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Choreoathetosis, Congenital Hypothyroidism, Neonatal Respiratory Distress Test


Syndrome Information

Clinical Description

Choreoathetosis, Hypothyroidism, and Neonatal Respiratory Distress (also known as Brain-Lung-Thyroid Syndrome or sometimes TTF1-deficiency Syndrome in older literature) involves (as originally characterized) the brain, lungs, and thyroid to variable degrees.  All three organs do not need to be affected to consider the diagnosis.

Neurologic symptoms include chorea, choreoathetosis, hypotonia and ataxia.  Developmental delays, both global and motor, and mental retardation have also been reported.  Hypothyroidism (sometimes compensated and not overt; as measured by elevated serum thyrotropin) is present in most patients, though the size of the thyroid can be small to normal.  Thyroid agenesis has also been reported.  Lung disease manifests as neonatal respiratory distress that can be fatal or recurrent pulmonary infections.  A significant number of surviving patients go on to develop chronic interstitial lung disease.  Though lung disease is the most infrequent symptom, it accounts for significant patient mortality. 

In one literature review, 50% of patients had brain, lung and thyroid findings; 13% had benign chorea only, and 6% had thyroid and lung or thyroid only symptoms. 

Inheritance Pattern

Autosomal Dominant

Genotype-Phenotype Correlation

None known

Test Information

Test Method

Sanger and/or NextGen sequencing (NGS) of the coding regions and intron-exon boundaries of NKX2-1;Multiplex ligation-dependent probe amplification (MLPA) for gene deletions

Clinical Utility

Identification of causative mutations in known or highly suspicious cases of Choreoathetosis, Hypothyroidism, Neonatal Respiratory Distress; rule-out of inherited causes of severe respiratory distress and/or hypothyroidism; diagnostic or presymptomatic testing of at-risk relatives of a proband;  predictive prenatal testing when familial mutation is known.  

Clinical Sensitivity

Of 56 patients included in two published series, 10 had NKX2-1 mutations (18%).  Of the identified mutations, two were gene deletions and 8 were point mutations identifiable by gene sequencing. Sequencing of the NKX2-1 gene is predicted to detect a mutation in approximately 14% of symptomatic patients.  MLPA analysis is predicted to detect a mutation in approximately 4% of patients.  

Analytic Sensitivity

Sanger Sequencing:  >97% for nucleotides analyzed.  All reports will indicate if a certain percentage of nucleotides were not called or were analyzed in a single direction.  

NGS:  >99% accuracy for inherited single nucleotide and small insertion/deletion variants for the nucleotides evaluated.   All reports will indicate if a certain percentage of nucleotides were not called.  

Sequence analysis parameters are not designed to assess mosaicism. 

MLPA:  Analytical sensitivity for deletions is estimated to be at least 90%.

Sample Requirements

3-6ml whole blood in EDTA (purple topped) tubes. (see Pediatric or Adult blood sample algorithms for additional information)

We prefer whole blood for all tests. If you are sending extracted DNA, please note that MLPA assays have been optimized to Qiagen Puregene extraction.  Other DNA extraction methods may contribute to increased assay failure rates.  

Turn Around Time

Sequencing: 2-3 weeks
MLPA: up to 4 weeks

Fee and CPT Codes

Sequencing:  $882 for routine testing on a blood or DNA sample
CPT Code:  81479

MLPA: $429 for routine testing on a blood or DNA sample
CPT Code:  81479

Special Considerations

This test is offered as an automatic reflex to MLPA analysis if the sequencing assay does not detect a potential disease-causing mutation.  NKX2-1 mutations are also associated with Benign Hereditary Chorea.

NKX2-1 testing may be ordered alone or as part of a neonatal respiratory distress/pulmonary alveolar proteinosis or childhood interstitial lung disease panel.

INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.