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Evidence for Autism Spectrum Disorder in Jacobsen Syndrome: Identification of a Candidate Gene in Distal 11Q

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Evidence for Autism Spectrum Disorder in Jacobsen Syndrome: Identification of a Candidate Gene in Distal 11Q © American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE Evidence for autism spectrum disorder in Jacobsen syndrome: identification of a candidate gene in distal 11q Natacha Akshoomoff, PhD1, Sarah N. Mattson, PhD2 and Paul D. Grossfeld, MD3 Purpose: Jacobsen syndrome, also called the 11q terminal dele- was no correlation between deletion size and the presence of autism tion disorder, is a contiguous gene disorder caused by the deletion of spectrum disorder, implicating at least one predisposing gene in the the end of the long arm of chromosome 11. Intellectual skills range distal 8.7 Mb of 11q. The findings from three additional patients with from low average to severe/profound intellectual disability and usu- autistic features and “atypical” distal 11q deletions led to the identi- ally correlate with deletion size. Comprehensive genotype/phenotype fication of an autism “critical region” in distal 11q containing four evaluations are limited, and little is known about specific behavioral annotated genes including ARHGAP32 (also known as RICS), a gene ­characteristics associated with 11q terminal deletion disorder. encoding rho GTPase activating protein. Methods: In this prospective study, 17 patients with 11q terminal Conclusion: Results from this study support early autism spectrum deletion disorder underwent cognitive and behavioral assessments. disorder screening for patients with 11q terminal deletion disor- Deletion sizes were determined by array comparative genomic der and provide further molecular insights into the pathogenesis of hybridization. autism spectrum disorder. Results: Deletion sizes ranged from 8.7 to 14.5 Mb across the patients. Genet Med advance online publication 24 July 2014 We found that 8 of 17 patients (47%) exhibited behavioral character- Key Words: autism spectrum disorder; ARHGAP32; behavioral istics consistent with an autism spectrum disorder diagnosis.­ There phenotype; Jacobsen syndrome; 11q terminal deletion INTRODUCTION MATERIALS AND METHODS Jacobsen syndrome (JBS; MIM 147791), also called the 11q ter- Subjects minal deletion disorder (11q-), is a contiguous gene disorder There were 5 male and 12 female patients with ages ranging caused by the deletion of the end of the long arm of chromo- from 3 to 21 years at the time of testing. All participants (n = some 11.1–3 There is considerable phenotypic variability, but 17) were prospectively recruited from the 11q Research and common problems include dysmorphic features, intellectual Resource Group, which has hosted a biennial conference in San disability, thrombocytopenia, congenital heart defects, pyloric Diego, California, since 1998. Most testing was conducted in stenosis, and structural renal anomalies.2–6 Our previous study conjunction with this conference. Before participation, written demonstrated a range of intellectual impairment across 14 informed consent (parents) and assent (children older than age patients with 11q- and a strong correlation between deletion 7 years) was obtained, as approved by the institutional review size and degree of cognitive impairment.7 These results also board. implicated at least two loci in distal 11q contributing to the Patients with a diagnosis of JBS by previous karyotype analy- cognitive deficits in 11q-. sis or array comparative genomic hybridization (aCGH) were There have been case reports of autistic-like features in 11q- eligible for participation in the study. We defined JBS as a con- patients,8–10 but there are no systematic prospective studies stellation of clinical features in association with a terminal 11q using standard research diagnostic procedures. The present deletion that includes the ETS-1 and FLI-1 genes. These two study is a prospective evaluation of 11q- patients with two aims: genes likely cause the two historically life-threatening aspects (i) to determine the likelihood that patients meet criteria for of the syndrome: congenital heart disease and Paris-Trousseau autism spectrum disorder (ASD) using standardized diagnostic bleeding disorder.2,3,11,12 Only patients with pure 11q termi- procedures and (ii) to identify the candidate gene(s) respon- nal deletions were included in the main cohort. We excluded sible for this phenotype. patients with unbalanced translocations (deletion of distal 11q All authors contributed equally to this work. 1Department of Psychiatry, School of Medicine, University of California, San Diego, San Diego, California, USA; 2Department of Psychology, San Diego State University, San Diego, California, USA; 3Department of Pediatrics, School of Medicine, University of California, San Diego, San Diego, California, USA. Correspondence: Natacha Akshoomoff ([email protected]) Submitted 21 April 2014; accepted 6 June 2014; advance online publication 24 July 2014. doi:10.1038/gim.2014.86 GeNeTICs in meDICINe | Volume 17 | Number 2 | February 2015 143 ORIGINAL RESEARCH ARTICLE AKSHOOMOFF et al | Autism and Jacobsen syndrome and duplication of another locus) inherited from a parent car- Schedule (ADOS).21 The ADOS is a standardized observation rying a balanced translocation. As expected, the majority of of social behavior in naturalistic and communicative con- patients have congenital heart defects, some of which have been texts, with different modules and tasks for children of different surgically repaired. ages and language levels. The ADOS was specifically designed Three additional patients with atypical deletions (i.e., inter- to assist with the diagnosis of ASD. The revised algorithm of stitial deletions in distal 11q or smaller terminal deletions not the ADOS (ADOS-2)22,23 was used for classification purposes. spanning the ETS-1 and FLI-1 genes), two of whom had a pre- This revised algorithm includes social, communication, and viously known diagnosis of ASD, are also described but not restricted repetitive behaviors and thus better represents all the included in the main cohort. Specifically, patient 18 initially observed diagnostic features of ASD than the previously used had autism diagnosed and subsequently underwent aCGH ADOS algorithm. analysis that identified a maternally inherited 6.1-Mb terminal The Autism Diagnostic Interview, Revised (ADI-R)24 was deletion in 11q. Patient 19 had many clinical features of JBS, administered to the parents of two of the subjects with atypical including intellectual disability, congenital heart disease, and deletions who were unavailable for testing with the ADOS. Paris-Trousseau bleeding disorder. Subsequent aCGH analysis The data from the Social Communication Questionnaire, identified a de novo 7.3-Mb interstitial deletion that spanned cognitive testing, VABS-II, and the ADOS or ADI-R for each the ETS-1 and FLI-1 genes. Patient 20 was originally identified subject were reviewed (by N.A.). Using a clinical best estimate in the UNIQUE database (http://www.rarechromo.org; patient diagnostic approach following criteria in the Diagnostic and ID 16270). This patient originally underwent aCGH testing Statistical Manual of Mental Disorders, Fifth Edition,25 and fol- because of intellectual disability and mild dysmorphic features, lowing a method used in previous published research studies which identified a de novo approximately 0.3-Mb interstitial that includes clinical judgment,23,26,27 each case was classified as deletion in distal 11q that was deleted in all 17 patients in our ASD or non-ASD. cohort and in the two other patients with atypical deletions described. Genetic testing. Blood samples from each patient underwent aCGH as described previously7 by Signature Genomics (www. Measures signaturegenomics.com) at the time of the conference, before the Parent questionnaires and interviews. Before testing, study by a Clinical Laboratory Improvement Admendments– parents completed a demographic and developmental certified laboratory ordered by the patient’s local primary care history questionnaire. Parents also completed the Social physician or geneticist, or in the laboratory of Dr. Orsetta Communication Questionnaire,13 which is a 40-item parent Zuffardi, Department of Medical Genetics, University of Pavia, report screening measure that provides a dimensional Italy, as described previously.28 measure of ASD symptomatology. The Social Communication Samples tested by the Signature Genomics laboratory uti- Questionnaire has good sensitivity and specificity with lized the custom-designed OS V2.0 platform, a system that uses respect to the separation of ASD from non-ASD diagnoses at 135,000 oligonucleotides with approximately 10-kb resolution all intelligence quotient levels. Children under 5 years of age in distal 11q, thereby providing a readout of individual genes who obtain a score of 11 or more points and children 5 years that are deleted in distal 11q. of age and older who obtain a score of 15 or more points are considered to be highly likely to meet criteria for an ASD.14 RESULTS On the day of testing, parents completed the Vineland Individual behavioral and genetic test results and are shown in Adaptive Behavior Scales, Second Edition Survey Interview Table 1. Of the 17 subjects in the main cohort, 8 (47%) were form (VABS-II) with a trained examiner.15 The VABS-II is determined to meet criteria for a research diagnosis of ASD. a parent interview measure of child adaptive behavior skills Among the male subjects, four of five (80%) subjects who and provides a standardized assessment of adaptive behavior underwent complete testing met research criteria for ASD. The in three subdomains (communication,
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