ArticleJournal of medical genetics2014
Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum.
Article in Journal of medical genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers, 4 of them syntheses that pooled it.
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Who cites it
44 citing papers in PubMed, 4 syntheses or guidelines pooled it, 113 citations in OpenAlex.
- Respiratory and other organ manifestations inFrontiers in medicine · 2025Pooled it
- Systematic review of thyroid function in NKX2-1-related disorders: Treatment and follow-up.PloS one · 2024Pooled it
- Systematic review of thyroid function in NKX2-1-related disorders: Screening and diagnosis.PloS one · 2024Pooled it
- Congenital Hypothyroidism: A 2020-2021 Consensus Guidelines Update-An ENDO-European Reference Network Initiative Endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology.Thyroid : official journal of the American Thyroid Association · 2021Guideline
- Crystal structure of the NKX2-1 homeodomain bound to a palindromic DNA recognition sequence.Acta crystallographica. Section F, Structural biology communications · 2026Article
- Approach to the patient: genetics and management of congenital hypothyroidism.The Journal of clinical endocrinology and metabolism · 2026Article
- International Registry of NKX2-1-Related Disorders: Clinical, Genetic, and Imaging Perspectives.Movement disorders : official journal of the Movement Disorder Society · 2026Observational
- Molecular Genetics of Primary Congenital Hypothyroidism: Established and Emerging Contributors to Thyroid Dysgenesis.International journal of molecular sciences · 2025Review
- Genetics of primary congenital hypothyroidism: three decades of discoveries and persisting etiological challenges.European thyroid journal · 2025Review
- Deciphering the pathogenicity of three NKX2-1 variants in ultra-severe forms of childhood interstitial lung disease.PloS one · 2025Article
- Case Report: Hydroxychloroquine in an infant withFrontiers in pediatrics · 2025Article
- Pulmonary fibrosis may begin in infancy: from childhood to adult interstitial lung disease.Thorax · 2024Review
- Review
- Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders.Journal of neural transmission (Vienna, Austria : 1996) · 2024Review
- Innovations in Childhood Interstitial and Diffuse Lung Disease.Clinics in chest medicine · 2024Review
- Functional characterization of two novel NKX2-1 frameshift variants that cause pulmonary surfactant dysfunction.Pediatric research · 2024Article
- Haploinsufficiency ofIntractable & rare diseases research · 2024Article
- Towards personalized therapies for genetic disorders of surfactant dysfunction.Seminars in fetal & neonatal medicine · 2023Review
- Clinical exome sequencing efficacy and phenotypic expansions involving anomalous pulmonary venous return.European journal of human genetics : EJHG · 2023Article
- NK2 homeobox gene cluster: Functions and roles in human diseases.Genes & diseases · 2023Review
Corrections and comments
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Authors and funding
29 authors at 14 institutions in 8 countries.
Funding
Abstract
backgroundNKX2-1 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.
methodsAfter 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.
resultsWithin 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.
conclusionsThe 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.
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