2026-04-14T03:46:45Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/125442025-10-24T10:35:50Zcom_2072_378070com_2072_378040col_2072_378092

00925njm 22002777a 4500 dc MANERO RUIZ DE AZUA, AFRICA author VADO RANEDO, YERAI author Gonzàlez Morlà, Judith author Pereda, Arrate author Mogas Viñals, Eduard author Perez de Nanclares, Guiomar author 2025-02-05T08:31:39Z 2025-02-05T08:31:39Z 2024-12-16 Heterodisomy; Pseudohypoparathyroidism Heterodisomía; Pseudohipoparatiroidismo Heterodisomia; Pseudohipoparatiroïdisme 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 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 the GNAS 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 GNAS and nearby differentially methylated regions (DMRs). Results: A 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, the GNAS locus was located on the heterodisomic zone. Conclusions: Paternal uniparental heterodisomy (hUPD) at the GNAS 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 GNAS locus and flanking DMRs, suggestive of uniparental disomy (UPD). We also suggest updating the actual guidelines to include hUPD at the GNAS locus as a cause of iPPSD3. The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was funded by the Instituto de Salud Carlos III (ISCIIII) of the Ministry of Economy and Competitiveness (Spain), which was co-financed by the European Regional Development Fund (grant number PI20/00950) and the Department of Health of the Basque Government (grant number GV2021/111056). http://hdl.handle.net/11351/12544 ADN - Metilació Anomalies cromosòmiques Metabolisme, Errors congènits del DISEASES::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Chromosome Aberrations::Nondisjunction, Genetic::Uniparental Disomy PHENOMENA AND PROCESSES::Chemical Phenomena::Biochemical Phenomena::Alkylation::Methylation::DNA Methylation DISEASES::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Metabolism, Inborn Errors::Metal Metabolism, Inborn Errors::Pseudohypoparathyroidism ENFERMEDADES::afecciones patológicas, signos y síntomas::procesos patológicos::aberraciones cromosómicas::no disyunción genética::disomía uniparental FENÓMENOS Y PROCESOS::fenómenos químicos::fenómenos bioquímicos::alquilación::metilación::metilación del ADN ENFERMEDADES::enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades genéticas congénitas::alteraciones congénitas del metabolismo::alteraciones congénitas del metabolismo de los metales::seudohipoparatiroidismo Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3)