Congenital Hypothyroidism and Thyroid Hormone Resistance Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
1989 DUOX2 81479,81479 Order Options and Pricing
DUOXA2 81479,81479
FOXE1 81479,81479
GLIS3 81479,81479
GNAS 81479,81479
HESX1 81479,81479
IGSF1 81479,81479
IYD 81479,81479
NKX2-1 81479,81479
NKX2-5 81479,81479
PAX8 81479,81479
POU1F1 81405,81479
PROP1 81404,81479
SECISBP2 81479,81479
SLC16A2 81405,81404
SLC26A4 81406,81479
SLC5A5 81479,81479
TG 81479,81479
THRA 81479,81479
THRB 81405,81479
TPO 81479,81479
TRH 81479,81479
TRHR 81479,81479
TSHB 81479,81479
TSHR 81479,81479
UBR1 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
1989Genes x (26)81479 81404, 81405, 81406, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

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 10% 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; Grasberger and Refetoff 2011). Thyroid hormone resistance (THR) is a rare genetic disorder caused by reduced tissue responsiveness to thyroid hormone. The estimated prevalence is about 1:40,000 births. The characteristic biochemical findings in patients with THR are elevated serum free thyroid hormone levels accompanied by nonsuppressed thyroid stimulating hormone production (Dumitrescu et al. 2013). The clinical presentation is highly variable and has a mixture of hypothyroidism and hyperthyroidism because of variable peripheral resistance among individuals as well as among different tissues within a single patient. Goiter is found in 66-95% of reported cases. Symptoms related to hypothyroidism include learning disabilities, delayed growth and bone development. Hyperactivity and tachycardia are associated with high thyroid hormone levels. In the mild form of THR, isolated biochemical abnormalities may be the only findings (Dumitrescu et al. 2013; Ferrara et al. 2012; Amor et al. 2014). A defect in the thyroid hormone receptor beta gene (THRB) accounts for almost 85% of THR cases. Heterozygous pathogenic variants in the thyroid hormone receptor alpha gene (THRA) lead to a rare form of THR with congenital hypothyroidism as the predominant clinical presentation (van Mullem et al. 2014).

Genetics

This NextGen test analyzes 26 genes leading to monogenic forms of congenital hypothyroidism and/or thyroid hormone resistance. Thyroid disorders listed below are inherited as autosomal dominant (PAX8, NKX2-1, NKX2-5, GNAS, and THRA) or recessive (SLC26A4/PDS, SLC5A5/NIS, TPO, TG, IYD/DEHAL1, DUOXA2, TSHB, SECISBP2, GLIS3, FOXE1, TRHR, PROP1 and UBR1), or X-linked (IGSF1 and SLC16A2) conditions. TSHR, POU1F1, HESX1, DUOX2, or THRB -associated diseases can present with either dominant or recessive patterns of inheritance (Péter and Muzsnai 2011; Grasberger and Refetoff 2011, Dumitrescu et al. 2013; Nettore et al. 2013). Primary thyrotropin-releasing hormone deficiency is expected to be caused by loss of function TRH variants. However, no pathogenic variants have been reported so far to be causative for primary TRH deficiency (Mori et al. 1991; Prieto-Tenreiro et al. 2010).

Thyroid dysgenesis: TSHR, PAX8, NKX2-1, FOXE1 and NKX2-5

Thyroid dyshormonogenesis: SLC26A4/PDS, SLC5A5/NIS, TPO, TG, IYD/DEHAL1, DUOXA2, and DUOX2

Central hypothyroidism: TSHB, IGSF1, TRH, TRHR and GNAS

Abnormal thyroid hormone metabolism: SECISBP2

Thyroid hormone resistance: THRA and THRB

Congenital hypothyroidism and neonatal diabetes mellitus: GLIS3

Pituitary hormone deficiency, combined: POU1F1, PROP1 and HESX1

Johanson-Blizzard syndrome: URB1

Allan-Herndon-Dudley syndrome: SLC16A2

See individual gene test descriptions for information on clinical features and molecular biology of gene products.

Clinical Sensitivity - Sequencing with CNV PGxome

Most cases of congenital hypothyroidism (CH) don't have an identifiable cause, but in about 10%-15% of cases the conditions are caused by pathogenic variants in genes associated with thyroid gland development and function. The majority of cases (~80%) are due to pathogenic variants in genes associated with thyroid dysgenesis (TSHR, PAX8, NKX2-1, FOXE1 and NKX2-5). The remaining ~15% are caused by defects in one of thyroid dyshormonogenesis-related genes (SLC26A4, SLC5A5, TPO, TG, IYD, DUOXA2, and DUOX2). Other causes appear to be very rare, including central hypothyroidism (TSHB, IGSF1, TRHR, THR and GNAS) and thyroid hormone resistance (THRA and THRB) (Péter and Muzsnai 2011; Nettore et al. 2013; Grasberger and Refetoff 2011). Over 85% of cases of thyroid hormone resistance (THR) are caused by THRB pathogenic variants. THRA pathogenic variants are a rare cause of THR (van Mullem et al. 2014; Tylki-Szymanska et al, 2015).

One gross deletion of the entire NKX2-5 gene was reported to be causative for congenital heart defects (Glessner et al. 2014).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.2% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

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

Diseases

Name Inheritance OMIM ID
Allan-Herndon-Dudley Syndrome AR 300523
Choreoathetosis, Hypothyroidism, And Neonatal Respiratory Distress AD 610978
Diabetes Mellitus, Neonatal, With Congenital Hypothyroidism AR 610199
Hyperthyroidism, Familial Gestational AD 603373
Hyperthyroidism, Nonautoimmune AD 609152
Hypothryoidism, Congenital, Nongoitrous 4 AR 275100
Hypothyroidism, Central, and Testicular Enlargement XL 300888
Hypothyroidism, Congenital, Due To Thyroid Dysgenesis AD 218700
Hypothyroidism, congenital, nongoitrous, 1 AR 275200
Hypothyroidism, Congenital, Nongoitrous, 5 AD 225250
Hypothyroidism, Congenital, Nongoitrous, 6 AD 614450
Johanson-Blizzard Syndrome AR 243800
Pendred Syndrome AR 274600
Pituitary Hormone Deficiency, Combined 1 AD 613038
Pituitary Hormone Deficiency, Combined 2 AD,AR 262600
Pseudohypoparathyroidism Type 1A AD 103580
Pseudohypoparathyroidism Type 1B AD 603233
Pseudohypoparathyroidism Type 1C AD 612462
Pseudopseudohypoparathyroidism AD 612463
Septooptic Dysplasia XL 182230
Thyroid Cancer, Nonmedullary, 4 AD 616534
Thyroid Dyshormonogenesis 1 AR 274400
Thyroid Dyshormonogenesis 2A AR 274500
Thyroid Dyshormonogenesis 3 AR 274700
Thyroid Dyshormonogenesis 4 AR 274800
Thyroid Dyshormonogenesis 5 AR 274900
Thyroid Dyshormonogenesis 6 AR 607200
Thyroid Hormone Metabolism, Abnormal AR 609698
Thyroid Hormone Resistance, Generalized, Autosomal Dominant AD 188570
Thyroid Hormone Resistance, Generalized, Autosomal Recessive AR 274300
Thyroid Hormone Resistance, Selective Pituitary AD 145650
Thyrotropin-Releasing Hormone Deficiency AR 275120

Related Test

Name
PGxome®

Citations

  • Amor A.J. et al. 2014. Hormones. 13: 74-8. PubMed ID: 24722129
  • Dumitrescu A.M., Refetoff S. 2013. Biochimica Et Biophysica Acta. 1830: 3987-4003. PubMed ID: 22986150
  • Ferrara A.M. et al. 2012. The Journal of Clinical Endocrinology and Metabolism. 97: 1328-36. PubMed ID: 22319036
  • Glessner J.T. et al. 2014. Circulation Research. 115: 884-96. PubMed ID: 25205790
  • Grasberger H., Refetoff S. 2011. Current Opinion in Pediatrics. 23: 421-8. PubMed ID: 21543982
  • Mori M. et al. 1991. Journal of Internal Medicine. 229: 285-8. PubMed ID: 1901077
  • Nettore I.C. et al. 2013. Journal of Endocrinological Investigation. 36: 654-64. PubMed ID: 23698639
  • Park S.M., Chatterjee V.K. 2005. Journal of Medical Genetics. 42: 379-89. PubMed ID: 15863666
  • Péter F., Muzsnai A. 2011. Pediatric Clinics of North America. 58: 1099-115, ix. PubMed ID: 21981951
  • Prieto-Tenreiro A., Diaz-Guardiola P. 2010. Hormones. 9: 176-80. PubMed ID: 20687402
  • Rose S.R., et al. 2006. Pediatrics 117: 2290–303. PubMed ID: 16740880
  • Tylki-Szymanska A. et al. 2015. Journal of Medical Genetics. 52: 312-6. PubMed ID: 25670821
  • van Mullem A.A. et al. 2014. European Thyroid Journal. 3: 17-24. PubMed ID: 24847461
  • Weber G. et al. 2013. Journal of Endocrinological Investigation. 36: 261-6. 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.

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

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

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