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, 87:575-580.
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 diagnosis of congenital hypothyroidism in individuals who have tested negative for sequence analysis
- Carrier testing in adults with a family history of congenital hypothyroidism who have tested negative for sequence analysis
Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations. Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.
Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.
- Sequence analysis of the PAX8 gene is available and is required before deletion/duplication analysis.
- Prenatal testing is available to couples who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.