Congenital Hypothyroidism (Thyroid Dysgenesis) via the NKX2-1/TTF1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8537 NKX2-1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8537NKX2-181479 81479(x2) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Greg Fischer, PhD

Clinical Features and Genetics

Clinical Features

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. It occurs in one of every 3,000-4,000 newborns and is twice as common in females as in males. Without early and adequate treatment, CH is characterized by growth failure, developmental delay, and permanent intellectual disability. Current newborn screening primarily detects the elevated thyroid stimulating hormone (TSH) level at birth in response to decreased or absent thyroid hormone production and can identify over 90% of CH cases. Most CH patients grow and develop normally after treatment with thyroxine (Park and Chatterjee 2005; Rose et al. 2006).

CH is usually a sporadic disorder, but growing evidence confirms several genetic mechanisms together account for at least 5% of cases. The majority of CH cases (~80%) are due to developmental defects of the thyroid gland known as thyroid dysgenesis, including thyroid agenesis, hypoplasia, and ectopy. The remaining ~15% are caused by defects in one of the steps of thyroid hormone biosynthesis (thyroid dyshormonogenesis). Other less common causes are central hypothyroidism (impaired hypothalamic-pituitary-thyroid axis), thyroid hormone transporter defects, and thyroid hormone resistance (Peter and Muzsnai 2011; Nettore et al. 2013; Weber et al. 2013).

Patients with a heterozygous pathogenic variant in NKX2-1 (also known as TTF1) show variable clinical presentations, ranging from benign hereditary chorea to choreoathetosis, congenital hypothyroidism, and with or without neonatal respiratory distress (also called as brain-lung-thyroid syndrome). NKX2-1-related CH results from thyroid dysgenesis. Some patients have developmental delay and short stature. The phenotypic variation is found both between and within families (Patel et al. 2014; Thorwarth et al. 2014).

Genetics

NKX2-1-related disorders are inherited in an autosomal dominant manner. NKX2-1/TTF1 encodes a transcription factor expressed in the thyroid, lung, and brain, which is essential for thyroid gland development (Nettore et al. 2013). Over 110 pathogenic variants have been reported, including missense, nonsense, splicing variants, small deletions/insertions, and gross deletions. The majority of NKX2-1-related cases are caused by haploinsufficiency of the NKX2-1 gene, and a dominant negative effect is less common. No genotype-phenotype correlations have been found (Nettore et al. 2013; Hamvas et al. 2013; Thorwarth et al. 2014).

Clinical Sensitivity - Sequencing with CNV PGxome

Congenital hypothyroidism (CH) is normally a sporadic disease, but in about 5% of cases a genetic cause has been demonstrated. Pathogenic variants in multiple genes from several molecular mechanisms are associated with CH (Nettore et al. 2013). In a study of 101 probands with brain-lung-thyroid syndrome, 27 patients were found to have NKX2-1 pathogenic variants, including 17 point mutations (~17%) and 10 deletions (~10%) (Thorwarth et al. 2014).

Testing Strategy

This test provides full coverage of all coding exons of the NKX2-1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Individuals with clinical symptoms consistent with hypothyroidism and absence of anti-thyroid antibodies.

Gene

Official Gene Symbol OMIM ID
NKX2-1 600635
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Congenital Hypothyroidism and Thyroid Hormone Resistance Panel
Interstitial Lung Disease Panel

Citations

  • Hamvas A, Deterding RR, Wert SE, White FV, Dishop MK, Alfano DN, Halbower AC, Planer B, Stephan MJ, Uchida DA, Williames LD, Rosenfeld JA, Lebel RR, Young LR, Cole FS, Nogee LM. 2013. Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 144: 794–804. PubMed ID: 23430038
  • Nettore IC, Cacace V, Fusco C De, Colao A, Macchia PE. 2013. The molecular causes of thyroid dysgenesis: a systematic review. J. Endocrinol. Invest. 36: 654–664. PubMed ID: 23698639
  • Park SM, Chatterjee VKK. 2005. Genetics of congenital hypothyroidism. J. Med. Genet. 42: 379–389. PubMed ID: 15863666
  • Patel NJ, Jankovic J. 2014. NKX2-1-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 24555207
  • Péter F, Muzsnai A. 2011. Congenital disorders of the thyroid: hypo/hyper. Pediatr. Clin. North Am. 58: 1099–1115, ix. PubMed ID: 21981951
  • Rose SR, Brown RS, Foley T, Kaplowitz PB, Kaye CI, Sundararajan S, Varma SK, American Academy of Pediatrics; Section on Endocrinology and Committee on Genetics, American Thyroid Association; Public Health Committee, Lawson Wilkins Pediatric Endocrine Society. 2006. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 117: 2290–2303. PubMed ID: 16740880
  • Thorwarth A, Schnittert-Hübener S, Schrumpf P, Müller I, Jyrch S, Dame C, Biebermann H, Kleinau G, Katchanov J, Schuelke M, Ebert G, Steininger A, Bönnemann C, Brockmann K, Christen HJ, Crock P, deZegher F, Griese M, Hewitt J, Ivarsson S, Hübner C, Kapelari K, Plecko B, Rating D, Stoeva I, Ropers HH, Grüters A, Ullmann R, Krude H. 2014. Comprehensive genotyping and clinical characterisation reveal 27 novel NKX2-1 mutations and expand the phenotypic spectrum. J. Med. Genet. 51: 375–387. PubMed ID: 24714694
  • Weber G, Rabbiosi S, Zamproni I, Fugazzola L. 2013. Genetic defects of hydrogen peroxide generation in the thyroid gland. J. Endocrinol. Invest. 36: 261–266. PubMed ID: 23404134

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
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