title: Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency.
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.
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. alexander.kolevzon@mssm.edu.
authors.forename: Latha
authors.initials: L
authors.lastname: Soorya
authors.forename: Alexander
authors.initials: A
authors.lastname: Kolevzon
authors.forename: Jessica
authors.initials: J
authors.lastname: Zweifach
authors.forename: Teresa
authors.initials: T
authors.lastname: Lim
authors.forename: Yuriy
authors.initials: Y
authors.lastname: Dobry
authors.forename: Lily
authors.initials: L
authors.lastname: Schwartz
authors.forename: Yitzchak
authors.initials: Y
authors.lastname: Frank
authors.forename: A Ting
authors.initials: AT
authors.lastname: Wang
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Elena
authors.initials: E
authors.lastname: Parkhomenko
authors.forename: Danielle
authors.initials: D
authors.lastname: Halpern
authors.forename: David
authors.initials: D
authors.lastname: Grodberg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Angarita
authors.forename: Judith P
authors.initials: JP
authors.lastname: Willner
authors.forename: Amy
authors.initials: A
authors.lastname: Yang
authors.forename: Roberto
authors.initials: R
authors.lastname: Canitano
authors.forename: William
authors.initials: W
authors.lastname: Chaplin
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum