22q11.2 duplication syndrome: elevated rate of autism spectrum disorder and need for medical screening

Abstract

BackgroundWidespread use of microarray technology has led to increasing identification of 22q11.2 duplication syndrome (22q11.2DupS), the reciprocal syndrome of the well-characterized 22q11.2 deletion syndrome (22q11.2DS). Individuals with 22q11.2DS have elevated rates of community diagnoses of autism spectrum disorder (ASD), schizophrenia, and a range of medical problems and birth defects that necessitate extensive medical screening. Case reports of 22q11.2DupS include patients with ASD, fewer medical problems, and no schizophrenia; however, no prospective cohort study has been reported. The goals of the study were to (1) characterize the neuropsychiatric functioning of a cohort of individuals with 22q11.2DupS in comparison to large samples of typically developing controls (TDCs), ASD and 22q11.2DS; (2) estimate the prevalence of ASD in 22q11.2DupS; (3) determine whether the indications that prompted the genetic testing in 22q11.2DupS differ from 22q11.2DS and (4) determine whether comprehensive medical screening should be recommended for those diagnosed with 22q11.2DupS.MethodsMedical characterization was done by parental questionnaire and medical chart review of individuals with 22q11.2DupS (n = 37) and 22q11.2DS (n = 101). Neuropsychiatric characterization of children with 22.11.2DupS, 22q11.2DS, TDCs, and ASD was done by parent-report questionnaires; in addition, the ASD and 22q11.2DupS groups received the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule.ResultsIndividuals with 22q11.2DupS, 22q11.2DS, and ASD had significantly impaired social interaction and adaptive behavior skills compared to TDCs. Overall, 38 % of children aged 2–18 with 22q11.2DupS had community diagnoses of ASD, but fewer (14–25 %) met on the basis of best clinical judgment that included ADI-R and ADOS data. Indications for genetic testing were significantly different for 22q11.2DupS and 22q11.2DS, with the deletions more commonly tested because of birth defects or medical problems, and the duplications because of developmental delay. However, when the screening protocol for 22q11.2DS was applied to the 22q11.2DupS sample, several medical problems were identified that would pose significant risk if left undetected.Conclusions22q11.2DupS has a high rate of ASD at 14–25 %, among the highest of any genetic disorder. Prospective medical screening should be done for all patients with 22q11.2DupS, including those diagnosed due to developmental delays and ASD alone.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0090-z) contains supplementary material, which is available to authorized users.

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance

“…Thus, we calculated the incidence of ASD in symptomatic individuals in our study together with those reported in the literature and from the DECIPHER database to observe a prevalence rate of 31% (8/26; see Table ), including two DECIPHER patients (#249936 and #276067). Our finding is in agreement with estimated rates of 14%–25% for ASD diagnosis in symptomatic individuals with a typical duplication (Wenger et al., ).…”

“…We found that nested duplications in this study were not associated with congenital heart disease, although there are two such cases reported in DECIPHER (#280410 and #278381). Despite this, nested duplications remain less frequently associated with congenital heart defects when compared to typical A‐D duplications (8% atypical nested vs. 24% typical) (Wenger et al., ); however, we acknowledge that our results are based on a small sample size. Nevertheless, this observation suggests that nested atypical duplications could present with reduced penetrance for significant clinical phenotypes such as cardiac defects, hypotonia, and hearing impairment when compared to the larger typical duplications.…”

“…The incidence of seizures was not appreciably different between atypical (15%) and typical duplications (19%) (Wenger et al., ). In contrast, we observed reductions in the frequency of association with hypotonia (8% atypical vs. 27% typical) and hearing impairment (4% vs. 16%) (Wenger et al., ). We found that nested duplications in this study were not associated with congenital heart disease, although there are two such cases reported in DECIPHER (#280410 and #278381).…”

“…Central duplications cases included those between LCR22B and LCR22D described in this study, published in the literature (Diehl et al., ; Fan et al., ; Fernandez et al., ; Ou et al., ; Pebrel‐Richard et al., ; Tucker et al., ) and within the DECIPHER database with clinical information and one CNV (https://decipher.sanger.ac.uk). Typical proximal duplication cases included those 3 Mb in size between LCR22A and LCR22D (Wenger et al., ).…”

<b><i>TOP3B</i></b>: A Novel Candidate Gene in Juvenile Myoclonic Epilepsy?

“…Frequently, both gain and loss variations are found and associated with severe phenotypes including neurological conditions such as seizures, intellectual disability, and cerebral malformations. 22q11.2 microdeletion/duplication syndrome is strongly associated with neurological and psychiatric disorders such as autism, bipolar disorder, schizophrenia, intellectual disability, and epilepsy [Kao et al, 2004;Robin et al, 2006;Lemke et al, 2009;Karayiorgou et al, 2010;Stoll et al, 2013;Kim et al, 2016;Strehlow et al, 2016;Wenger et al, 2016]. The TOP3B gene encodes a topoisomerase DNA (III) β protein.…”