title: Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features.
abstract: OBJECTIVE
  Submicroscopic chromosomal rearrangements are the most common identifiable causes of intellectual disability and autism spectrum disorders associated with dysmorphic features. Chromosomal microarray (CMA) can detect copy number variants <1 Mb and identifies size and presence of known genes. The aim of this study was to demonstrate the usefulness of CMA, as a first-tier tool in detecting the etiology of unexplained intellectual disability/autism spectrum disorders (ID/ASDs) associated with dysmorphic features in a large cohort of pediatric patients.
  
  
  METHODS
  We studied 349 individuals; 223 males, 126 females, aged 5 months-19 years. Blood samples were analyzed with CMA at a resolution ranging from 1 Mb to 40 Kb. The imbalance was confirmed by FISH or qPCR. We considered copy number variants (CNVs) causative if the variant was responsible for a known syndrome, encompassed gene/s of known function, occurred de novo or, if inherited, the parent was variably affected, and/or the involved gene/s had been reported in association with ID/ASDs in dedicated databases.
  
  
  RESULTS
  91 CNVs were detected in 77 (22.06%) patients: 5 (6.49%) of those presenting with borderline cognitive impairment, 54 (70.13%) with a variable degree of DD/ID, and 18/77 (23.38%) with ID of variable degree and ASDs. 16/77 (20.8%) patients had two different rearrangements. Deletions exceeded duplications (58 versus 33); 45.05% (41/91) of the detected CNVs were de novo, 45.05% (41/91) inherited, and 9.9% (9/91) unknown. The CNVs caused the phenotype in 57/77 (74%) patients; 12/57 (21.05%) had ASDs/ID, and 45/57 (78.95%) had DD/ID.
  
  
  CONCLUSIONS
  Our study provides further evidence of the high diagnostic yield of CMA for genetic testing in children with unexplained ID/ASDs who had dysmorphic features. We confirm the value of CMA as the first-tier tool in the assessment of those conditions in the pediatric setting.
authors.affiliation: Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, via dei Giacinti, 2, 56128 Calambrone, Pisa, Italy. Electronic address: agatino.battaglia@inpe.unipi.it.
authors.forename: Agatino
authors.initials: A
authors.lastname: Battaglia
authors.forename: Viola
authors.initials: V
authors.lastname: Doccini
authors.forename: Laura
authors.initials: L
authors.lastname: Bernardini
authors.forename: Antonio
authors.initials: A
authors.lastname: Novelli
authors.forename: Sara
authors.initials: S
authors.lastname: Loddo
authors.forename: Anna
authors.initials: A
authors.lastname: Capalbo
authors.forename: Tiziana
authors.initials: T
authors.lastname: Filippi
authors.forename: John C
authors.initials: JC
authors.lastname: Carey
mesh_terms: D000293:Adolescent; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis* / Q000235:genetics; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D012189:Retrospective Studies; D055815:Young Adult
keywords: ASDs; Array-CGH; Autism spectrum disorders; CMA; Chromosomal microarray (CMA); DD; Developmental delay; Dysmorphic features; ID; Intellectual disability; Neurodevelopmental disorders; autism spectrum disorders; chromosomal microarray; developmental delay; intellectual disability