Exonic Deletions in AUTS2 Cause a Syndromic Form of Intellectual Disability and Suggest a Critical Role for the C Terminus

• Published in: American journal of human genetics Vol. 92; no. 2; pp. 210 - 220
• Main Authors: Beunders, Gea, Voorhoeve, Els, Golzio, Christelle, Pardo, Luba M., Rosenfeld, Jill A., Talkowski, Michael E., Simonic, Ingrid, Lionel, Anath C., Vergult, Sarah, Pyatt, Robert E., van de Kamp, Jiddeke, Nieuwint, Aggie, Weiss, Marjan M., Rizzu, Patrizia, Verwer, Lucilla E.N.I., van Spaendonk, Rosalina M.L., Shen, Yiping, Wu, Bai-lin, Yu, Tingting, Yu, Yongguo, Chiang, Colby, Gusella, James F., Lindgren, Amelia M., Morton, Cynthia C., van Binsbergen, Ellen, Bulk, Saskia, van Rossem, Els, Vanakker, Olivier, Armstrong, Ruth, Park, Soo-Mi, Greenhalgh, Lynn, Maye, Una, Neill, Nicholas J., Abbott, Kristin M., Sell, Susan, Ladda, Roger, Farber, Darren M., Bader, Patricia I., Cushing, Tom, Drautz, Joanne M., Konczal, Laura, Nash, Patricia, de Los Reyes, Emily, Carter, Melissa T., Hopkins, Elizabeth, Marshall, Christian R., Osborne, Lucy R., Gripp, Karen W., Thrush, Devon Lamb, Hashimoto, Sayaka, Gastier-Foster, Julie M., Astbury, Caroline, Ylstra, Bauke, Meijers-Heijboer, Hanne, Posthuma, Danielle, Menten, Björn, Mortier, Geert, Scherer, Stephen W., Eichler, Evan E., Girirajan, Santhosh, Katsanis, Nicholas, Groffen, Alexander J., Sistermans, Erik A.
• Format: Journal Article Web Resource
• Language: English
• Published: United States Elsevier Inc 07.02.2013; Cell Press; University of Chicago Press; Elsevier
• Subjects: Adolescent; Adult; Amino Acid Sequence; Animals; Base Sequence; Brain; Child; Child, Preschool; Cytoskeletal Proteins; Danio rerio; Exons - genetics; Facies; Female; Gene expression; Genetic Predisposition to Disease; Genetics & genetic processes; Genomics; Génétique & processus génétiques; Human subjects; Humans; Infant; Intellectual Disability - genetics; Learning disabilities; Life sciences; Male; Molecular Sequence Data; Phenotype; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms/chemistry/genetics; Proteins - chemistry; Proteins - genetics; Proteins/chemistry/genetics; Sciences du vivant; Sequence Deletion - genetics; Suppression, Genetic; Syndrome; Transcription Factors; Young Adult; Zebrafish - embryology; Zebrafish - genetics; Zebrafish Proteins - chemistry; Zebrafish Proteins - genetics; Zebrafish Proteins/chemistry/genetics; Zebrafish/embryology/genetics
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2012.12.011

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3′ AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.