Format

Send to

Choose Destination
J Med Genet. 2014 Jun;51(6):375-87. doi: 10.1136/jmedgenet-2013-102248. Epub 2014 Apr 8.

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

Author information

1
Institute for Experimental Pediatric Endocrinology, Charité University Medicine, Berlin, Germany Max Planck Institute for Molecular Genetics, Berlin, Germany.
2
Institute for Experimental Pediatric Endocrinology, Charité University Medicine, Berlin, Germany.
3
Max Planck Institute for Molecular Genetics, Berlin, Germany.
4
Department of Neonatology, Charité University Medicine, Berlin, Germany.
5
Department of Neurology, Charité University Medicine, Berlin, Germany.
6
Department of Neuropediatrics, Charité University Medicine, Berlin, Germany.
7
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
8
Interdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center, Georg August University, Göttingen, Germany.
9
Department for Neuropediatrics, Children's and Youth Hospital "Auf der Bult", Hannover, Germany.
10
Division of Pediatric Endocrinology & Diabetes, John Hunter Children's Hospital, Newcastle, Australia.
11
Department of Woman and Child, University of Leuven, Leuven, Belgium.
12
Dr. von Haunersches Kinderspital, Member of the German Center for Lung Research, University of Munich, Munich, Germany.
13
Division of Endocrinology & Diabetes, Royal Children's Hospital Melbourne, Melbourne, Australia.
14
Department of Clinical Sciences- Pediatric Endocrinology, University Hospital MAS, Malmö, Sweden.
15
Department of Pediatric and Adolescent Medicine, Medical University of Innsbruck, Innsbruck, Austria.
16
Division of Child Neurology, University Childrens Hospital Zurich, Zurich, Switzerland.
17
Department for Neuropediatrics, Heidelberg University Hospital, Heidelberg, Germany.
18
Department of Paediatric Endocrinology Screening and Functional Endocrine Diagnostics, University Paediatric Hospital, Medical University Sofia, Sofia, Bulgaria.

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.

KEYWORDS:

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

PMID:
24714694
PMCID:
PMC5240655
DOI:
10.1136/jmedgenet-2013-102248
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center