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  Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type

Flöttmann, R., Wagner, J., Kobus, K., Curry, C. J., Savarirayan, R., Nishimura, G., et al. (2015). Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type. Journal of Medical Genetics, 52(7), 476-483. doi:10.1136/jmedgenet-2015-103108.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-020E-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-020F-2
Genre: Journal Article

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© 2015 by the BMJ Publishing Group Ltd
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Flöttmann, R., Author
Wagner, J., Author
Kobus, K.1, Author
Curry, C. J., Author
Savarirayan, R., Author
Nishimura, G., Author
Yasui, N., Author
Spranger, J., Author
Van Esch, H., Author
Lyons, M. J., Author
DuPont, B. R., Author
Dwivedi, A., Author
Klopocki, E., Author
Horn, D., Author
Mundlos, Stefan1, 2, 3, Author              
Spielmann, M.1, 2, 3, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany , ou_persistent22              
3Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany , ou_persistent22              

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 Abstract: INTRODUCTION: Mesomelic dysplasias are a group of skeletal disorders characterised by shortness of the middle limb segments (mesomelia). They are divided into 11 different categories. Among those without known molecular basis is mesomelic dysplasia Savarirayan type, characterised by severe shortness of the middle segment of the lower limb. OBJECTIVE: To identify the molecular cause of mesomelic dysplasia Savarirayan type. METHODS AND RESULTS: We performed array comparative genomic hybridisation in three unrelated patients with mesomelic dysplasia Savarirayan type and identified 2 Mb overlapping de novo microdeletions on chromosome 6p22.3. The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4. All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae. We identified a fourth patient with intellectual disability and an overlapping slightly larger do novo deletion also encompassing the flanking gene ID4. Given the fact that the fourth patient had no skeletal abnormalities and none of the genes in the deleted interval are known to be associated with abnormalities in skeletal development, other mutational mechanisms than loss of function of the deleted genes have to be considered. Analysis of the genomic region showed that the deletion removes two regulatory boundaries and brings several potential limb enhancers into close proximity of ID4. Thus, the deletion could result in the aberrant activation and misexpression of ID4 in the limb bud, thereby causing the mesomelic dysplasia. CONCLUSIONS: Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae.

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Language(s): eng - English
 Dates: 2015-06-012015-07
 Publication Status: Published in print
 Pages: 8
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1136/jmedgenet-2015-103108
ISSN: 1468-6244 (Electronic)0022-2593 (Print)
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Title: Journal of Medical Genetics
Source Genre: Journal
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Publ. Info: London : British Medical Association
Pages: - Volume / Issue: 52 (7) Sequence Number: - Start / End Page: 476 - 483 Identifier: ISSN: 0022-2593
CoNE: /journals/resource/954925415940_2