De Novo Pathogenic Variant in FBRSL1, Non OMIM Gene Paralogue AUTS2, Causes a Novel Recognizable Syndromic Manifestation with Intellectual Disability; An Additional Patient and Review of the Literature

first_pagesettingsOrder Article Reprints Open AccessArticle De Novo Pathogenic Variant in FBRSL1, Non OMIM Gene Paralogue AUTS2, Causes a Novel Recognizable Syndromic Manifestation with Intellectual Disability; An Additional Patient and Review of the Literature by Nenad Bukvic 1,2,*ORCID,Marta De Rinaldis 3,Massimiliano Chetta 4ORCID,Antonio Trabacca 5ORCID,Maria Teresa Bassi 6ORCID,René Massimiliano Marsano 7ORCID,Lenka Holoubkova 8,Maria Rivieccio 4,Maria Oro 4,Nicoletta Resta 1,2ORCID,Jennifer Kerkhof 9ORCID,Bekim Sadikovic 9,10 andLuigi Viggiano 7 1 Medical Genetic, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy 2 Medical Genetics Section, University Hospital Consortium Corporation Polyclinics of Bari, 70124 Bari, Italy 3 Unit for Severe Disabilities in Developmental Age and Young Adults, Associazione “La Nostra Famiglia”—IRCCS “E. Medea”, Scientific Hospital for Neurorehabilitation, Piazza A. Di Summa, 72100 Brindisi, Italy 4 Medical Genetics Laboratory, A.O.R.N. Cardarelli, Building Y, 80127 Naples, Italy 5 Scientific Direction, Scientific Institute IRCCS Eugenio Medea, Via D. L. Monza 20, Bosisio Parini, 23842 Lecco, Italy 6 Laboratory of Molecular Biology, Scientific Institute IRCCS Eugenio Medea, Via D. L. Monza 20, Bosisio Parini, 23842 Lecco, Italy 7 Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70125 Bari, Italy 8 ReStart—Professional Practice of Occupational Therapy, Via di Vittorio, 76125 Trani, Italy 9 Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 3K7, Canada 10 Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada * Author to whom correspondence should be addressed. Genes 2024, 15(7), 826; https://doi.org/10.3390/genes15070826 Submission received: 20 May 2024 / Revised: 13 June 2024 / Accepted: 19 June 2024 / Published: 22 June 2024 (This article belongs to the Special Issue Molecular Basis and Genetics of Intellectual Disability) Downloadkeyboard_arrow_down Browse Figures Versions Notes Abstract FBRSL1, together with FBRS and AUTS2 (Activator of Transcription and Developmental Regulator; OMIM 607270), constitutes a tripartite AUTS2 gene family. AUTS2 and FBRSL1 are evolutionarily more closely related to each other than to FBRS (Fibrosin 1; OMIM 608601). Despite its paralogous relation to AUTS2, FBRSL1’s precise role remains unclear, though it likely shares functions in neurogenesis and transcriptional regulation. Herein, we report the clinical presentation with therapeutic approaches and the molecular etiology of a patient harboring a de novo truncating variant (c.371dupC) in FBRSL1, leading to a premature stop codon (p.Cys125Leufs*7). Our study extends previous knowledge by highlighting potential interactions and implications of this variant, alongside maternal and paternal duplications, for the patient’s phenotype. Using sequence conservation data and in silico analysis of the truncated protein, we generated a predicted domain structure. Furthermore, our in silico analysis was extended by taking into account SNP array results. The extension of in silico analysis was performed due to the possibility that the coexistence of FBRSL1 truncating variant contemporary with maternal and paternal duplication could be a modifier of proband’s phenotype and/or influence the novel syndrome clinical characteristics. FBRSL1 protein may be involved in neurodevelopment due to its homology with AUTS2, together with distinctive neuronal expression profiles, and thus should be considered as a potential modulation of clinical characteristics in a novel syndrome. Finally, considering that FBRSL1 is apparently involved in neurogenesis and in transcriptional regulatory networks that orchestrate gene expression, together with the observation that different genetic syndromes are associated with distinct genomic DNA methylation patterns, the specific episignature has been explored.