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A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

ABSTRACT: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders.To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion.We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls.When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations.The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

SUBMITTER: Zufferey F

PROVIDER: S-EPMC3494011 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

Zufferey Flore F Sherr Elliott H EH Beckmann Noam D ND Hanson Ellen E Maillard Anne M AM Hippolyte Loyse L Macé Aurélien A Ferrari Carina C Kutalik Zoltán Z Andrieux Joris J Aylward Elizabeth E Barker Mandy M Bernier Raphael R Bouquillon Sonia S Conus Philippe P Delobel Bruno B Faucett W Andrew WA Goin-Kochel Robin P RP Grant Ellen E Harewood Louise L Hunter Jill V JV Lebon Sébastien S Ledbetter David H DH Martin Christa Lese CL Männik Katrin K Martinet Danielle D Mukherjee Pratik P Ramocki Melissa B MB Spence Sarah J SJ Steinman Kyle J KJ Tjernagel Jennifer J Spiro John E JE Reymond Alexandre A Beckmann Jacques S JS Chung Wendy K WK Jacquemont Sébastien S

Journal of medical genetics 20121001 10

<h4>Background</h4>The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders.<h4>Objective</h4>To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion.<h4>Methods</h4>We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls.<h4>Results</h4>When compared ...[more]

PMID: 23054248

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Project description:Background22q11.2 deletion syndrome (22q11DS) is a common recurrent neurogenetic condition associated with elevated risk for developmental neuropsychiatric disorders and intellectual disability. Children and adults with 22q11DS often exhibit marked social impairment as well as neurocognitive deficits, and have elevated rates of both autism spectrum disorder (ASD) and psychosis. However, the relationship between the basic processes of social cognition and cognitive ability has not been well studied in 22q11DS. Here, we examined differences in social cognition in 22q11DS, relative to multiple groups of idiopathic neuropsychiatric disorders, and typically developing healthy controls (HC). Additionally, we examined differences in intellectual functioning and its relationship to social cognitive abilities. Finally, we examined the relationship between social cognitive abilities and real-world social behavior.MethodsWe examined social cognition and intellectual functioning in 273 participants (mean age = 17.74 ± 5.18% female = 44.3%): 50 with 22q11DS, 49 youth with first episode psychosis (FEP), 48 at clinical high-risk (CHR) for psychosis, 24 participants with ASD, and 102 HC. Social cognition was assessed using The Awareness of Social Inference Test (TASIT), while reciprocal social behavior was assessed via parent/caregiver ratings on the Social Responsiveness Scale (SRS). Participants were also administered the Wechsler Abbreviated Scale of Intelligence, 2nd edition (WASI-II) to assess intellectual functioning.ResultsThe 22q11DS group exhibited significantly lower social cognitive abilities compared to CHR, FEP, and HC groups after controlling for intellectual functioning, but not in comparison to the ASD group. Significant positive correlations were found between social cognition, as measured by the TASIT and IQ across groups. In contrast, no significant relationships were found between TASIT and real-world social behavior (SRS) for any group.ConclusionsOur findings indicate social cognitive deficits are more prominent in 22q11DS than idiopathic neuropsychiatric conditions across the age range, even after adjusting for global intellectual function. These results contribute to our understanding of the intellectual and social vulnerabilities of 22q11DS in comparison to idiopathic neuropsychiatric disorders. Our findings of robust associations between intellectual ability and social cognition emphasizes the importance of accounting for neurocognitive deficits in social skills interventions and tailoring these existing treatment models for 22q11DS and other populations with intellectual impairment.

Project description:Neurodevelopmental disorders (NDDs) are polygenic in nature and copy number variants (CNVs) are ideal candidates to study the nature of this polygenic risk. The disruption of striatal circuits is considered a central mechanism in NDDs. The 16p11.2 hemi-deletion (16p11.2 del) is one of the most common CNVs associated with NDD, and 16p11.2 del/+ mice show sex-specific striatum-related behavioral phenotypes. However, the critical genes among the 27 genes in the 16p11.2 region that underlie these phenotypes remain unknown. Previously, we applied a novel strategy to identify candidate genes associated with the sex-specific phenotypes of 16p11.2 del/+ mice and identified 3 genes of particular importance within the deleted region: thousand and one amino acid protein kinase 2 (Taok2), seizure-related 6 homolog-like 2 (Sez6l2), and major vault protein (Mvp). Using the CRISPR/Cas9 technique, we generated 3 gene hemi-deletion (3g del/+) mice carrying null mutations in Taok2, Sez6l2, and Mvp. We assessed striatum-dependent phenotypes of these 3g del/+ mice in behavioral, molecular, and imaging studies. Hemi-deletion of Taok2, Sez6l2, and Mvp induces sex-specific behavioral alterations in striatum-dependent behavioral tasks, specifically male-specific hyperactivity and impaired motivation for reward seeking, resembling behavioral phenotypes of 16p11.2 del/+ mice. Moreover, RNAseq analysis revealed that 3g del/+ mice exhibit gene expression changes in the striatum similar to 16p11.2 del/+ mice, but only in males. Pathway analysis identified ribosomal dysfunction and translation dysregulation as molecular mechanisms underlying male-specific, striatum-dependent behavioral alterations. Together, the mutation of 3 genes within the 16p11.2 region phenocopies striatal sex-specific phenotypes of 16p11.2 del/+ mice, unlike single gene mutation studies. These results support the importance of a polygenic approach to study NDDs and our novel strategy to identify genes of interest using gene expression patterns in brain regions, such as the striatum, which are impacted in these disorders.

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A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

Publications

A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

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