Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications.

Jill A Rosenfeld,Santhosh Girirajan,Blake C Ballif,Justine Coppinger,Lisa G Shaffer,Bassem A Bejjani,Evan E Eichler

doi:10.1007/s11689-009-9037-4

Abstract

Microdeletions and microduplications encompassing a ~593-kb region of 16p11.2 have been implicated as one of the most common genetic causes of susceptibility to autism/autism spectrum disorder (ASD). We report 45 microdeletions and 32 microduplications of 16p11.2, representing 0.78% of 9,773 individuals referred to our laboratory for microarray-based comparative genomic hybridization (aCGH) testing for neurodevelopmental and congenital anomalies. The microdeletion was de novo in 17 individuals and maternally inherited in five individuals for whom parental testing was available. Detailed histories of 18 individuals with 16p11.2 microdeletions were reviewed; all had developmental delays with below-average intelligence, and a majority had speech or language problems or delays and various behavioral problems. Of the 16 individuals old enough to be evaluated for autism, the speech/behavior profiles of seven did not suggest the need for ASD evaluation. Of the remaining nine individuals who had speech/behavior profiles that aroused clinical suspicion of ASD, five had formal evaluations, and three had PDD-NOS. Of the 19 microduplications with parental testing, five were de novo, nine were maternally inherited, and five were paternally inherited. A majority with the microduplication had delayed development and/or specific deficits in speech or language, though these features were not as consistent as seen with the microdeletions. This study, which is the largest cohort of individuals with 16p11.2 alterations reported to date, suggests that 16p11.2 microdeletions and microduplications are associated with a high frequency of cognitive, developmental, and speech delay and behavior abnormalities. Furthermore, although features associated with these alterations can be found in individuals with ASD, additional factors are likely required to lead to the development of ASD.Electronic supplementary materialThe online version of this article (doi:10.1007/s11689-009-9037-4) contains supplementary material, which is available to authorized users.

Highlights

Between November 2007 and October 2008, we analyzed 9,773 individuals, 820 of whom had an autism spectrum disorder (ASD) as the indication for study, using whole-genome bacterial artificial chromosome or oligonucleotide microarrays with expanded coverage of 16p11.2
The 16p11.2 microdeletion (n=45) and microduplication (n=32) represent 3.1% of all abnormalities reported by our laboratory, second only to the 22q11.2 velocardiofacial/ DiGeorge syndrome region (n=60 deletions and 22 duplications; 3.3% of all abnormalities)
These may be overestimates of frequency because some cases of Smith-Magenis syndrome (SMS) and Williams syndrome are diagnosed by other methods, and not all individuals with these syndromes will have aCGH, while 16p11.2 abnormalities would not be expected to be diagnosed by other methods

Summary

Introduction

Electronic supplementary material The online version of this article (doi:10.1007/s11689-009-9037-4) contains supplementary material, which is available to authorized users. The microdeletion has been reported in individuals with cognitive impairment but without autism (Ghebranious et al 2007; Rosenberg et al 2006; Shiow et al 2008; Bijlsma et al 2009); in 1.76% (9/512) of children (including two monozygotic twins) with mental retardation, developmental delay or ASD (Weiss et al 2008); in 0.33% (14/4284) of patients with mental retardation or multiple congenital anomalies (Bijlsma et al 2009); and in 1.23% (1/81) of another smaller sample of individuals with mental retardation, dysmorphic features and a normal karyotype (Rosenberg et al 2006) Both events have been found in control populations, including a group that contained individuals with bipolar disorder and a population of 19,000 unscreened individuals (Table 1) (Weiss et al 2008). In the largest study to date, we characterized the clinical features associated with microdeletions and microduplications of 16p11.2 to provide a genotype-phenotype correlation of individuals with these events

Results

Discussion

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