Complex Genomic Rearrangement Within the GNAS Region Associated With Familial Pseudohypoparathyroidism Type 1b

J Clin Endocrinol Metab. 2016 Jul;101(7):2623-7. doi: 10.1210/jc.2016-1725. Epub 2016 Jun 2.


Context: Pseudohypoparathyroidism type 1b (PHP-1b) results from methylation defects at the G protein stimulatory α subunit (GNAS) exon A/B-differentially methylated region (DMR). Although microduplications in the GNAS region were recently identified in two PHP-1b patients, genetic information on these patients remained fragmentary.

Case description: A 20-year-old Japanese male and his mother presented with hypocalcemia and elevated blood levels of intact PTH. The proband had a maternal uncle who was previously diagnosed with PHP-1b. Methylation-specific multiplex ligation-dependent probe amplification, array-based comparative genomic hybridization, pyrosequencing, fluorescence in situ hybridization, and whole-genome sequencing were performed for this family. The proband, mother, and uncle carried maternally derived approximately 133-kb duplication-triplication-duplication rearrangements at 20q13.32 involving NESP55, NESPAS, XLαs, and exon A/B-DMR but not STX16 or the Gsα coding region. These individuals exhibited partial methylation defects of NESP55-, NESPAS-, and XLαs-DMRs, which were ascribable to the increased copy numbers of these regions retaining the maternally derived methylation pattern and loss of methylation of exon A/B-DMR, which was inexplicable by the copy-number alterations. Fusion junctions of the rearrangement resided within non-repeat sequences and were accompanied by short-templated insertions.

Conclusions: Our results indicate that maternally derived copy-number gains in the GNAS region mediated by nonhomologous end-joining and/or by break-induced replication can underlie autosomal dominant PHP-1b. These rearrangements likely affect methylation of exon A/B-DMR by disconnecting or disrupting its cis-acting regulator(s). This study provides a novel example of human disorders resulting from functional disturbance in the cis-regulatory machinery of DNA methylation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Chromogranins / genetics*
  • Chromosome Aberrations*
  • Female
  • GTP-Binding Protein alpha Subunits, Gs / genetics*
  • Humans
  • Male
  • Mothers
  • Nuclear Family
  • Pseudohypoparathyroidism / diagnosis
  • Pseudohypoparathyroidism / genetics*
  • Young Adult


  • Chromogranins
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs

Supplementary concepts

  • Pseudohypoparathyroidism Type 1B