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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Pediatric Endocrinology
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1505244

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

Provisionally accepted
Africa Manero-Azua Africa Manero-Azua 1Yerai Vado Yerai Vado 1Judith Gonzàlez Morlà Judith Gonzàlez Morlà 2Eduard Mogas Eduard Mogas 3Arrate Pereda Arrate Pereda 1,4Guiomar Perez De Nanclares Guiomar Perez De Nanclares 4*
  • 1 BioAraba Health Research Institute - OSI Araba, Vitoria-Gasteiz, Basque Country, Spain
  • 2 Hospital de Palamós, Palamos, Spain
  • 3 Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain
  • 4 Osakidetza Basque Health Service, Vitoria-Gasteiz, Spain

The final, formatted version of the article will be published soon.

    Objective: To identify the genetic cause underlying the methylation defect in a patient with clinical suspicion of PHP1B/iPPSD3.Imprinting is an epigenetic mechanism that allows the regulation of gene expression. GNAS 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 GNAS locus has been described as one of the possible underlying genetic causes of the methylation alteration.We present the case of a patient clinically diagnosed with iPPSD3. We performed commercial MS-MLPA, SNP array and microsatellite study. In addition, we designed a custom MS-MLPA to analyze GNAS and nearby DMRs.Results: Methylation defect at the four GNAS-DMRs was detected, confirming the clinical diagnosis. Complementary techniques revealed the presence of a mixed isodisomy and heterodisomy of chromosome 20. Surprisingly GNAS locus is located on the heterodisomic zone.Conclusions: Paternal heterodisomy at GNAS locus is also a genetic defect associated with iPPSD3. In absence of parental samples, our custom MS-MLPA allows detecting methylation defect at GNAS locus and flanking DMRs, suggestive of UPD. We also suggest to update actual guidelines to include hUPD at GNAS locus as a cause of iPPSD3.

    Keywords: PHP1B, iPPSD3, Gnas, Heterodisomy, Upd(20)pat, MS-MLPA

    Received: 02 Oct 2024; Accepted: 18 Nov 2024.

    Copyright: © 2024 Manero-Azua, Vado, Gonzàlez Morlà, Mogas, Pereda and Perez De Nanclares. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Guiomar Perez De Nanclares, Osakidetza Basque Health Service, Vitoria-Gasteiz, Spain

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