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Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus

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Abstract
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.
Keywords
ABNORMALITIES, GENERATION, AUTISM, TRANSLOCATION BREAKPOINT, MUTATIONS, PHENOTYPE, DATABASE, GENES

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Chicago
Beunders, Gea, Els Voorhoeve, Christelle Golzio, Luba M Pardo, Jill A Rosenfeld, Michael E Talkowski, Ingrid Simonic, et al. 2013. “Exonic Deletions in AUTS2 Cause a Syndromic Form of Intellectual Disability and Suggest a Critical Role for the C Terminus.” American Journal of Human Genetics 92 (2): 210–220.
APA
Beunders, G., Voorhoeve, E., Golzio, C., Pardo, L. M., Rosenfeld, J. A., Talkowski, M. E., Simonic, I., et al. (2013). Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. AMERICAN JOURNAL OF HUMAN GENETICS, 92(2), 210–220.
Vancouver
1.
Beunders G, Voorhoeve E, Golzio C, Pardo LM, Rosenfeld JA, Talkowski ME, et al. Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. AMERICAN JOURNAL OF HUMAN GENETICS. 2013;92(2):210–20.
MLA
Beunders, Gea, Els Voorhoeve, Christelle Golzio, et al. “Exonic Deletions in AUTS2 Cause a Syndromic Form of Intellectual Disability and Suggest a Critical Role for the C Terminus.” AMERICAN JOURNAL OF HUMAN GENETICS 92.2 (2013): 210–220. Print.
@article{3207976,
  abstract     = {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.},
  author       = {Beunders, Gea and Voorhoeve, Els and Golzio, Christelle and Pardo, Luba M and Rosenfeld, Jill A and Talkowski, Michael E and Simonic, Ingrid and Lionel, Anath C and Vergult, Sarah and Pyatt, Robert E and van de Kamp, Jiddeke and Nieuwint, Aggie and Weiss, Marjan M and Rizzu, Patrizia and Verwer, Lucilla ENI and van Spaendonk, Rosalina ML and Shen, Yiping and Wu, Bai-lin and Yu, Tingting and Yu, Yongguo and Chiang, Colby and Gusella, James F and Lindgren, Amelia M and Morton, Cynthia C and van Binsbergen, Ellen and Bulk, Saskia and van Rossem, Els and Vanakker, Olivier and Armstrong, Ruth and Park, Soo-Mi and Greenhalgh, Lynn and Maye, Una and Neill, Nicholas J and Abbott, Kristin M and Sell, Susan and Ladda, Roger and Farber, Darren M and Bader, Patricia I and Cushing, Tom and Drautz, Joanne M and Konczal, Laura and Nash, Patricia and de Los Reyes, Emily and Carter, Melissa T and Hopkins, Elizabeth and Marshall, Christian R and Osborne, Lucy R and Gripp, Karen W and Thrush, Devon Lamb and Hashimoto, Sayaka and Gastier-Foster, Julie M and Astbury, Caroline and Ylstra, Bauke and Meijers-Heijboer, Hanne and Posthuma, Danielle and Menten, Bj{\"o}rn and Mortier, Geert and Scherer, Stephen W and Eichler, Evan E and Girirajan, Santhosh and Katsanis, Nicholas and Groffen, Alexander J and Sistermans, Erik A},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {ABNORMALITIES,GENERATION,AUTISM,TRANSLOCATION BREAKPOINT,MUTATIONS,PHENOTYPE,DATABASE,GENES},
  language     = {eng},
  number       = {2},
  pages        = {210--220},
  title        = {Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2012.12.011},
  volume       = {92},
  year         = {2013},
}

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