Article
Author: Korotko, Urszula ; Rahikkala, Elisa ; Chwiałkowska, Karolina ; Renieri, Alessandra ; Kwasniewski, Miroslaw ; Garavelli, Livia ; Tartaglia, Marco ; Toschi, Benedetta ; Dahan, Karin ; Herissant, Lucas ; Elting, Mariet W ; Beunders, Gea ; Piatelli, Gianluca ; Caraffi, Stefano Giuseppe ; Varvara, Dora ; Möllring, Anna Charlotte ; Novelli, Antonio ; Digilio, Maria Cristina ; Van Esch, Hilde ; Jezela-Stanek, Aleksandra ; van Haelst, Mieke M ; Caumes, Roseline ; Perrin, Laurence ; Stieber, Daniel ; Zenker, Martin ; Dallapiccola, Bruno ; Bruttini, Mirella ; Coubes, Christine ; Casamassima, Giulia ; Herget, Theresia ; Dentici, Maria Lisa ; Braun, Dominique ; van der Laan, Liselot ; Mauro, Salvatore Pietro ; Levy, Jonathan ; Lisfeld, Jasmin ; Genevieve, David ; Groffen, Alexander J ; Caputo, Valentina ; De Razza, Francesca ; Elbracht, Miriam ; van de Kamp, Jiddeke M ; Mencarelli, Maria Antonietta ; Zuffardi, Orsetta ; Kortüm, Fanny ; Sinibaldi, Lorenzo ; Tabet, Anne-Claude ; Antolini, Enrica ; Baldassarri, Margherita ; Gaspar, Harald ; Longo, Ilaria ; Sorlin, Arthur ; Leeuwen, Lisette ; Broekema, Marjoleine F ; Gorzałczyńska, Ewelina ; Maruani, Anna ; Genesio, Rita ; Maier, Andrea ; Pinto, Anna Maria ; Lausberg, Eva ; Capolino, Rossella ; Ruault, Valentin ; Kick, Johanna ; Canitano, Roberto ; Alders, Marielle ; Loberti, Lorenzo ; Knopp, Cordula ; Mattern, Larissa ; Valenzuela, Irene ; Tita, Rossella ; Adamo, Loredaria ; Destrèe, Anne ; Christophe, Philippe ; Brunetti-Pierri, Nicola ; Grosso, Salvatore
PURPOSEAUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator.METHODSThrough a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs).RESULTSPathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs.CONCLUSIONThis study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.