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

Thorwarth, Anne; Schnittert-Huebener, Sarah; Schrumpf, Pamela; Mueller, Ines; Jyrch, Sabine; Dame, Christof; Biebermann, Heike; Kleinau, Gunnar; Katchanov, Juri and Schuelke, Markus, et al. (2014) In Journal of Medical Genetics 51(6). p.375-387
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... (More)
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. (Less)
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Journal of Medical Genetics
volume
51
issue
6
pages
375 - 387
publisher
BMJ Publishing Group
external identifiers
  • wos:000336841300003
  • scopus:84901454226
ISSN
0022-2593
DOI
10.1136/jmedgenet-2013-102248
language
English
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yes
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7dd7eaa2-2aba-4df6-80ef-ede1a7963e3c (old id 4549174)
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2014-08-01 07:38:16
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2017-11-19 04:00:08
@article{7dd7eaa2-2aba-4df6-80ef-ede1a7963e3c,
  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.},
  author       = {Thorwarth, Anne and Schnittert-Huebener, Sarah and Schrumpf, Pamela and Mueller, Ines and Jyrch, Sabine and Dame, Christof and Biebermann, Heike and Kleinau, Gunnar and Katchanov, Juri and Schuelke, Markus and Ebert, Grit and Steininger, Anne and Boennemann, Carsten and Brockmann, Knut and Christen, Hans-Juergen and Crock, Patricia and deZegher, Francis and Griese, Matthias and Hewitt, Jacqueline and Ivarsson, Sten and Huebner, Christoph and Kapelari, Klaus and Plecko, Barbara and Rating, Dietz and Stoeva, Iva and Ropers, Hans-Hilger and Grueters, Annette and Ullmann, Reinhard and Krude, Heiko},
  issn         = {0022-2593},
  language     = {eng},
  number       = {6},
  pages        = {375--387},
  publisher    = {BMJ Publishing Group},
  series       = {Journal of Medical Genetics},
  title        = {Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum},
  url          = {http://dx.doi.org/10.1136/jmedgenet-2013-102248},
  volume       = {51},
  year         = {2014},
}