Congenital Hypothyroidism: PAX8 Gene Sequencing
Test Code: 5480
Turnaround time: 5 weeks
Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80-85% of cases, the thyroid gland is absent (agenesis), ectopically located, and/or severely reduced in size (hypoplasia) . In the remaining cases, a normal-sized or enlarged thyroid gland is present, but production of thyroid hormones is decreased or absent. If treatment begins in the first month after birth, infants usually develop normally. However, if thyroid hormone therapy is not initiated within the first two months of life, congenital hypothyroidism can cause severe neurological, mental, and motor damage (cretinism). In the United States and many other countries, all newborns are tested for congenital hypothyroidism.
Studies have shown that 2% of congenital hypothyroidism patients with thyroid dysgenesis have a positive familial history . A segregation analysis led to the conclusion that thyroid developmental abnormalities are compatible with an autosomal dominant mode of inheritance with a low penetrance . Mutations in many genes are known to cause congenital hypothyroidism. Multiple affected individuals have been shown to be heterozygous for mutations in the Paired Box Gene 8 (PAX8 2q12-q14), including individuals with positive family histories [4-8].
1. Macchia et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nature Genet. 1998, 19:83-86.
2. Castanet et al. Familial forms of thyroid dysgenesis among infants with congenital hypothyroidism. (Letter) New Eng. J. Med. 2000, 343:441-442. 3. Leger et al. Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism. J. Clin. Endocr. Metab. 2002,
4. Macchia et al. PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. Nature Genet. 1998, 19:83-86.
5. Vilain et al. Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. J. Clin. Endocr. Metab. 2001, 86:234-238.
6. Congdon et al. A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child. J. Clin. Endocr. Metab. 2001, 86: 3962-3967.
7. Meeus et al. Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid. J. Clin. Endocr. Metab. 2004, 89: 4285-4291.
8. Grasberger et al. Thyroid transcription factor 1 rescues PAX8/p300 synergism impaired by a natural PAX8 paired domain mutation with dominant negative activity. Molec. Endocr. 2005, 19: 1779-1791.
This test is indicated for:
- Confirmation of a clinical/biochemical diagnosis of congenital hypothyroidism.
PCR amplification of 11 exons contained in the PAX8 gene is performed on the patient’s genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions using automated fluorescence dideoxy sequencing methods. The patient’s gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.
Clinical Sensitivity: unknown. Mutations in the promoter region, some mutations in the introns, other regulatory element mutations, and large deletions will not be detected by this analysis.
Analytical Sensitivity: ~99%. Results of molecular analysis should be interpreted in the context of the patient’s biochemical phenotype.
Submit only 1 of the following specimen types
* Preferred specimen type: Whole Blood
Type: Whole Blood
In EDTA (purple top) or ACD (yellow top) tube: Infants (2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
OrageneTM Saliva Collection kit (available through CEN4GEN) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
Please submit copies of diagnostic biochemical test results along with the sample.
• Known Mutation Analysis (test code: 6875) is available to family members if mutations are identified by sequencing.