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

Zufferey, Flore; Sherr, Elliott H.; Beckmann, Noam D.; Hanson, Ellen; Maillard, Anne; Hippolyte, Loyse; Macé, Aurélien; Ferrari, Carina; Kutalik, Zoltán; Andrieux, Joris; Aylward, Elizabeth H.; Barker, Mandy; Bernier, Raphael; Bouquillon, Sonia; Conus, Philippe; Delobel, Bruno; Faucett, W. Andrew; Goin-Kochel, Robin P.; Grant, Ellen; Harewood, Louise; Hunter, Jill V.; Lebon, Sébastien; Ledbetter, David H.; Martin, Christa Lese; Männik, Katrin; Martinet, Danielle; Mukherjee, Pratik; Ramocki, Melissa B.; Spence, Sarah; Steinman, Kyle J.; Tjernagel, Jennifer; Spiro, John E.; Reymond, Alexandre; Beckmann, Jacques S.; Chung, Wendy K.; Jacquemont, Sébastien

doi:10.1136/jmedgenet-2012-101203

Cited by 261 publications

(329 citation statements)

References 53 publications

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“…It is confirmed that a region of chromosome 16p11.2 influences susceptibility to autism when either deleted or duplicated [14]. Furthermore, a 600 kb deletion at 16p11.2 leads to a group of neuropsychiatric disorders [21]. 16p11.2 encompasses twenty-five genes, which spans 500 kb and is flanked by 147 kb low copy repeats that are 99% identical [20].…”

Section: Introductionmentioning

confidence: 70%

16p11.2 is required for neuronal polarity

Li¹,

Feng²

2013

WJNS

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Since Autism Spectrum Disorder (ASD) is strongly associated with chromosomal abnormalities of 16p11.2, and Autism has been linked to neuronal polarity defect, our study aimed to explore the role of 16p11.2 genes in regulating neuronal polarity. We performed a neuronal polarity assay in a high throughput manner for candidate genes at 16p11.2. Our most interesting finding was that three 16p11.2 candidate genes, DOC2a, Tbx-6 and KIF 22, affected neuronal polarity. Our research, for the first time, indicates a novel association between 16p11.2 and neuronal polarity. Our results support the hypothesis that 16p11.2 is required for neuronal polarity. Our research provides new important insights into molecular mechanisms underlying the tight association between 16p11.2 and several neural developmental disorders, including autism, epilepsy, mental retardation and schizophrenia.

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Section: Introductionmentioning

confidence: 70%

16p11.2 is required for neuronal polarity

Li¹,

Feng²

2013

WJNS

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“…2,4,6,7,9,15,17 As shown by 4C-seq, FISH, and Hi-C, the two 16p11.2 CNV-prone regions are reciprocally engaged in evolutionary-conserved complex chromatin looping, as well as coordinated expression of encompassed genes. 17,45 Here we assessed whether these findings were paralleled by genetic interactions between the 28 and 9 single-copy genes within the 16p11.2 600 kb BP4-BP5 and 220 kb BP2-BP3 intervals, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4][5]9,10 The two CNVs have also been shown to interact at the chromatin level, by 4C, FISH, Hi-C, and concomitant expression changes. 17,45 To investigate whether the two regions are also conducive to genetic interactions, we co-injected LAT, the driver of the HC phenotype of the BP2-BP3 CNVs, with mRNAs encoding KCTD13, the driver of the HC phenotype of the BP4-BP5 CNVs, and MAPK3 or MVP, modifiers of the same BP4-BP5 HC phenotype, and we evaluated the number of proliferating cells.…”

Section: A B C D E F H Gmentioning

confidence: 99%

“…1 This pattern likely arose through selection and placed the whole region at risk for recurrent rearrangements through non-allelic homologous recombination. 2 Deletions (MIM: 611913) and duplications (MIM: 614671) of the 16p11.2 600 kb BP4-BP5 region are among the most frequent causes of neurodevelopmental and neuropsychiatric disorders. [2][3][4][5][6][7] They are associated with Rolandic epilepsy 8 and mirror phenotypes on body mass index (BMI), head circumference (HC), and brain volume.…”

Section: Introductionmentioning

confidence: 99%

“…2 Deletions (MIM: 611913) and duplications (MIM: 614671) of the 16p11.2 600 kb BP4-BP5 region are among the most frequent causes of neurodevelopmental and neuropsychiatric disorders. [2][3][4][5][6][7] They are associated with Rolandic epilepsy 8 and mirror phenotypes on body mass index (BMI), head circumference (HC), and brain volume. [9][10][11][12] The deletion of the distal 16p11.2 220 kb BP2-BP3 locus (MIM: 613444) is likewise enriched in individuals with early-onset obesity and is also associated with developmental delay, intellectual disability, autism spectrum disorders (ASD), and schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

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Copy Number Variations and Cognitive Phenotypes in Unselected Populations

Männik

Mägi

Macé

et al. 2015

JAMA

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148

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The association of copy number variations (CNVs), differing numbers of copies of genetic sequence at locations in the genome, with phenotypes such as intellectual disability has been almost exclusively evaluated using clinically ascertained cohorts. The contribution of these genetic variants to cognitive phenotypes in the general population remains unclear.OBJECTIVE To investigate the clinical features conferred by CNVs associated with known syndromes in adult carriers without clinical preselection and to assess the genome-wide consequences of rare CNVs (frequency Յ0.05%; size Ն250 kilobase pairs [kb]) on carriers' educational attainment and intellectual disability prevalence in the general population. DESIGN, SETTING, AND PARTICIPANTSThe population biobank of Estonia contains 52 000 participants enrolled from 2002 through 2010. General practitioners examined participants and filled out a questionnaire of health-and lifestyle-related questions, as well as reported diagnoses. Copy number variant analysis was conducted on a random sample of 7877 individuals and genotype-phenotype associations with education and disease traits were evaluated. Our results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. MAIN OUTCOMES AND MEASURESPhenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of these variants with educational attainment (from less than primary school through scientific degree) and prevalence of intellectual disability. RESULTSOf the 7877 in the Estonian cohort, we identified 56 carriers of CNVs associated with known syndromes. Their phenotypes, including cognitive and psychiatric problems, epilepsy, neuropathies, obesity, and congenital malformations are similar to those described for carriers of identical rearrangements ascertained in clinical cohorts. A genome-wide evaluation of rare autosomal CNVs (frequency, Յ0.05%; Ն250 kb) identified 831 carriers (10.5%) of the screened general population. Eleven of 216 (5.1%) carriers of a deletion of at least 250 kb (odds ratio [OR], 3.16; 95% CI, 1.51-5.98; P = 1.5e-03) and 6 of 102 (5.9%) carriers of a duplication of at least 1 Mb (OR, 3.67; 95% CI, 1.29-8.54; P = .008) had an intellectual disability compared with 114 of 6819 (1.7%) in the Estonian cohort. The mean education attainment was 3.81 (P = 1.06e-04) among 248 (Ն250 kb) deletion carriers and 3.69 (P = 5.024e-05) among 115 duplication carriers (Ն1 Mb). Of the deletion carriers, 33.5% did not graduate from high school (OR, 1.48; 95% CI, 1.12-1.95; P = .005) and 39.1% of duplication carriers did not graduate high school (OR, 1.89; 95% CI, 1.27-2.8; P = 1.6e-03). Evidence for an association between rare CNVs and lower educational attainment was supported by analyses of cohorts of adults from Italy and the United States and adolescents from the United Kingdom.CONCLUSIONS AND RELEVANCE Known pathogenic CNVs in unselected, but assumed to be healthy, adult popu...

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

Cited by 261 publications

References 53 publications

16p11.2 is required for neuronal polarity

16p11.2 is required for neuronal polarity

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Copy Number Variations and Cognitive Phenotypes in Unselected Populations

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