TY - JOUR 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 SP - 375 LP - 387 DO - 10.1136/jmedgenet-2013-102248 VL - 51 IS - 6 AU - Anne Thorwarth AU - Sarah Schnittert-Hübener AU - Pamela Schrumpf AU - Ines Müller AU - Sabine Jyrch AU - Christof Dame AU - Heike Biebermann AU - Gunnar Kleinau AU - Juri Katchanov AU - Markus Schuelke AU - Grit Ebert AU - Anne Steininger AU - Carsten Bönnemann AU - Knut Brockmann AU - Hans-Jürgen Christen AU - Patricia Crock AU - Francis deZegher AU - Matthias Griese AU - Jacqueline Hewitt AU - Sten Ivarsson AU - Christoph Hübner AU - Klaus Kapelari AU - Barbara Plecko AU - Dietz Rating AU - Iva Stoeva AU - Hans-Hilger Ropers AU - Annette Grüters AU - Reinhard Ullmann AU - Heiko Krude Y1 - 2014/06/01 UR - http://jmg.bmj.com/content/51/6/375.abstract N2 - 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. ER -