RT Journal Article
SR Electronic
T1 Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 375
OP 387
DO 10.1136/jmedgenet-2013-102248
VO 51
IS 6
A1 Anne Thorwarth
A1 Sarah Schnittert-Hübener
A1 Pamela Schrumpf
A1 Ines Müller
A1 Sabine Jyrch
A1 Christof Dame
A1 Heike Biebermann
A1 Gunnar Kleinau
A1 Juri Katchanov
A1 Markus Schuelke
A1 Grit Ebert
A1 Anne Steininger
A1 Carsten Bönnemann
A1 Knut Brockmann
A1 Hans-Jürgen Christen
A1 Patricia Crock
A1 Francis deZegher
A1 Matthias Griese
A1 Jacqueline Hewitt
A1 Sten Ivarsson
A1 Christoph Hübner
A1 Klaus Kapelari
A1 Barbara Plecko
A1 Dietz Rating
A1 Iva Stoeva
A1 Hans-Hilger Ropers
A1 Annette Grüters
A1 Reinhard Ullmann
A1 Heiko Krude
YR 2014
UL http://jmg.bmj.com/content/51/6/375.abstract
AB 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.