Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3)
ObjectiveTo identify the genetic cause underlying the methylation defect in a patient with clinical suspicion of PHP1B/iPPSD3.DesignImprinting 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 met...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-12-01
|
| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2024.1505244/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850118920792440832 |
|---|---|
| author | Africa Manero-Azua Yerai Vado Judith Gonzàlez Morlà Eduard Mogas Arrate Pereda Guiomar Perez de Nanclares |
| author_facet | Africa Manero-Azua Yerai Vado Judith Gonzàlez Morlà Eduard Mogas Arrate Pereda Guiomar Perez de Nanclares |
| author_sort | Africa Manero-Azua |
| collection | DOAJ |
| description | ObjectiveTo identify the genetic cause underlying the methylation defect in a patient with clinical suspicion of PHP1B/iPPSD3.DesignImprinting 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.MethodsWe 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).ResultsA 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.ConclusionsPaternal 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. |
| format | Article |
| id | doaj-art-64370bfa1e514f149e892d2f9e6fba8b |
| institution | OA Journals |
| issn | 1664-2392 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj-art-64370bfa1e514f149e892d2f9e6fba8b2025-08-20T02:35:46ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922024-12-011510.3389/fendo.2024.15052441505244Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3)Africa Manero-Azua0Yerai Vado1Judith Gonzàlez Morlà2Eduard Mogas3Arrate Pereda4Guiomar Perez de Nanclares5Rare Disease Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, Vitoria-Gasteiz, SpainRare Disease Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, Vitoria-Gasteiz, SpainPediatric Endocrinology Section, Hospital Comarcal de Palamós, Girona, SpainPediatric Endocrinology Section, Hospital Universitari Vall d’Hebron, Barcelona, SpainRare Disease Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, Vitoria-Gasteiz, SpainRare Disease Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, Vitoria-Gasteiz, SpainObjectiveTo identify the genetic cause underlying the methylation defect in a patient with clinical suspicion of PHP1B/iPPSD3.DesignImprinting 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.MethodsWe 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).ResultsA 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.ConclusionsPaternal 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.https://www.frontiersin.org/articles/10.3389/fendo.2024.1505244/fullPHP1BiPPSD3GNASheterodisomyupd(20)patMS-MLPA |
| spellingShingle | Africa Manero-Azua Yerai Vado Judith Gonzàlez Morlà Eduard Mogas Arrate Pereda Guiomar Perez de Nanclares Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3) Frontiers in Endocrinology PHP1B iPPSD3 GNAS heterodisomy upd(20)pat MS-MLPA |
| title | Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3) |
| title_full | Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3) |
| title_fullStr | Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3) |
| title_full_unstemmed | Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3) |
| title_short | Heterodisomy in the GNAS locus is also a cause of pseudohypoparathyroidism type 1B (iPPSD3) |
| title_sort | heterodisomy in the gnas locus is also a cause of pseudohypoparathyroidism type 1b ippsd3 |
| topic | PHP1B iPPSD3 GNAS heterodisomy upd(20)pat MS-MLPA |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2024.1505244/full |
| work_keys_str_mv | AT africamaneroazua heterodisomyinthegnaslocusisalsoacauseofpseudohypoparathyroidismtype1bippsd3 AT yeraivado heterodisomyinthegnaslocusisalsoacauseofpseudohypoparathyroidismtype1bippsd3 AT judithgonzalezmorla heterodisomyinthegnaslocusisalsoacauseofpseudohypoparathyroidismtype1bippsd3 AT eduardmogas heterodisomyinthegnaslocusisalsoacauseofpseudohypoparathyroidismtype1bippsd3 AT arratepereda heterodisomyinthegnaslocusisalsoacauseofpseudohypoparathyroidismtype1bippsd3 AT guiomarperezdenanclares heterodisomyinthegnaslocusisalsoacauseofpseudohypoparathyroidismtype1bippsd3 |