Critical region within 22q11.2 linked to higher rate of autism spectrum disorder

Abstract

BackgroundPrevious studies have reported no clear critical region for medical comorbidities in children with deletions or duplications of 22q11.2. The purpose of this study was to evaluate whether individuals with small nested deletions or duplications of the LCR-A to B region of 22q11.2 show an elevated rate of autism spectrum disorder (ASD) compared to individuals with deletions or duplications that do not include this region.MethodsWe recruited 46 patients with nested deletions (n = 33) or duplications (n = 13) of 22q11.2, including LCR-A to B (n del = 11), LCR-A to C (n del = 4), LCR-B to D (n del = 14; n dup = 8), LCR-C to D (n del = 4; n dup = 2), and smaller nested regions (n = 3). Parent questionnaire, record review, and, for a subset, in-person evaluation were used for ASD diagnostic classification. Rates of ASD in individuals with involvement of LCR-B to LCR-D were compared with Fisher’s exact test to LCR-A to LCR-B for deletions, and to a previously published sample of LCR-A to LCR-D for duplications. The rates of medical comorbidities and psychiatric diagnoses were determined from questionnaires and chart review. We also report group mean differences on psychiatric questionnaires.ResultsIndividuals with deletions involving LCR-A to B showed a 39–44% rate of ASD compared to 0% in individuals whose deletions did not involve LCR-A to B. We observed similar rates of medical comorbidities in individuals with involvement of LCR-A to B and LCR-B to D for both duplications and deletions, consistent with prior studies.ConclusionsChildren with nested deletions of 22q11.2 may be at greater risk for autism spectrum disorder if the region includes LCR-A to LCR-B. Replication is needed.Electronic supplementary materialThe online version of this article (10.1186/s13229-017-0171-7) 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, while we cannot rule out the possibility that nested atypical duplications represent a benign variant, our study supports the notion that atypical nested 22q11.2 LCR22B‐LCR22D duplications are associated with an increased risk for neurodevelopmental phenotypes particularly ASD. Furthermore, our conclusion is consistent with a recent study reporting that the incidence of ASD is similar in both typical and the nested atypical duplication cases, further suggesting that the nested duplication and its genes constitute the minimal interval which is relevant to neurodevelopmental phenotypes including ASD (Clements et al., ).…”

“…It is interesting to note that this is not the case for the incidence of neurodevelopmental traits, which are relatively prevalent for both typical and atypical nested cases. This is supported by a recent report describing similar rates of ASD in individuals with typical duplications and atypical nested duplications B‐D (Clements et al., ). Therefore, it is plausible that the critical genes associated with these neurodevelopmental phenotypes including ASD may be located within the nested region between LCR22B and LCR22D.…”

“…Clinical features can also include more significant degrees of intellectual disability, delayed psychomotor development, growth retardation, and muscular hypotonia (Wentzel, Fernstrom, Ohrner, Anneren, & Thuresson, 2008). Autism spectrum disorder is also a feature of 22q11.2 duplication carriers, with an estimated rate of 14%-25% (Clements et al, 2017;Wenger et al, 2016). Patients diagnosed with the typical 3 Mb duplication, or the nested 1.5 Mb duplication, show no apparent correlation between duplication size and phenotype (Van Campenhout et al, 2012).…”

“…To date, many individuals have been described with atypical nested 22q11.2 deletions between LCR22B and LCR22D (Clements et al., ; Rump et al., ; Wentzel et al., ). In contrast, very few cases with atypical nested 22q11.2 duplications have been reported (Clements et al., ; Diehl, Mu, Batista, & Gunay‐Aygun, ; Fan et al., ; Fernandez et al., ; Pebrel‐Richard et al., ; Tucker et al., , ). Here, we describe 13 individuals from six families with atypical nested 22q11.2 duplications between LCR22B and LCR22D.…”

Genotypic and phenotypic variability of 22q11.2 microduplications: An institutional experience

“…Furthermore, Woodward et al () noted that duplication size appeared to be independent of ASD diagnosis, with the smallest 22q11.2 duplication associated with diagnosed ASD being a 120 kb CD duplication and the largest being a 700 kb BD duplication. Clements et al () reported similar incidence rates of ASD in both typical proximal AD duplications and central CD duplications, encouraging the notion that central 22q11.2 duplications are associated with an increased risk for neurodevelopmental delays such as ASD.…”