
van Bon, B., Mefford, H., Menten, B., Koolen, D., Sharp, A., Nillesen, W., Innis, J., et al. (2009). Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. JOURNAL OF MEDICAL GENETICS, 46(8), 511–523.
Chicago author-date
van Bon, BWM, HC Mefford, Björn Menten, DA Koolen, AJ Sharp, WM Nillesen, JW Innis, et al. 2009. “Further Delineation of the 15q13 Microdeletion and Duplication Syndromes: a Clinical Spectrum Varying from Non-pathogenic to a Severe Outcome.” Journal of Medical Genetics 46 (8): 511–523.
Chicago author-date (all authors)
van Bon, BWM, HC Mefford, Björn Menten, DA Koolen, AJ Sharp, WM Nillesen, JW Innis, TJL de Ravel, CL Mercer, M Fichera, H Stewart, LE Connell, K Ounap, K Lachlan, B Castle, N Van der Aa, C van Ravenswaaij, MA Nobrega, C Serra-Juhe, I Simonic, N de Leeuw, R Pfundt, EM Bongers, C Baker, P Finnemore, S Huang, VK Maloney, JA Crolla, M van Kalmthout, M Elia, G Vandeweyer, JP Fryns, Sandra Janssens, N Foulds, S Reitano, K Smith, S Parkel, Bart Loeys, CG Woods, Ann Oostra, Franki Speleman, AC Pereira, A Kurg, L Willatt, SJL Knight, JR Vermeesch, C Romano, JC Barber, Geert Mortier, LA Perez-Jurado, F Kooy, HG Brunner, EE Eichler, T Kleefstra, and BBA de Vries. 2009. “Further Delineation of the 15q13 Microdeletion and Duplication Syndromes: a Clinical Spectrum Varying from Non-pathogenic to a Severe Outcome.” Journal of Medical Genetics 46 (8): 511–523.
Vancouver
1.
van Bon B, Mefford H, Menten B, Koolen D, Sharp A, Nillesen W, et al. Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. JOURNAL OF MEDICAL GENETICS. LONDON: B M J PUBLISHING GROUP; 2009;46(8):511–23.
IEEE
[1]
B. van Bon et al., “Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome,” JOURNAL OF MEDICAL GENETICS, vol. 46, no. 8, pp. 511–523, 2009.
@article{839113,
  abstract     = {Background: Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy.

Methods: To assess further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region.

Results: The 15q13.3 microdeletion in our series was associated with a highly variable intra-and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients.

Conclusions: Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.},
  author       = {van Bon, BWM and Mefford, HC and Menten, Björn and Koolen, DA and Sharp, AJ and Nillesen, WM and Innis, JW and de Ravel, TJL and Mercer, CL and Fichera, M and Stewart, H and Connell, LE and Ounap, K and Lachlan, K and Castle, B and Van der Aa, N and van Ravenswaaij, C and Nobrega, MA and Serra-Juhe, C and Simonic, I and de Leeuw, N and Pfundt, R and Bongers, EM and Baker, C and Finnemore, P and Huang, S and Maloney, VK and Crolla, JA and van Kalmthout, M and Elia, M and Vandeweyer, G and Fryns, JP and Janssens, Sandra and Foulds, N and Reitano, S and Smith, K and Parkel, S and Loeys, Bart and Woods, CG and Oostra, Ann and Speleman, Franki and Pereira, AC and Kurg, A and Willatt, L and Knight, SJL and Vermeesch, JR and Romano, C and Barber, JC and Mortier, Geert and Perez-Jurado, LA and Kooy, F and Brunner, HG and Eichler, EE and Kleefstra, T and de Vries, BBA},
  issn         = {0022-2593},
  journal      = {JOURNAL OF MEDICAL GENETICS},
  keywords     = {LINKAGE DISEQUILIBRIUM,CHROMOSOME 22Q11,PRADER-WILLI,MENTAL-RETARDATION,SEGMENTAL DUPLICATIONS,MOLECULAR CHARACTERIZATION,ARRAY-CGH,ABSENT-RADIUS SYNDROME,HUMAN GENOME,COPY-NUMBER VARIATION},
  language     = {eng},
  number       = {8},
  pages        = {511--523},
  publisher    = {B M J PUBLISHING GROUP},
  title        = {Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome},
  url          = {http://dx.doi.org/10.1136/jmg.2008.063412},
  volume       = {46},
  year         = {2009},
}

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