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Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum
  1. Anne Thorwarth1,2,
  2. Sarah Schnittert-Hübener1,
  3. Pamela Schrumpf1,
  4. Ines Müller2,
  5. Sabine Jyrch1,
  6. Christof Dame3,
  7. Heike Biebermann1,
  8. Gunnar Kleinau1,
  9. Juri Katchanov4,
  10. Markus Schuelke5,
  11. Grit Ebert2,
  12. Anne Steininger2,
  13. Carsten Bönnemann6,
  14. Knut Brockmann7,
  15. Hans-Jürgen Christen8,
  16. Patricia Crock9,
  17. Francis deZegher10,
  18. Matthias Griese11,
  19. Jacqueline Hewitt12,
  20. Sten Ivarsson13,
  21. Christoph Hübner5,
  22. Klaus Kapelari14,
  23. Barbara Plecko15,
  24. Dietz Rating16,
  25. Iva Stoeva17,
  26. Hans-Hilger Ropers2,
  27. Annette Grüters1,
  28. Reinhard Ullmann2,
  29. Heiko Krude1
  1. 1Institute for Experimental Pediatric Endocrinology, Charité University Medicine, Berlin, Germany
  2. 2Max Planck Institute for Molecular Genetics, Berlin, Germany
  3. 3Department of Neonatology, Charité University Medicine, Berlin, Germany
  4. 4Department of Neurology, Charité University Medicine, Berlin, Germany
  5. 5Department of Neuropediatrics, Charité University Medicine, Berlin, Germany
  6. 6Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
  7. 7Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center, Georg August University, Göttingen, Germany
  8. 8Department for Neuropediatrics, Children's and Youth Hospital “Auf der Bult”, Hannover, Germany
  9. 9Division of Pediatric Endocrinology & Diabetes, John Hunter Children's Hospital, Newcastle, Australia
  10. 10Department of Woman and Child, University of Leuven, Leuven, Belgium
  11. 11Dr. von Haunersches Kinderspital, Member of the German Center for Lung Research, University of Munich, Munich, Germany
  12. 12Division of Endocrinology & Diabetes, Royal Children's Hospital Melbourne, Melbourne, Australia
  13. 13Department of Clinical Sciences- Pediatric Endocrinology, University Hospital MAS, Malmö, Sweden
  14. 14Department of Pediatric and Adolescent Medicine, Medical University of Innsbruck, Innsbruck, Austria
  15. 15Division of Child Neurology, University Childrens Hospital Zurich, Zurich, Switzerland
  16. 16Department for Neuropediatrics, Heidelberg University Hospital, Heidelberg, Germany
  17. 17Department of Paediatric Endocrinology Screening and Functional Endocrine Diagnostics, University Paediatric Hospital, Medical University Sofia, Sofia, Bulgaria
  1. Correspondence to Professor Dr H Krude, Charité University Medicine Berlin, Institute for Experimental Pediatric Endocrinology, Augustenburger Platz 1, Berlin 13353, Germany; heiko.krude{at} Dr R Ullmann, Institut für Radiobiologie der Bundeswehr in Verbindung mit der Universität Ulm, D-80937 Munich, Germany; ullmann{at}


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.

  • NKX2-1
  • choreoathetosis
  • array CGH
  • CNV
  • hypothyroidism

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