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

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.

Surfactant proteins in pediatric interstitial lung disease

“…Sequences were aligned to the reference sequence (RefSeq accession NG_029334) using Mutation Surveyor 4.0 (SoftGenetics, State College, PA). ABCA3 and TTF1 were determined as described previously (38,39).…”

NovelNKX2-1Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome

“…In humans, heterozygous loss-of-function mutations in NKX2-1 gene (OMIM #600635) have been reported to cause a complex phenotype called brain-lung-thyroid (BLT) syndrome (OMIM #610978) [1,2,3,4,5,6,7]. The BLT syndrome is a rare disease characterized by a highly variable penetrance and expressivity and combining neurological manifestations (hypotonia evolving into benign chorea and ataxia), pulmonary disease (neonatal respiratory distress and/or interstitial lung disease), and congenital hypothyroidism (CH) of variable severity, associated either with athyreosis, hypoplasia or an apparently normal gland in situ [1,2,3,4,5,6,7], but not with ectopy as recently indicated also in the document of the CH Consensus Conference Group [8].…”

ADCY5 mutations are another cause of benign hereditary chorea

“…3,4 However, a number of families with BHC do not carry mutations in NKX2-1, suggesting that other genes may be responsible for this syndrome. [5][6][7][8] Familial dyskinesia with facial myokymia (FDFM) (OMIM 606703) was first described by Fernandez et al 9 in 2001. They reported a 5-generation kindred with 18 members affected with an autosomal dominant movement disorder, mainly characterized by childhood or early adolescent onset of hyperkinetic movements and perioral and periorbital myokymia.…”