{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:52:33Z","timestamp":1753890753649,"version":"3.41.2"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T00:00:00Z","timestamp":1672790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI20\/00950"],"award-info":[{"award-number":["PI20\/00950"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010585","name":"Osasun Saila, Eusko Jaurlaritzako","doi-asserted-by":"publisher","award":["GV2021\/111056"],"award-info":[{"award-number":["GV2021\/111056"]}],"id":[{"id":"10.13039\/501100010585","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>iPPSD2 (which includes PHP1A and PPHP\/POH) is a rare inherited autosomal dominant endocrine disorder caused by inactivating <jats:italic>GNAS<\/jats:italic> pathogenic variants. A high percentage of <jats:italic>de novo<\/jats:italic> cases has been suggested. In rare cases, parental mosaicism has been described, but its real frequency is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>A retrospective study including a series of 95 genetically confirmed iPPSD2 probands.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The frequency of <jats:italic>de novo<\/jats:italic> cases was evaluated and the distribution of the type of variants was compared according to the type of inheritance. The putative involved allele was determined by reverse transcriptase PCR (RT-PCR) or allele specific oligonucleotide RT-PCR (ASO-RT-PCR). The possibility of <jats:italic>GNAS<\/jats:italic> mosaicism was studied by next-generation sequencing (NGS) on the corresponding parental DNA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In 41 patients the variant was of <jats:italic>de novo<\/jats:italic> origin and in 24 the origin could not be established. In both cases 66.67% of variants generated a truncated or absent protein whereas the rest of the variants were missense or in-frame deletion\/duplication. Parental origin was studied in 45 of those patients and determined in 35. Curiously, the percentage of <jats:italic>de novo<\/jats:italic> variants at the paternal allele was higher than when paternally inherited (31.1% vs 6.67%). NGS detected mosaicism in three independent families: one from paternal DNA (allelic ratio 10%) and two from maternal DNA (allelic ratio 10% and 2%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>De novo<\/jats:italic> pathogenic variants are frequent in iPPSD2 (around 45%). Parental mosaicism is infrequent (8.11%) but should be analyzed with NGS, taking into account its importance in genetic counselling.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2022.1055431","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T19:34:16Z","timestamp":1672860856000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Frequency of de novo variants and parental mosaicism in families with inactivating PTH\/PTHrP signaling disorder type 2"],"prefix":"10.3389","volume":"13","author":[{"given":"Yerai","family":"Vado","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arrate","family":"Pereda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Africa","family":"Manero-Azua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Spanish Network for Imprinting Disorders","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guiomar","family":"Perez de Nanclares","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-0956-8_8","article-title":"G Protein-coupled receptor mutations and human genetic disease","volume":"1175","author":"Thompson","year":"2014","journal-title":"Methods Mol Biol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1038\/s41574-018-0042-0","article-title":"Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement","volume":"14","author":"Mantovani","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2018.09.008","article-title":"Parathyroid hormone resistance syndromes - inactivating PTH\/PTHrP signaling disorders (iPPSDs)","volume":"32","author":"Elli","year":"2018","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B4","doi-asserted-by":"publisher","first-page":"P1","DOI":"10.1530\/EJE-16-0107","article-title":"From pseudohypoparathyroidism to inactivating PTH\/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network","volume":"175","author":"Thiele","year":"2016","journal-title":"Eur J Endocrinol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(50)80173-7","article-title":"Pseudohypoparathyroidism - an example of \u201cSeabright-bantam syndrome\u201d","volume":"30","author":"Albright","year":"1942","journal-title":"Endocrinology"},{"key":"B6","article-title":"Pseudo-pseudohypoparathyroidism","volume":"65","author":"Albright","year":"1952","journal-title":"TransAssoc Am Physicians"},{"key":"B7","doi-asserted-by":"publisher","first-page":"37","DOI":"10.2147\/TACG.S51064","article-title":"Progressive osseous heteroplasia: diagnosis, treatment, and prognosis","volume":"8","author":"Pignolo","year":"2015","journal-title":"Appl Clin Genet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2014.10.006","article-title":"Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in","volume":"71","author":"Turan","year":"2015","journal-title":"GNAS. 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