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Open Access Research

Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency

Latha Soorya1132, Alexander Kolevzon123*, Jessica Zweifach1, Teresa Lim2, Yuriy Dobry2, Lily Schwartz1, Yitzchak Frank1234, A Ting Wang125, Guiqing Cai126, Elena Parkhomenko12, Danielle Halpern12, David Grodberg12, Benjamin Angarita2, Judith P Willner36, Amy Yang36, Roberto Canitano114, William Chaplin8, Catalina Betancur10119 and Joseph D Buxbaum1122567

Author Affiliations

1 Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA

2 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

3 Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

4 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

5 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

6 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

7 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

8 Department of Psychology, St John’s University, Jamaica, NY, USA

9 INSERM U952, Paris, France

10 CNRS UMR 7224, Paris, France

11 Université Pierre et Marie Curie, Paris, France

12 Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

13 Present address: Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA

14 Present address: Division of Child Neuropsychiatry, General University Hospital of Siena, Siena, Italy

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Molecular Autism 2013, 4:18  doi:10.1186/2040-2392-4-18

Published: 11 June 2013

Abstract

Background

22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype of SHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal of providing a comprehensive picture of the medical and behavioral profile of the syndrome.

Methods

A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G.

Results

Thirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features.

Conclusions

This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the prominence of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

Keywords:
22q13 deletion syndrome; Autism; Microarrays; Mutation; Phelan-McDermid syndrome; SHANK3