Dataset Information

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

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.

SUBMITTER: Beunders G

PROVIDER: S-EPMC3567268 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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

Beunders Gea G Voorhoeve Els E Golzio Christelle C Pardo Luba M LM Rosenfeld Jill A JA Talkowski Michael E ME Simonic Ingrid I Lionel Anath C AC Vergult Sarah S Pyatt Robert E RE van de Kamp Jiddeke J Nieuwint Aggie A Weiss Marjan M MM Rizzu Patrizia P Verwer Lucilla E N I LE van Spaendonk Rosalina M L RM Shen Yiping Y Wu Bai-lin BL Yu Tingting T Yu Yongguo Y Chiang Colby C Gusella James F JF Lindgren Amelia M AM Morton Cynthia C CC van Binsbergen Ellen E Bulk Saskia S van Rossem Els E Vanakker Olivier O Armstrong Ruth R Park Soo-Mi SM Greenhalgh Lynn L Maye Una U Neill Nicholas J NJ Abbott Kristin M KM Sell Susan S Ladda Roger R Farber Darren M DM Bader Patricia I PI Cushing Tom T Drautz Joanne M JM Konczal Laura L Nash Patricia P de Los Reyes Emily E Carter Melissa T MT Hopkins Elizabeth E Marshall Christian R CR Osborne Lucy R LR Gripp Karen W KW Thrush Devon Lamb DL Hashimoto Sayaka S Gastier-Foster Julie M JM Astbury Caroline C Ylstra Bauke B Meijers-Heijboer Hanne H Posthuma Danielle D Menten Björn B Mortier Geert G Scherer Stephen W SW Eichler Evan E EE Girirajan Santhosh S Katsanis Nicholas N Groffen Alexander J AJ Sistermans Erik A EA

American journal of human genetics 20130117 2

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 inclu ...[more]

PMID: 23332918

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Project description:INTRODUCTION:Recent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations. METHODS:Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause. RESULTS:Our cohort comprised 16 individuals aged 4-16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898-1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain. CONCLUSIONS:These patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

Dataset Information

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

Publications

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

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