{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:06:23Z","timestamp":1791371183313,"version":"4.3.1"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify the genetic cause underlying the methylation defect in a patient with clinical suspicion of PHP1B\/iPPSD3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Imprinting is an epigenetic mechanism that allows the regulation of gene expression. The <jats:italic>GNAS<\/jats: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 <jats:italic>GNAS<\/jats:italic> locus has been described as one of the possible underlying genetic causes of the methylation alteration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats: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 <jats:italic>GNAS<\/jats:italic> and nearby differentially methylated regions (DMRs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A methylation defect at the four <jats:italic>GNAS<\/jats:italic>-DMRs was detected, confirming the clinical diagnosis. Complementary techniques revealed the presence of a mixed isodisomy and heterodisomy of chromosome 20. Surprisingly, the <jats:italic>GNAS<\/jats:italic> locus was located on the heterodisomic zone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Paternal uniparental heterodisomy (hUPD) at the <jats:italic>GNAS<\/jats: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 <jats:italic>GNAS<\/jats:italic> locus and flanking DMRs, suggestive of uniparental disomy (UPD). We also suggest updating the actual guidelines to include hUPD at the <jats:italic>GNAS<\/jats:italic> locus as a cause of iPPSD3.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2024.1505244","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T04:18:48Z","timestamp":1734322728000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3)"],"prefix":"10.3389","volume":"15","author":[{"given":"Africa","family":"Manero-Azua","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yerai","family":"Vado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Gonz\u00e0lez 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