{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T07:42:59Z","timestamp":1773042179881,"version":"3.50.1"},"reference-count":16,"publisher":"BMJ","issue":"10","funder":[{"DOI":"10.13039\/501100015694","name":"Fondazione Cassa di Risparmio di Firenze","doi-asserted-by":"crossref","award":["Brain Project"],"award-info":[{"award-number":["Brain Project"]}],"id":[{"id":"10.13039\/501100015694","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009888","name":"Regione Toscana","doi-asserted-by":"crossref","award":["Call for Health 2018 [grant DECODE-EE]"],"award-info":[{"award-number":["Call for Health 2018 [grant DECODE-EE]"]}],"id":[{"id":"10.13039\/501100009888","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["Current Research 2023"],"award-info":[{"award-number":["Current Research 2023"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,7,17]]},"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:p>We aim to describe double gonosomal mosaicism in the <jats:italic>GRIN2A<\/jats:italic> gene in a mother who passed on two different pathogenic variants at the same nucleotide to her two affected children. We studied a boy with epilepsy and intellectual disability, along with his sister and mother who exhibited language impairment and learning difficulties without epilepsy. We identified in the proband a splice-site variant in <jats:italic>GRIN2A<\/jats:italic> (c.1008\u20131G&gt;A) inherited from his mother. Subsequent testing of his sister revealed a different change at the same nucleotide c.1008\u20131G&gt;T, which was also present in the mother\u2019s DNA at 3.9% allele frequency. The co-occurrence of two mutational events at the same nucleotide is extremely rare. Since a chance occurrence is unlikely, we hypothesise that a base mismatch may introduce instability triggering a second event. In this family, the mother carries three alleles, of which one is at very low frequency. This complex genetic landscape poses diagnostic challenges since low-level mosaicism may escape detection via conventional methods. Applying specific technology becomes crucial, as double mosaicism might prove to be more prevalent than anticipated severely impacting diagnostic accuracy and genetic counselling.<\/jats:p>","DOI":"10.1136\/jmg-2024-110101","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T13:29:17Z","timestamp":1722432557000},"page":"999-1002","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Double gonosomal mosaicism as an unusual hereditary mechanism in familial <i>GRIN2A<\/i>-related disorder"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8549-4158","authenticated-orcid":false,"given":"Valentina","family":"Cetica","sequence":"first","affiliation":[{"name":"Paediatric Neurology Unit and Laboratories, Neuroscience Department, Member of ERN Epicare and ITHACA, Meyer Children's Hospital IRCCS, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mara","family":"Cavallin","sequence":"additional","affiliation":[{"name":"Paediatric Neurology Unit and Laboratories, Neuroscience Department, Member of ERN Epicare and ITHACA, Meyer Children's Hospital IRCCS, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Luisa","family":"Ricci","sequence":"additional","affiliation":[{"name":"Paediatric Neurology Unit and Laboratories, Neuroscience Department, Member of ERN Epicare and ITHACA, Meyer Children's Hospital IRCCS, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Mandorlini","sequence":"additional","affiliation":[{"name":"Paediatric Neurology Unit and Laboratories, Neuroscience Department, Member of ERN Epicare and ITHACA, Meyer Children's Hospital IRCCS, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Bartolini","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Foundation Stella Maris, Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Parrini","sequence":"additional","affiliation":[{"name":"Paediatric Neurology Unit and Laboratories, Neuroscience Department, Member of ERN Epicare and ITHACA, Meyer Children's Hospital IRCCS, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renzo","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Paediatric Neurology Unit and Laboratories, Neuroscience Department, Member of ERN Epicare and ITHACA, Meyer Children's Hospital IRCCS, Florence, Italy"},{"name":"University of Florence, Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2024,7,31]]},"reference":[{"key":"2025101713361436000_61.10.999.1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.114"},{"key":"2025101713361436000_61.10.999.2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181e04325"},{"key":"2025101713361436000_61.10.999.3","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1002\/acn3.50815","article-title":"Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA","volume":"6","author":"Lee","year":"2019","journal-title":"Ann Clin Transl Neurol"},{"key":"2025101713361436000_61.10.999.4","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz194"},{"key":"2025101713361436000_61.10.999.5","doi-asserted-by":"crossref","DOI":"10.1212\/NXG.0000000000000333","article-title":"Double somatic mosaicism in a child with dravet 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