AUTHOR=Manero-Azua Africa , Vado Yerai , Gonzàlez Morlà Judith , Mogas Eduard , Pereda Arrate , Perez de Nanclares Guiomar 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1505244

DOI=10.3389/fendo.2024.1505244

ISSN=1664-2392

ABSTRACT=<sec><title>Objective</title><p>To identify the genetic cause underlying the methylation defect in a patient with clinical suspicion of PHP1B/iPPSD3.</p></sec><sec><title>Design</title><p>Imprinting is an epigenetic mechanism that allows the regulation of gene expression. The <italic>GNAS</italic> 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 <italic>GNAS</italic> locus has been described as one of the possible underlying genetic causes of the methylation alteration.</p></sec><sec><title>Methods</title><p>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 <italic>GNAS</italic> and nearby differentially methylated regions (DMRs).</p></sec><sec><title>Results</title><p>A methylation defect at the four <italic>GNAS</italic>-DMRs was detected, confirming the clinical diagnosis. Complementary techniques revealed the presence of a mixed isodisomy and heterodisomy of chromosome 20. Surprisingly, the <italic>GNAS</italic> locus was located on the heterodisomic zone.</p></sec><sec><title>Conclusions</title><p>Paternal uniparental heterodisomy (hUPD) at the <italic>GNAS</italic> 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 <italic>GNAS</italic> locus and flanking DMRs, suggestive of uniparental disomy (UPD). We also suggest updating the actual guidelines to include hUPD at the <italic>GNAS</italic> locus as a cause of iPPSD3.</p></sec>