{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T22:11:42Z","timestamp":1757628702997,"version":"3.44.0"},"reference-count":15,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Pathogenic variants in <jats:italic>GNAS<\/jats:italic> can cause a wide range of diseases including pseudohypoparathyroidism, pseudopseudohypoparathyroidism, McCune\u2010Albright syndrome, among others. The specific phenotypic features that may be seen are influenced by the variant type and location in the gene, whether it causes loss or gain of function, and whether it is germline or somatic in nature. The <jats:italic>GNAS<\/jats:italic> locus is imprinted, which also results in a parent\u2010of\u2010origin effect. Typically, germline loss of function variants on the maternal allele are associated with variable hormonal resistances, obesity, intrauterine growth restriction, and cognitive impairment. Here, we describe a mother and daughter with a unique splicing variant near exon 5 of the <jats:italic>GNAS<\/jats:italic> gene (NM_000516.5:c.432\u2009+\u20095G&gt;A), shown to cause alternative splicing through RNA sequencing (RNA\u2010seq), likely resulting in a loss\u2010of\u2010function effect. Segregation testing revealed that the variant arose <jats:italic>de novo<\/jats:italic> in the mother, and phasing showed it was on her paternal allele. The resultant phenotype includes a SHOX deficiency\u2010like disorder with Madelung deformity in the mother, and significant growth restriction with brachydactyly in the daughter, further expanding the phenotypic spectrum of <jats:italic>GNAS<\/jats:italic> inactivation disorders.<\/jats:p>","DOI":"10.1002\/ajmg.a.64131","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T05:54:03Z","timestamp":1748843643000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Splice\u2010Region Variant Causes an Atypical Presentation of <scp>GNAS<\/scp> Inactivation Disorder"],"prefix":"10.1002","volume":"197","author":[{"given":"Brandon S.","family":"Stone","sequence":"first","affiliation":[{"name":"Division of Genetic and Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University College of Medicine  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swetha","family":"Ramadesikan","sequence":"additional","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Regan","family":"McGinley","sequence":"additional","affiliation":[{"name":"Division of Genetic and Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott E.","family":"Hickey","sequence":"additional","affiliation":[{"name":"Division of Genetic and Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University College of Medicine  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leeran B.","family":"Dublin\u2010Ryan","sequence":"additional","affiliation":[{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8632-1080","authenticated-orcid":false,"given":"Steven I.","family":"Estes","sequence":"additional","affiliation":[{"name":"Division of Genetic and Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria A.","family":"Elliott","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Ohio State University College of Medicine  Columbus Ohio USA"},{"name":"Division of Endocrinology Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Karabasz","sequence":"additional","affiliation":[{"name":"Division of Endocrinology Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesse M.","family":"Hunter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Ohio State University College of Medicine  Columbus Ohio USA"},{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0115-949X","authenticated-orcid":false,"given":"Bimal P.","family":"Chaudhari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Ohio State University College of Medicine  Columbus Ohio USA"},{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard K.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Ohio State University College of Medicine  Columbus Ohio USA"},{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3204-3067","authenticated-orcid":false,"given":"Daniel C.","family":"Koboldt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Ohio State University College of Medicine  Columbus Ohio USA"},{"name":"Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children's Hospital  Columbus Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1159\/000083895"},{"key":"e_1_2_11_3_1","first-page":"1993","volume-title":"GeneReviews","author":"Binder 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