ESPE Abstracts

Background: Patients affected by pseudohypoparathyroidism type 1b (PHPI-b) develop resistance to PTH leading to hypocalcemia and hyperphosphoremia, which is often associated with resistance to TSH. PHP-Ib is associated with methylation changes at one or several differentially methylated regions (DMRs) within the GNAS complex locus, located at 20q13.2–13.3. This locus gives rise to several different transcripts (NESP55, XL, A/B), with varying patterns of imprinted expression depending on the methylation status of the specific exon 1 promoters. PHP-Ib may follow an autosomal dominant pattern of maternal inheritance (AD-PHPI-b), or it can occur as a disorder that appears to arise sporadically (SPO-PHP I-b).

Objective and hypotheses: Epigenetic changes observed in genomic DNAs from SPO- PHP-Ib mimic the paternal-specific methylation pattern. Uniparental disomy (UPD) is a condition in which a chromosomally disomic individual inherited both copies of a chromosome from one parent only. Thus, paternal UPD20 without maternal contribution is a plausible cause of PHP1b.

Method: We screened a cohort of 57 unrelated patients presenting with SPO-PHP1b and broad GNAS epigenetic changes to evaluate the frequency of patUPD20. Comparative genomic hybridization (CGH) combined with SNP-array (Agilent 4x180K sureprint G3 Cancer) was used to identify copy number variant and loss of heterozygosity (LOH). To confirm LOH, single nucleotide polymorphisms or short tandem repeats were studied along chromosome 20 in the proband and compared to his two parents.

Results: Because GCH arrays required high quality DNA only 20 samples were tested. We found four patients (20%) with patUPD20: two patients with complete patUPD, one patient with patUPD of the long arm of chromosome 20 and one patient with a large interstitial UPD including GNAS locus. We also detailed the phenotype and the DNA methylation pattern of these patients.

Conclusion: This study suggests that patUPD20 is a frequent cause of PHP1b that should be tested in the evaluation of patients with sporadic PHP1b.