{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T22:11:59Z","timestamp":1787868719345,"version":"build-2784847793"},"reference-count":49,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"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\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["GV2021\/111056"],"award-info":[{"award-number":["GV2021\/111056"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003086","name":"Basque Government","doi-asserted-by":"publisher","award":["PI20\/00950"],"award-info":[{"award-number":["PI20\/00950"]}],"id":[{"id":"10.13039\/501100003086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003086","name":"Basque Government","doi-asserted-by":"publisher","award":["GV2021\/111056"],"award-info":[{"award-number":["GV2021\/111056"]}],"id":[{"id":"10.13039\/501100003086","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Society of Paediatric Endocrinology","award":["PI20\/00950"],"award-info":[{"award-number":["PI20\/00950"]}]},{"name":"European Society of Paediatric Endocrinology","award":["GV2021\/111056"],"award-info":[{"award-number":["GV2021\/111056"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>GNAS-activating somatic mutations give rise to Fibrous Dysplasia\/McCune\u2013Albright syndrome (FD\/MAS). The low specificity of extra-skeletal signs of MAS and the mosaic status of the mutations generate some difficulties for a proper diagnosis. We studied the clinical and molecular statuses of 40 patients referred with a clinical suspicion of FD\/MAS to provide some clues. GNAS was sequenced using both Sanger and Next-Generation Sequencing (NGS). We were able to identify the pathogenic variants in 25% of the patients. Most of them were identified in the affected tissue, but not in blood. Additionally, NGS demonstrated the ability to detect more patients with mosaicism (8\/34) than Sanger sequencing (4\/39). Even if in some cases, the clinical information was not complete, we confirmed that, as in previous works, when the patients were young children with a single manifestation, such as hyperpigmented skin macules or precocious puberty, the molecular diagnosis was usually negative. In conclusion, as FD\/MAS is caused by mosaic variants, it is essential to use sensitive techniques that allow for the detection of low percentages and to choose the right tissue to study. When not possible, and due to the low positive genetic rate, patients with FD\/MAS should only be genetically tested when the clinical diagnosis is really uncertain.<\/jats:p>","DOI":"10.3390\/genes15010120","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T11:28:46Z","timestamp":1705577326000},"page":"120","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Choosing the Best Tissue and Technique to Detect Mosaicism in Fibrous Dysplasia\/McCune\u2013Albright Syndrome (FD\/MAS)"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4156-9159","authenticated-orcid":false,"given":"Yerai","family":"Vado","sequence":"first","affiliation":[{"name":"Rare Disease Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Africa","family":"Manero-Azua","sequence":"additional","affiliation":[{"name":"Rare Disease Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5442-7873","authenticated-orcid":false,"given":"Arrate","family":"Pereda","sequence":"additional","affiliation":[{"name":"Rare Disease Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2424-5294","authenticated-orcid":false,"given":"Guiomar","family":"Perez de Nanclares","sequence":"additional","affiliation":[{"name":"Rare Disease Research Group, Molecular (Epi) Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1749-6632.2002.tb04335.x","article-title":"Gs(Alpha) Mutations and Imprinting Defects in Human Disease","volume":"968","author":"Weinstein","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","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":"ref_3","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/humu.21438","article-title":"LOVD v.2.0: The next Generation in Gene Variant Databases","volume":"32","author":"Fokkema","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1210\/jc.2015-4310","article-title":"The Prevalence of GNAS Deficiency-Related Diseases in a Large Cohort of Patients Characterized by the EuroPHP Network","volume":"101","author":"Elli","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1006\/bmme.1996.0027","article-title":"Concurrent Hormone Resistance (Pseudohypoparathyroidism Type Ia) and Hormone Independence (Testotoxicosis) Caused by a Unique Mutation in the G\u03b1s Gene","volume":"58","author":"Nakamoto","year":"1996","journal-title":"Biochem. Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/371164a0","article-title":"Rapid GDP Release from Gs\u03b1 in Patients with Gain and Loss of Endocrine Function","volume":"371","author":"Iiri","year":"1994","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/340692a0","article-title":"GTPase Inhibiting Mutations Activate the \u03b1 Chain of Gs and Stimulate Adenylyl Cyclase in Human Pituitary Tumours","volume":"340","author":"Landis","year":"1989","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1186\/s13023-019-1102-9","article-title":"Best Practice Management Guidelines for Fibrous Dysplasia\/McCune-Albright Syndrome: A Consensus Statement from the FD\/MAS International Consortium","volume":"14","author":"Javaid","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1097\/00005792-199607000-00001","article-title":"Clinical Implications of Genetic Defects in G Proteins. The Molecular Basis of McCune-Albright Syndrome and Albright Hereditary Osteodystrophy","volume":"75","author":"Ringel","year":"1996","journal-title":"Medicine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1681\/ASN.2018121268","article-title":"Germline-Derived Gain-of-Function Variants of Gs \u03b1-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis","volume":"30","author":"Miyado","year":"2019","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1210\/jc.2018-01250","article-title":"A New Multisystem Disorder Caused by the G\u03b1s Mutation p.F376V","volume":"104","author":"Biebermann","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11657-016-0271-6","article-title":"Improving Patient Outcomes in Fibrous Dysplasia\/McCune-Albright Syndrome: An International Multidisciplinary Workshop to Inform an International Partnership","volume":"12","author":"Boyce","year":"2017","journal-title":"Arch. Osteoporos."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11832-007-0006-8","article-title":"Current Approach to Fibrous Dysplasia of Bone and McCune\u2013Albright Syndrome","volume":"1","author":"Leet","year":"2007","journal-title":"J. Child. Orthop."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJM193704292161701","article-title":"Syndrome Characterized by Osteitis Fibrosa Disseminata, Areas of Pigmentation and Endocrine Dysfunction, with Precocious Puberty in Females","volume":"216","author":"Albright","year":"1937","journal-title":"N. Engl. J. Med."},{"key":"ref_15","first-page":"743","article-title":"Osteitis Fibrosa Cystica: The Case of a Nine-Year-Old Girl Who Also Exhibits Precocious Puberty, Multiple Pigmen-Tation of the Skin and Hyperthyroidism","volume":"52","author":"McCune","year":"1936","journal-title":"Am. J. Dis. Child"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1750-1172-3-12","article-title":"McCune-Albright Syndrome","volume":"3","author":"Dumitrescu","year":"2008","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_17","first-page":"419","article-title":"Treatment of Precocious Puberty in McCune-Albright Syndrome","volume":"4","author":"Mieszczak","year":"2007","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1359\/jbmr.2000.15.1.120","article-title":"Mutations of the GNAS1 Gene, Stromal Cell Dysfunction, and Osteomalacic Changes in Non-McCune-Albright Fibrous Dysplasia of Bone","volume":"15","author":"Bianco","year":"2000","journal-title":"J. Bone Miner. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/jbmr.4766","article-title":"Identification of GNAS Variants in Circulating Cell-Free DNA from Patients with Fibrous Dysplasia\/McCune Albright Syndrome","volume":"38","author":"Roszko","year":"2023","journal-title":"J. Bone Miner. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1111\/j.1365-2559.2007.02676.x","article-title":"A Sensitive Mutation-Specific Screening Technique for GNAS1 Mutations in Cases of Fibrous Dysplasia: The First Report of a Codon 227 Mutation in Bone","volume":"50","author":"Idowu","year":"2007","journal-title":"Histopathology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1056\/NEJM199112123252403","article-title":"Activating Mutations of the Stimulatory G Protein in the McCune-Albright Syndrome","volume":"325","author":"Weinstein","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"P125","DOI":"10.1359\/jbmr.06s224","article-title":"Fibrous Dysplasia as a Stem Cell Disease","volume":"21","author":"Riminucci","year":"2006","journal-title":"J. Bone Miner. Res."},{"key":"ref_23","first-page":"355","article-title":"Review and Hypotheses: Somatic Mosaicism: Observations Related to Clinical Genetics","volume":"43","author":"Hall","year":"1988","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/nrg906","article-title":"Mechanisms and Consequences of Somatic Mosaicism in Humans","volume":"3","author":"Youssoufian","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"983668","DOI":"10.3389\/fgene.2022.983668","article-title":"De Novo Mutations, Genetic Mosaicism and Human Disease","volume":"13","author":"Mohiuddin","year":"2022","journal-title":"Front. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nrg3241","article-title":"De Novo Mutations in Human Genetic Disease","volume":"13","author":"Veltman","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"a006125","DOI":"10.1101\/mcs.a006162","article-title":"Mosaicism in Clinical Genetics","volume":"7","author":"Mefford","year":"2021","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1055431","DOI":"10.3389\/fendo.2022.1055431","article-title":"Frequency of de Novo Variants and Parental Mosaicism in Families with Inactivating PTH\/PTHrP Signaling Disorder Type 2","volume":"13","author":"Vado","year":"2023","journal-title":"Front. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s40246-023-00535-y","article-title":"Revealing Parental Mosaicism: The Hidden Answer to the Recurrence of Apparent de Novo Variants","volume":"17","author":"Lee","year":"2023","journal-title":"Hum. Genom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1002\/humu.20980","article-title":"Parallel Sequencing Used in Detection of Mosaic Mutations: Comparison with Four Diagnostic DNA Screening Techniques","volume":"30","author":"Rohlin","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.1002\/ajmg.a.37222","article-title":"A Girl with Incomplete Prader-Willi Syndrome and Negative MS-PCR, Found to Have Mosaic Maternal UPD-15 at SNP Array","volume":"167","author":"Morandi","year":"2015","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_32","first-page":"370","article-title":"Somatic and Germ-Line Mosaicism of Deletion 15q11.2-Q13 in a Mother of Dyzigotic Twins with Angelman Syndrome","volume":"164A","author":"Madruga","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10689-007-9169-1","article-title":"Gonadal Mosaicism and Familial Adenomatous Polyposis","volume":"7","author":"Schwab","year":"2008","journal-title":"Fam. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ajhg.2014.07.003","article-title":"Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders","volume":"95","author":"Campbell","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.jmoldx.2016.01.002","article-title":"Detection and Quantification of Mosaic Mutations in Disease Genes by Next-Generation Sequencing","volume":"18","author":"Qin","year":"2016","journal-title":"J. Mol. Diagn."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13100-014-0030-4","article-title":"A Droplet Digital PCR Detection Method for Rare L1 Insertions in Tumors","volume":"5","author":"White","year":"2014","journal-title":"Mob. DNA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1530\/ERC-16-0082","article-title":"Somatic Mosaicism Underlies X-Linked Acrogigantism Syndrome in Sporadic Male Subjects","volume":"23","author":"Daly","year":"2016","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1002\/pd.5156","article-title":"A Novel Approach Using Long-Read Sequencing and DdPCR to Investigate Gonadal Mosaicism and Estimate Recurrence Risk in Two Families with Developmental Disorders","volume":"37","author":"Wilbe","year":"2017","journal-title":"Prenat. Diagn."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"E2029","DOI":"10.1210\/jc.2014-1291","article-title":"McCune-Albright Syndrome: A Detailed Pathological and Genetic Analysis of Disease Effects in an Adult Patient","volume":"99","author":"Vasilev","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1136\/jmedgenet-2019-106498","article-title":"Improved Molecular Detection of Mosaicism in Beckwith-Wiedemann Syndrome","volume":"58","author":"Baker","year":"2021","journal-title":"J. Med. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.medcli.2023.06.009","article-title":"Vitamin D Deficiency in Adulthood: Presentation of 2familial Cases Simulating Pseudohypoparathyroidism","volume":"161","author":"Pereda","year":"2023","journal-title":"Med. Clin."},{"key":"ref_42","unstructured":"Illumina (2014). Somatic Variant Caller, Illumina."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative Genomics Viewer","volume":"29","author":"Robinson","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e2229","DOI":"10.1002\/mgg3.2229","article-title":"Application of Various Genetic Analysis Techniques for Detecting Two Rare Cases of 9p Duplication Mosaicism during Prenatal Diagnosis","volume":"11","author":"Zhang","year":"2023","journal-title":"Mol. Genet. Genomic Med."},{"key":"ref_45","first-page":"CD003252","article-title":"Amniocentesis and Chorionic Villus Sampling for Prenatal Diagnosis","volume":"9","author":"Alfirevic","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1159\/000463384","article-title":"Combining Real-Time COLD- and MAMA-PCR TaqMan Techniques to Detect and Quantify R201 GNAS Mutations in the McCune-Albright Syndrome","volume":"87","author":"Galliano","year":"2017","journal-title":"Horm. Res. Paediatr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2843","DOI":"10.1093\/bioinformatics\/btu356","article-title":"Toward Better Understanding of Artifacts in Variant Calling from High-Coverage Samples","volume":"30","author":"Li","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3","DOI":"10.20892\/j.issn.2095-3941.2016.0004","article-title":"Current Practices and Guidelines for Clinical Next-Generation Sequencing Oncology Testing","volume":"13","author":"Strom","year":"2016","journal-title":"Cancer Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Cazzato, G., Caporusso, C., Arezzo, F., Cimmino, A., Colagrande, A., Loizzi, V., Cormio, G., Lettini, T., Maiorano, E., and Scarcella, V.S. (2021). Formalin-Fixed and Paraffin-Embedded Samples for Next Generation Sequencing: Problems and Solutions. Genes, 12.","DOI":"10.3390\/genes12101472"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/1\/120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:49:55Z","timestamp":1760104195000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/1\/120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,18]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["genes15010120"],"URL":"https:\/\/doi.org\/10.3390\/genes15010120","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,18]]}}}