ALBRIGHT HEREDITARY OSTEODYSTROPHY (GNAS1)
Syndromes: Albright Hereditary Osteodystrophy (AHO), Pseudohypoparathyroidism type 1A (PHP 1A), Pseudopseudohypoparathyroidism (PPHP), Progressive Osseus Heteroplasia (POH)
Gene Symbol: GNAS1
Chromosomal Locus: 20q13.32
Protein: Gs-alpha protein
Pseudonyms: Adenylate cyclase-stimulating G alpha protein
TURNAROUND TIME: 4 weeks
TESTING METHODOLOGY: Polymerase chain reaction (PCR) and DNA sequencing of all 13 exons.
- Collect: Prefer two 5ml whole blood EDTA (lavender top) tube.
- Min. Collection: 0.7 ml whole blood EDTA.
- Transport: blood EDTA at Room Temp shipped regular next day air (No Saturday delivery; store specimen at 4°C and ship Monday).
- Stability: Ambient: up to 7 days; Refrigerated: 2 weeks. Frozen: unacceptable
- Unacceptable Conditions: Serum. Frozen or severely hemolyzed blood. Clotted blood.
- Prenatal testing: Direct: 5ml direct unspun amniotic fluid or 15mg CVS tissue with a backup flask growing. Culture: confluent T25 flask. Maternal blood sample is required for maternal cell contamination studies.
Counseling and informed consent are recommended for genetic testing. A consent form
is available but not required.
Inheritance: Autosomal dominant inheritance pattern.
Disease Characteristics: AHO phenotype is associated with various combinations of short stature, obesity, mental retardation, round face, brachydactyly and bone calcification. Other symptoms may include ectopic ossification, cataracts and dental hypoplasia. PHP Ia is AHO with multiple hormone resistance, and it is caused by mutations that affect the function of the Gs-alpha protein on the maternal allele. This results in expression of the Gs-alpha protein only from the paternal allele. PPHP is AHO without endocrine abnormalities. PPHP is caused by mutations that affect loss of function of the protein on the paternal allele, resulting in expression of the protein only from the maternal allele. POH is also caused by activating mutations on the GNAS1 gene that are inherited paternally.
Molecular Genetic Mechanism: Causative mutations have been found throughout the 13 exon gene.
Analytic Sensitivity: 99%
Clinical Sensitivity: 60-90%
Test Limitations: The sequencing test cannot detect the following: mutations located outside of the gene, McCune Albright Syndrome ( a mosaic mutation presentation for R201 requires special methods of detection) nor PHP 1B (methylation characterization is required to detect the genetic abnormality). Rare diagnostic errors can occur due to primer or probe site mutations or rare polymorphisms.
INDICATIONS FOR USE:
- Obesity associated with brachydactyly.
- Ectopic ossification - especially in the skin.
- Family history of any of these conditions.