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

G Beunders, E Voorhoeve, C Golzio, LM Pardo, JA Rosenfeld, ME Talkowski, I Simonic, AC Lionel, S Vergult, RE Pyatt, J Kamp, A Nieuwint, MM Weiss, P Rizzu, LENI Verwer, RML (Rosalina) van Spaendonk, YP Shen, BL Wu, TT Yu, YG YuC Chiang, JF Gusella, AM Lindgren, CC Morton, E van Binsbergen, S Bulk, E van Rossem, O Vanakker, R Armstrong, SM Park, L Greenhalgh, U Maye, NJ Neill, KM Abbott, S Sell, R Ladda, DM Farber, PI Bader, T Cushing, JM Drautz, L Konczal, P Nash, E de Los Reyes, MT Carter, E Hopkins, CR Marshall, LR Osborne, KW Gripp, DL Thrush, S Hashimoto, JM Gastier-Foster, C Astbury, B Ylstra, H Meijers-Heijboer, Daniëlle Posthuma, B Menten, G Mortier, SW Scherer, EE Eichler, S Girirajan, N Katsanis, AJ Groffen, EA Sistermans

Research output: Contribution to journalArticleAcademicpeer-review

109 Citations (Scopus)


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.
Original languageUndefined/Unknown
Pages (from-to)210-220
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 2013

Cite this