Association between Microdeletion and Microduplication at 16p11.2 and Autism

Weiss, Lauren A.; Shen, Yiping; Korn, Joshua M.; Arking, Dan E.; Miller, David T.; Fossdal, Ragnheiður; Sæmundsen, Evald; Stefánsson, Hreinn; Green, Todd; Platt, Orah S.; Ruderfer, Douglas M.; Walsh, Christopher A.; Altshuler, David; Chakravarti, Aravinda; Tanzi, Rudolph E.; Stefánsson, Kāri; Santangelo, Susan L.; Gusella, James F.; Sklar, Pamela; Wu, Bai-Lin; Daly, Mark J.

doi:10.1056/nejmoa075974

Cited by 1,467 publications

(1,267 citation statements)

References 15 publications

Supporting

Mentioning

1,202

Contrasting

Unclassified

Order By: Relevance

“…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 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%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…[17][18][19][20] Other citations involving 1q21.1 duplication cases were also assessed. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] Cases of 1q21.1 duplication in GeneReviews (http://www.ncbi.nlm. nih.gov/books/NBK52787) and the four references provided therein 1,2,10,25 were reviewed as well, but no new subjects or phenotypic data were identified.…”

Section: Materials and Methods Literature Reviewmentioning

confidence: 99%

1q21.1 Microduplication expression in adults

Dolcetti

Silversides

Marshall

et al. 2013

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

“…The alleles of the 16p11.2 CNV confer mirrored effects on anthropometric traits 13 . The deletion, conferring high risk of autism 14 , shows the greatest impairments in the cognitive domains tested in the control carriers. The reciprocal duplication, conferring risk of schizophrenia 15 and autism 14 , confers somewhat different abnormalities on the control carriers (Supplementary Table 5).…”

Section: The Neuropsychiatric Cnvs As a Classmentioning

confidence: 97%

“…The deletion, conferring high risk of autism 14 , shows the greatest impairments in the cognitive domains tested in the control carriers. The reciprocal duplication, conferring risk of schizophrenia 15 and autism 14 , confers somewhat different abnormalities on the control carriers (Supplementary Table 5). Although the deletion is strongly associated with impaired verbal IQ and deficits in verbal letter and category fluency tests, in keeping with what is seen in autism, the duplication more selectively impairs the spatial working memory and executive functions that seem to be more important in the pathophysiology of schizophrenia 16 .…”

Section: The Neuropsychiatric Cnvs As a Classmentioning

confidence: 97%

CNVs conferring risk of autism or schizophrenia affect cognition in controls

Stefánsson

Meyer‐Lindenberg

Steinberg

et al. 2013

Nature

Self Cite

605

568

View full text Add to dashboard Cite

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNVonly confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.Little information is available on whether or how rare CNVs conferring high risk of schizophrenia and/or autism affect physiologic function of otherwise normal brains. As none of these CNVs hitherto described are fully penetrant for the diseases, and both schizophrenia and autism affect cognition, we aimed to examine the possibility that the CNVs affect cognition in control carriers, those who do not suffer either disease or intellectual disability. We based our selection of CNVs on a literature search for CNVs associated with schizophrenia and/or autism ('neuropsychiatric CNVs'); this search produced 26 CNV alleles (Supplementary Table 1) 1-3 . These CNV alleles are rare, found in 0.002% to 0.2% frequency, and cumulatively in 1.16% of our sample of 101,655 genotyped subjects, representing approximately one-third of the Icelandic population ( Supplementary Tables 1 and 2).We used the subset of genotyped subjects born before 1968, without excluding patients, to examine the association of each neuropsychiatric CNV with reproductive outcome ('fecundity'), defined simply as the number of children each subject had by age 45. After correction for multiple comparisons, three neuropsychiatric CNVs were significantly associated with fecundity (Table 1). Subjects carrying the 16p11.2 deletion or the 22q11.21 duplication show reduced fecundity, with the effect in males significantly greater than in females (P 5 0.0083 and P 5 0.029 for the difference in effect by sex for the 16p11.2 deletion and the 22q11.21 duplication, respectively). In contrast, individuals carrying the 16p12.1 deletion have more children than do controls (Table 1). Those with deletions at 15q11.2(...

show abstract

Association between Microdeletion and Microduplication at 16p11.2 and Autism

Abstract: We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations.

Cited by 1,467 publications

References 15 publications

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

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

1q21.1 Microduplication expression in adults

CNVs conferring risk of autism or schizophrenia affect cognition in controls

Contact Info

Product

Resources

About