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  Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum

Thorwarth, A., Schnittert-Hübener, S., Schrumpf, P., Müller, I., Jyrch, S., Dame, C., et al. (2014). Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum. Journal of Medical Genetics, 51(6), 375-387. doi:10.1136/jmedgenet-2013-102248.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-C08A-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-C08B-9
Genre: Journal Article

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 Creators:
Thorwarth, A.1, Author
Schnittert-Hübener, S., Author
Schrumpf, P., Author
Müller, I.2, Author              
Jyrch, S., Author
Dame, C., Author
Biebermann, H., Author
Kleinau, G., Author
Katchanov, J., Author
Schuelke, M., Author
Ebert, G.2, Author              
Steininger, A.2, Author              
Bonnemann, C., Author
Brockmann, K., Author
Christen, H. J., Author
Crock, P., Author
deZegher, F., Author
Griese, M., Author
Hewitt, J., Author
Ivarsson, S., Author
Hübner, C., AuthorKapelari, K., AuthorPlecko, B., AuthorRating, D., AuthorStoeva, I., AuthorRopers, H. H.3, Author              Grüters, A., AuthorUllmann, R.2, Author              Krude, H., Author more..
Affiliations:
1Max Planck Society, ou_persistent13              
2Molecular Cytogenetics (Reinhard Ullmann), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479645              
3Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              

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Free keywords: Adolescent Child Child, Preschool Comparative Genomic Hybridization DNA Copy Number Variations/genetics Electrophoretic Mobility Shift Assay Female Gene Deletion *Genetic Diseases, Inborn/genetics/physiopathology Humans Infant Infant, Newborn Male Nuclear Proteins/*genetics Phenotype Point Mutation/genetics Transcription Factors/*genetics
 Abstract: BACKGROUND: NKX2-1 encodes a transcription factor with large impact on the development of brain, lung and thyroid. Germline mutations of NKX2-1 can lead to dysfunction and malformations of these organs. Starting from the largest coherent collection of patients with a suspected phenotype to date, we systematically evaluated frequency, quality and spectrum of phenotypic consequences of NKX2-1 mutations. METHODS: After identifying mutations by Sanger sequencing and array CGH, we comprehensively reanalysed the phenotype of affected patients and their relatives. We employed electrophoretic mobility shift assay (EMSA) to detect alterations of NKX2-1 DNA binding. Gene expression was monitored by means of in situ hybridisation and compared with the expression level of MBIP, a candidate gene presumably involved in the disorders and closely located in close genomic proximity to NKX2-1. RESULTS: Within 101 index patients, we detected 17 point mutations and 10 deletions. Neurological symptoms were the most consistent finding (100%), followed by lung affection (78%) and thyroidal dysfunction (75%). Novel symptoms associated with NKX2-1 mutations comprise abnormal height, bouts of fever and cardiac septum defects. In contrast to previous reports, our data suggest that missense mutations in the homeodomain of NKX2-1 not necessarily modify its DNA binding capacity and that this specific type of mutations may be associated with mild pulmonary phenotypes such as asthma. Two deletions did not include NKX2-1, but MBIP, whose expression spatially and temporarily coincides with NKX2-1 in early murine development. CONCLUSIONS: The high incidence of NKX2-1 mutations strongly recommends the routine screen for mutations in patients with corresponding symptoms. However, this analysis should not be confined to the exonic sequence alone, but should take advantage of affordable NGS technology to expand the target to adjacent regulatory sequences and the NKX2-1 interactome in order to maximise the yield of this diagnostic effort.

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Language(s): eng - English
 Dates: 2014-04-082014-06
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1136/jmedgenet-2013-102248
ISSN: 1468-6244 (Electronic)0022-2593 (Print)
 Degree: -

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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: 51 (6) Sequence Number: - Start / End Page: 375 - 387 Identifier: ISSN: 0022-2593
CoNE: /journals/resource/954925415940_2