Title Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16 p 11 . 2 in individuals ascertained for diagnosis of autism spectrum disorder

Background Recurrent microdeletions and microduplications of w555 kb at 16p11.2 confer susceptibility to autism spectrum disorder (ASD) in up to 1% of ASD patients. No physical or behavioural features have been identified that distinguish these individuals as having a distinct ASD subtype, but clinical data are limited. Methods We report five autistic probands identified by microarray analysis with copy number variation (CNV) of 16p11.2 (three deletions, two duplications). Each patient was assessed for ASD and dysmorphic features. We also describe a deletion positive 26-month-old female who has developmental delay (DD) and autistic features. Results Proband 1 (female with ASD, de novo deletion) is not dysmorphic. Proband 2 (male with autism, de novo deletion) and proband 3 and his brother (males with autism, inherited deletions) are dysmorphic, but the two probands do not resemble one another. The mother of proband 3 has mild mental retardation (MR), minor dysmorphism and meets the criteria for ASD. Proband 4 (dysmorphic autistic male, de novo duplication) had a congenital diaphragmatic hernia. Proband 5 (nondysmorphic ASD female with a duplication) has two apparently healthy duplication positive relatives. Probands 1 and 2 have deletion negative siblings with ASD and Asperger syndrome, respectively. Proband 6 (a female with DD and an inherited duplication) is dysmorphic, but has oligohydramnios sequence. Conclusions The phenotypic spectrum associated with CNV at 16p11.2 includes ASD, MR/DD and/or possibly other primary psychiatric disorders. Compared with the microduplications, the reciprocal microdeletions are more likely to be penetrant and to be associated with nonspecific major or minor dysmorphism. There are deletion positive ASD probands with a less severe phenotype than deletion negative ASD siblings underscoring the significant phenotypic heterogeneity. INTRODUCTION Autism (OMIM 209850), typically apparent by the age of 3 years, is characterised by impaired communication, impaired reciprocal social interaction skills, and by restricted repetitive behaviours and interests. Autism spectrum disorder (ASD) is a broader phenotype, which includes autism as well as less severe conditions such as Asperger syndrome and pervasive developmental disorder-not otherwise specified (PDD-NOS). The prevalence of autism is 3 per 1000 and rises to 6 per 1000 when all forms of ASD are included. The male to female ratio isw4:1 and after syndromic forms of ASD are excluded, it is associated with an empiric sibling recurrence risk of 5e10%. The ASDs are aetiologically heterogeneous. About 10% are associated with a Mendelian syndrome (eg, fragile X syndrome and tuberous sclerosis complex). Another 5e7% are associated with a cytogenetically visible chromosome abnormality, the most frequently observed being a maternally derived duplication of 15q11-13. Teratogens, including in utero exposure to rubella and valproate, have also been implicated. The remainder of affected individuals are presumed to have multifactorial forms of ASD and linkage scans have mapped candidate risk loci. More recently, de novo copy number variations (CNVs) have been observed in 7e10% of sporadic ASD patients and in 2e3% of affected individuals from multiplex families. 8 Three studies have recently discovered recurrent microdeletions and microduplications at the 16p11.2 locus in ASD cohorts. This 555 kb CNV region, which is flanked by segmental duplications having>99% sequence identity, is presumed to have an elevated mutation rate due to its genomic architecture. In our previous study, we identified 4/427 (w1%) unrelated Canadian ASD patients who had chromosome 16p11.2 CNVs. The equivalent change was not observed in 1652 controls. Weiss and colleagues made a similar observation in 12 of 751 (1.6%) families having two or more ASD siblings (multiplex families) from the Autism Genetic Resource Exchange (AGRE) repository. Moreover, they found dosage changes at 16p11.2 in 5/512 children (w1%) who had either developmental delay (DD) or suspected ASD, in 3/299 (w1%) patients from an Icelandic ASD cohort, and in 2/18 834 (0.01%) of Icelandic unscreened controls. Kumar et al found 16p11.2 CNVs in 5/712 (0.7%) unrelated autism probands comprised of 410 AGRE cases and 302 probands from the National Institutes of Mental Health Genetics Initiative (total of 87 simplex cases and 635 multiplex cases). Four of the microdeletion patients reported byWeiss et al overlapped with the Kumar study (see < Supplementary tables are published online only at http:// jmg.bmj. com/content/vol47/ issue3 Discipline of Genetics, Memorial University of Newfoundland, St John’s, Newfoundland, Canada Discipline of Pediatrics Memorial University of Newfoundland, St John’s, Newfoundland, Canada Provincial Medical Genetics Program, Eastern Health, St. John’s, Newfoundland, Canada Child Health Program, Eastern Health, St. John’s Newfoundland, Canada The Autism Research Unit, Hospital for Sick Children, Toronto, Ontario, Canada Department of Pediatrics, Division of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada Offord Center for Child Studies, McMaster University, Hamilton, Ontario, Canada The Centre for Applied Genomics, Hospital for Sick Children, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada Department of Pediatric Laboratory Medicine, Cytogenetics Laboratory, Hospital for Sick Children, Toronto, Ontario, Canada Correspondence to Bridget Fernandez, Provincial Medical Genetics Program, Health Sciences Center, 300 Prince Philip Drive, St. John’s Newfoundland, A1B 3V6, Canada; bfernandez@nl.rogers. com Received 12 May 2009 Revised 13 August 2009 Accepted 14 August 2009 Published Online First 15 September 2009 J Med Genet 2010;47:195e203. doi:10.1136/jmg.2009. 069369 195 Letter to JMG group.bmj. com on October 4, 2010 Published by jmg.bmj. com Downloaded from