The Cognitive and Behavioral Phenotype of the 16p11.2 Deletion in a Clinically Ascertained Population

Abstract

Background Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. Method To clarify the phenotype of 16p11.2 deletion, we examined psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. 85 Individuals with the 16p11.2 deletion, and 153 familial controls, were evaluated for symptom presentation and clinical diagnosis using an extensive standardized assessment battery across 3 clinical sites. Results Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonological processing disorder, expressive and receptive language disorders (71% of individuals over 3 years of age with a speech and language related disorder), and autism spectrum disorder (ASD). Individuals with the 16p11.2 deletion not meeting diagnostic criteria for ASD had significantly higher prevalence of autism-related characteristics compared to the familial non-carrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than non-carrier family members on average. Conclusion Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly those associated with the broader autism phenotype.

Multiple roles of Ulk4 in neurogenesis and brain function

“…A good example of this is that reciprocal deletions and duplications of »600kb region at 16p11.2 are strongly associated with behavioral disorders, cognitive deficits and brain volume. 16p11.2 deletions are associated with speech/language and motor deficits, intellectual impairment, restrictive and repetitive behavior and macrocephaly, 28,29 whereas duplications are associated with ADHD, schizophrenia and microcephaly. 28,30 Decreased neurogenesis in the Ulk4 mutants has provided a cellular mechanism for its association with neurodevelopmental disorders.…”

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

“…Contextual and cued fear conditioning were normal in +/2. These cognitive phenotypes may be relevant to some aspects of cognitive impairments in humans with 16p11.2 deletion, and support the use of 16p11.2+/2 mice as a model system for discovering treatments for cognitive impairments in 16p11.2 deletion syndrome.Recurrent heterozygous deletions of a 600-kb segment on human chromosome 16 is found in 0.4% of individuals with intellectual disability (Bijlsma et al 2009;Hanson et al 2015) and 0.6% of individuals with autism (Marshall et al 2008;Weiss et al 2008;Walsh and Bracken 2011). 16p11.2 deletion syndrome presents with a range of mild-to-severe cognitive impairments, with IQ scores averaging 2 SDs lower than controls, and a confirmed diagnosis of autism in 15% of affected individuals (Hanson et al…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…This 593-kb segment encompasses 25 genes and accounts for approximately 1% of cases of ASD [98,102]. Both deletions and duplications are associated with language delays, ASD, behavioral problems, congenital anomalies, and seizures [129][130][131], although the deletion may appear more commonly in autism [102,132], and the duplication appears to be more common in schizophrenia [112]. Contrasting phenotypes are observed: deletions are associated with increased brain volume/macrocephaly and increased body mass index/obesity, while duplications are associated with decreased brain volume/microcephaly and decreased body mass index [129,133,134].…”