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

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• 作者：Gea Beunders¹ ; ³⁷ ; Els Voorhoeve¹ ; ³⁷ ; Christelle Golzio² ; Luba M. Pardo¹ ; Jill A. Rosenfeld³ ; Michael E. Talkowski⁴ ; ⁵ ; Ingrid Simonic⁶ ; Anath C. Lionel⁷ ; ⁸ ; Sarah Vergult⁹ ; Robert E. Pyatt¹⁰ ; ¹¹ ; Jiddeke van de Kamp¹ ; Aggie Nieuwint¹ ; Marjan M. Weiss¹ ; Patrizia Rizzu¹ ; Lucilla E.N.I. Verwer¹ ; Rosalina M.L. van Spaendonk¹ ; Yiping Shen⁴ ; ¹² ; ¹³ ; Bai-lin Wu¹² ; ¹⁴ ; Tingting Yu¹² ; ¹³ ; Yongguo Yu¹² ; ¹³ ; Colby Chiang⁴ ; James F. Gusella⁴ ; ⁵ ; Amelia M. Lindgren¹⁵ ; ¹⁶ ; Cynthia C. Morton⁵ ; ¹⁵ ; ¹⁶ ; Ellen van Binsbergen¹⁷ ; Saskia Bulk¹⁷ ; Els van Rossem¹⁸ ; Olivier Vanakker⁹ ; Ruth Armstrong⁶ ; Soo-Mi Park⁶ ; Lynn Greenhalgh¹⁹ ; Una Maye¹⁹ ; Nicholas J. Neill³ ; Kristin M. Abbott⁶ ; Susan Sell²⁰ ; Roger Ladda²⁰ ; Darren M. Farber²¹ ; Patricia I. Bader²² ; Tom Cushing²³ ; Joanne M. Drautz²³ ; Laura Konczal²⁴ ; Patricia Nash²⁵ ; Emily de Los Reyes²⁶ ; Melissa T. Carter²⁷ ; Elizabeth Hopkins²⁸ ; Christian R. Marshall⁷ ; ⁸ ; Lucy R. Osborne²⁹ ; Karen W. Gripp²⁸ ; Devon Lamb Thrush¹⁰ ; ³⁰ ; Sayaka Hashimoto¹⁰ ; Julie M. Gastier-Foster¹⁰ ; ¹¹ ; Caroline Astbury¹⁰ ; ¹¹ ; Bauke Ylstra³¹ ; Hanne Meijers-Heijboer¹ ; Danielle Posthuma¹ ; ³² ; ³³ ; Bj&ouml ; rn Menten⁹ ; Geert Mortier³⁴ ; Stephen W. Scherer⁷ ; ⁸ ; Evan E. Eichler³⁵ ; Santhosh Girirajan³⁵ ; ³⁶ ; Nicholas Katsanis² ; Alexander J. Groffen¹ ; ³² ; Erik A. Sistermans¹ ; ^{e.sistermans@vumc.nl}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：7 February, 2013
• 年：2013
• 卷：92
• 期：2
• 页码：210-220
• 全文大小：1159 K

文摘

Genomic rearrangements involving m>AUTS2m> (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 m>AUTS2m>, as well as one translocation and one inversion each with a breakpoint within the m>AUTS2m> 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¡ä m>AUTS2m> 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 m>auts2m> 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.