Sporadic pseudohypoparathyroidism type 1B in monozygotic twins: insights into the pathogenesis of methylation defects

Context: Sporadic pseudohypoparathyroidism type 1B (sporPHP1B) is an imprinting disease without a defined genetic cause, characterized by broad methylation changes in differentially methylated regions (DMRs) of the GNAS gene.
Objective: This work aims to provide insights into the causative event leading to the GNAS methylation defects through comprehensive molecular genetic analyses of a pair of female monozygotic twins concordant for sporPHP1B who were conceived naturally i.e., without assisted reproductive techniques.
Methods: Using the leukocyte genome of the twins and family members, we performed targeted bisulfite sequencing, methylation-sensitive restriction enzyme (MSRE)-qPCR, whole-genome sequencing (WGS), high-density SNP array, and Sanger sequencing.
Results: Methylation analyses by targeted bisulfite sequencing and MSRE-qPCR revealed almost complete loss of methylation at the GNAS AS, XL, and A/B DMRs and gain of methylation at the NESP55 DMR in the twins, but not in other fa..., , ,