PHP 1b

Pseudohypoparathyroidism Type 1b (PHP1b)
	Gene:	GNAS; chr20pq13.2

Syndrome Information
	Clinical Description:	PHP1b is characterized by hypocalcemia, hyperphosphatemia and elevated serum parathyroid hormone (PTH) due to isolated renal PTH resistance. Resistance to thyroid stimulating hormone (TSH) is also described. Some PHP1b patients may manifest clinical features that overlap with PHP1a such as bracydactyly or mild Albright Hereditary Osteodystrophydy (AHO).
	Inheritance Pattern:	Autosomal dominant or non-inherited epigenetic change
	Genotype-Phenotype Correlation:	None known; This is an imprinted locus, and the phenotype is determined by parental inheritance.

Test Information
	Test Method:	Methylation analysis by bisulfite sequencing of a portion of the Exon 1A Differentially Methylated Region (DMR) of the GNAS locus
	Clinical Utility:	Identification of epigenetic defects in known or highly suspicious cases of PHP1b; differentiation between PHP 1b and PHP1a in patients with mild features of Albright Hereditary Osteodystrophy. This assay WILL NOT detect the somatic gain of function mutations in GNAS associated with McCune Albright Syndrome.
	Clinical Sensitivity:	Methylation analysis of the GNAS locus should detect at least 99% of patients clinically diagnosed with PHP1b. Up to 2% of samples evaluated by this assay will demonstrate a partial loss of methylation (LOM) in the GNAS exon 1A region (either partial LOM across all CpG sites or partial/complete LOM at some, but not all, CpG sites), and the clinical significance will be uncertain.
	Analytic Sensitivity:	Greater than 99% accuracy for nucleotides evaluated by bisulfite sanger sequencing as compared with bisulfate pyrosequencing. All reports will indicate the number of CpG sites analyzed. Our analysis parameters are designed to detect greater than 10% methylation at the observed CpG sites
	Turn Around Time:	2-3 weeks
	Fee and CPT Codes:	$482 for routine testing on a blood sample. 83891 x 1; 83898 x 1; 83904 x 2; 83909 x 2; 83912 x 1 Please contact the lab to arrange testing for samples other than blood.

Special Considerations
	This methylation test examines the GNAS Exon 1A DMR for the loss of methylation pattern associated with PHP1b. Although this loss of methylation is not inherited in the majority of cases, loss of methylation at the Exon 1A DMR may result from an autosomal dominantly inherited STX16 deletion. However, since this test does not examine the STX16 gene, risk of inheritance cannot be determined. Prenatal methylation testing is currently not available.

	INFORMED CONSENT from the patient is required prior to ordering a genetic test. The DNA Diagnostic Lab's consent is located on the second page of the requisition form. There is also a patient brochure, "Things Every Patient Should Know Before Consenting to a Genetic Test", available for download.
Helpful Links
	Sample Requirements Requisition and Billing forms Clinical information on PHP 1b Link to the General Test Information page for a discussion of the uses and limitations of genetic testing Patient and Family Page for general resources on genetic testing.