{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:46:07Z","timestamp":1790693167242,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T00:00:00Z","timestamp":1658188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: We report on a 20-week-old female fetus with a diaphragmatic hernia and other malformations, all of which appeared after the first-trimester ultrasound. Methods and Results: Whole trio exome sequencing (WES) on cell-free fetal DNA (cff-DNA) revealed a de novo frameshift variant of the X-linked STAG2 gene. Loss-of-function (LoF) STAG2 variants cause either holoprosencephaly (HPE) or Mullegama\u2013Klein\u2013Martinez syndrome (MKMS), are de novo, and only affect females, indicating male lethality. In contrast, missense mutations associate with milder forms of MKMS and follow the classic X-linked recessive inheritance transmitted from healthy mothers to male offspring. STAG2 has been reported to escape X-inactivation, suggesting that disease onset in LoF females is dependent on inadequate dosing for at least some of the transcripts, as is the case with a part of the autosomal dominant diseases. Missense STAG2 variants produce a quantity of transcripts, which, while resulting in a different protein, leads to disease only in hemizygous males. Similar inheritance patterns are described for other escapee genes. Conclusions: This study confirms the advantage of WES on cff-DNA and emphasizes the role of the type of the variant in X-linked disorders.<\/jats:p>","DOI":"10.3390\/jcm11144182","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T05:37:53Z","timestamp":1658209073000},"page":"4182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Non-Invasive Detection of a De Novo Frameshift Variant of STAG2 in a Female Fetus: Escape Genes Influence the Manifestation of X-Linked Diseases in Females"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4249-8412","authenticated-orcid":false,"given":"Aldesia","family":"Provenzano","sequence":"first","affiliation":[{"name":"Medical Genetics Unit, Department of Experimental and Clinical Biomedical Sciences \u201cMario Serio\u201d, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0606-8404","authenticated-orcid":false,"given":"Andrea","family":"La Barbera","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Lai","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Perra","sequence":"additional","affiliation":[{"name":"Unit of Oncology and Molecular Pathology, Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6862-1810","authenticated-orcid":false,"given":"Antonio","family":"Farina","sequence":"additional","affiliation":[{"name":"Division of Obstetrics and Prenatal Medicine, Department of Medicine and Surgery (DIMEC), IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettore","family":"Cariati","sequence":"additional","affiliation":[{"name":"Villa Cherubini Hospital, 50133 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orsetta","family":"Zuffardi","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3954-326X","authenticated-orcid":false,"given":"Sabrina","family":"Giglio","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy"},{"name":"CeSAR, University Service for Research, University of Cagliari, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.1111\/1471-0528.16616","article-title":"Evidence to Support the Clinical Utility of Prenatal Exome Sequencing in Evaluation of the Fetus with Congenital Anomalies: Scientific Impact Paper No. 64 [February] 2021","volume":"128","author":"Mone","year":"2021","journal-title":"BJOG"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/pd.6115","article-title":"Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta-analysis","volume":"42","author":"Mellis","year":"2022","journal-title":"Prenat. 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