Heterodisomy in the locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3).

Objective: To identify the genetic cause underlying the methylation defect in a patient with clinical suspicion of PHP1B/iPPSD3.

Design: Imprinting is an epigenetic mechanism that allows the regulation of gene expression. The locus is one of the loci within the genome that is imprinted. When the methylation pattern is affected, it causes pseudohypoparathyroidism type 1B (PHP1B) or inactivating PTH/PTHrP signaling disorder 3 (iPPSD3). Paternal uniparental isodisomy (iUPDpat) of the chromosomal region comprising the locus has been described as one of the possible underlying genetic causes of the methylation alteration.

Methods: We present the case of a patient clinically diagnosed with iPPSD3. We performed a commercial methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), single-nucleotide polymorphism (SNP) array, and microsatellite study. In addition, we designed a custom MS-MLPA to analyze and nearby differentially methylated regions (DMRs).

Results: A methylation defect at the four -DMRs was detected, confirming the clinical diagnosis. Complementary techniques revealed the presence of a mixed isodisomy and heterodisomy of chromosome 20. Surprisingly, the locus was located on the heterodisomic zone.

Conclusions: Paternal uniparental heterodisomy (hUPD) at the locus is also a genetic defect associated with iPPSD3. In the absence of parental samples, our custom MS-MLPA allows for the detection of a methylation defect at the locus and flanking DMRs, suggestive of uniparental disomy (UPD). We also suggest updating the actual guidelines to include hUPD at the locus as a cause of iPPSD3.