{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:25:57Z","timestamp":1768523157236,"version":"3.49.0"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background and Clinical Significance: Adams\u2013Oliver syndrome type 3 (AOS3) is a rare congenital disorder typically characterised by terminal transverse limb defects and variable involvement of other organ systems. Although pathogenic variants in RBPJ are well established in AOS3, associated neurodevelopmental or psychiatric features have been only sporadically documented. Case Presentation: We describe a male patient first evaluated at the age of 10 years and subsequently re-evaluated at 14 years, with AOS3 presenting terminal limb defects together with autistic-like behaviour, cognitive difficulties, dyslexia, and recurrent depressive symptoms. Whole-exome sequencing (WES) identified a heterozygous pathogenic variant in RBPJ (c.505A&gt;G; p.Lys169Glu), confirming the molecular diagnosis of autosomal dominant AOS3. Additional findings included a heterozygous missense variant in CACNA1A (p.Arg1678Cys), a gene linked to neurological disorders with broad phenotypic variability. Because of elevated homocysteine levels, the patient was also tested for MTHFR variants and was found to be heterozygous for C677T and A1298C. Conclusions: This case illustrates a rare combination of a validated AOS3-associated RBPJ variant, along with additional CACNA1A and MTHFR variants that may influence the patient\u2019s neurocognitive and psychiatric characteristics. The results underscore the importance of comprehensive genetic testing in atypical AOS presentations and highlight the complexity of interpreting overlapping genetic factors.<\/jats:p>","DOI":"10.3390\/diagnostics16020274","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:26:36Z","timestamp":1768465596000},"page":"274","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adams\u2013Oliver Syndrome Type 3: A Case Report of Concurrent RBPJ, CACNA1A, and Double-Heterozygous MTHFR Variants"],"prefix":"10.3390","volume":"16","author":[{"given":"Gra\u021bian Cosmin","family":"Damian","sequence":"first","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, \u201cVasile Goldi\u0219\u201d Western University of Arad, 94-96 Revolutiei Blvd., 310025 Arad, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerica","family":"Belengeanu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, \u201cVasile Goldi\u0219\u201d Western University of Arad, 94-96 Revolutiei Blvd., 310025 Arad, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0550-8404","authenticated-orcid":false,"given":"Cristina","family":"Popescu","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, \u201cVasile Goldi\u0219\u201d Western University of Arad, 94-96 Revolutiei Blvd., 310025 Arad, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2585-2632","authenticated-orcid":false,"given":"Diana","family":"Marian","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Dentistry, \u201cVasile Goldi\u0219\u201d Western University of Arad, 94-96 Revolutiei Blvd., 310025 Arad, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3852-9060","authenticated-orcid":false,"given":"Ramona Amina","family":"Popovici","sequence":"additional","affiliation":[{"name":"Department I, Faculty of Dental Medicine, Victor Babes University of Medicine and Pharmacy of Timisoara, 300041 Timisoara, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Cojocariu","sequence":"additional","affiliation":[{"name":"Department of Dentistry, Faculty of Dentistry, \u201cVasile Goldi\u0219\u201d Western University of Arad, 94-96 Revolutiei Blvd., 310025 Arad, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/oxfordjournals.jhered.a105415","article-title":"Hereditary deformities in man: Due to arrested development","volume":"36","author":"Adams","year":"1945","journal-title":"J. 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