Abstract
BackgroundPseudohypoparathyroidism (PHP) is caused by (epi)genetic defects in the imprinted GNAS cluster. Current classification of PHP patients is hampered by clinical and molecular diagnostic overlaps. The European Consortium for the study of PHP designed a genome-wide methylation study to improve molecular diagnosis.MethodsThe HumanMethylation 450K BeadChip was used to analyze genome-wide methylation in 24 PHP patients with parathyroid hormone resistance and 20 age- and gender-matched controls. Patients were previously diagnosed with GNAS-specific differentially methylated regions (DMRs) and include 6 patients with known STX16 deletion (PHPΔstx16) and 18 without deletion (PHPneg).ResultsThe array demonstrated that PHP patients do not show DNA methylation differences at the whole-genome level. Unsupervised clustering of GNAS-specific DMRs divides PHPΔstx16 versus PHPneg patients. Interestingly, in contrast to the notion that all PHP patients share methylation defects in the A/B DMR while only PHPΔstx16 patients have normal NESP, GNAS-AS1 and XL methylation, we found a novel DMR (named GNAS-AS2) in the GNAS-AS1 region that is significantly different in both PHPΔstx16 and PHPneg, as validated by Sequenom EpiTYPER in a larger PHP cohort. The analysis of 58 DMRs revealed that 8/18 PHPneg and 1/6 PHPΔstx16 patients have multi-locus methylation defects. Validation was performed for FANCC and SVOPL DMRs.ConclusionsThis is the first genome-wide methylation study for PHP patients that confirmed that GNAS is the most significant DMR, and the presence of STX16 deletion divides PHP patients in two groups. Moreover, a novel GNAS-AS2 DMR affects all PHP patients, and PHP patients seem sensitive to multi-locus methylation defects.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0175-8) contains supplementary material, which is available to authorized users.
Highlights
Pseudohypoparathyroidism (PHP) is caused bygenetic defects in the imprinted GNAS cluster
PHP type I (PHP1A and PHP1B) patients are characterized by endorgan resistance to the action of the parathyroid hormone (PTH), which leads to hypocalcemia, hyperphosphatemia, and elevated levels of PTH in the absence of vitamin D deficiency
PHP1A patients have in addition to hormone resistance clinical features collectively referred to as Albright’s hereditary osteodystrophy (AHO) that include brachydactyly, short stature, and round face; they may present with obesity, subcutaneous ossifications, mental retardation, and behavior problems [4, 5]
Summary
Pseudohypoparathyroidism (PHP) is caused by (epi)genetic defects in the imprinted GNAS cluster. PHP type I (PHP1A and PHP1B) patients are characterized by endorgan resistance to the action of the parathyroid hormone (PTH), which leads to hypocalcemia, hyperphosphatemia, and elevated levels of PTH in the absence of vitamin D deficiency. They often have thyroid-stimulating hormone (TSH) resistance [2, 3]. All PHP1B patients have methylation abnormalities in the GNAS cluster with loss of imprinting at the A/B DMR [6]. Sporadic PHP1B patients have broad GNAS methylation defects that involve all four GNAS DMRs without a known underlying genetic cause [2, 3, 6]
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