Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci

Moreno‐De‐Luca, Daniel; Moreno-De-Luca, Andrés; Cubells, Joseph F.; Sanders, Stephan J.

doi:10.1007/s40142-014-0045-7

Cited by 25 publications

(21 citation statements)

References 84 publications

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“…The overlap with schizophrenia loci appears to be more selective; for example, 16p11.2 duplications are associated with schizophrenia, while 16p11.2 deletions are not (Szatkiewicz et al, 2014). These observations are consistent with a model in which CNVs contribute risk to a number of neuropsychiatric disorders (Moreno-De-Luca et al, 2013a; Stefansson et al, 2014); however, the extent of this risk varies between phenotypes for each locus (Moreno-De-Luca et al, 2014). …”

Section: Discussionsupporting

confidence: 89%

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Sanders

Willsey

et al. 2015

Neuron

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SUMMARY Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

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Section: Discussionsupporting

confidence: 89%

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Sanders

Willsey

et al. 2015

Neuron

Self Cite

1,293

1,581

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“…This interpretation is supported by the results of the Low Confidence comparison (see Supplemental Information). Alternatively, other explanatory models regarding differential thresholds for behavioral expression of ASD based on heightened risk from rare de novo mutations and/or compensatory mechanisms may be relevant to those with High Confidence genes diagnosed with ASD (34, 35). Regardless, continued study of these early milestone and autism symptom profiles, both in samples of heterogeneous genetic abnormalities and with specific genetic abnormalities (e.g., Fragile X), is required to move these findings from observational to informing risk assessment for genetic testing in clinics (36).…”

Section: Discussionmentioning

confidence: 99%

Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder

Bishop

Farmer

Bal

et al. 2017

AJP

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Objective Aside from features associated with risk of neurogenetic syndromes in general (e.g., cognitive impairment), limited progress has been made in identifying phenotype-genotype relationships in autism spectrum disorder (ASD). Method This study extends work in the Simons Simplex Collection (SSC) by comparing the phenotypic profiles of ASD probands with or without identified de novo loss of function mutations (LoF) or Copy Number Variants (CNV) in high confidence ASD-associated genes/loci (Sanders et al., 2015). Analyses pre-emptively accounted for documented differences in sex and IQ in affected individuals with de novo mutations, by matching probands with and without these genetic events on sex, IQ, and age before comparing them on multiple behavioral domains. Results Children with de novo mutations (n=112) showed greater likelihood of motor delays during early development (i.e., later age of walking), but less impairment in certain measures of ASD core symptoms (parent-rated social-communication impairment and clinician-rated diagnostic certainty) in later childhood. These children also showed relative strengths in verbal and language abilities, including a smaller discrepancy between nonverbal and verbal IQ and a greater likelihood of having achieved fluent language. Conclusions Children with ASD with de novo mutations may exhibit a “muted” symptom profile with respect to social-communication and language deficits, relative to those with ASD with no identified genetic abnormalities. Such findings suggest that examining early milestone differences and standardized testing results may be helpful in etiologic efforts, and potentially in clinical differentiation of various subtypes of ASD, but only if developmental/demographic variables are properly accounted for first.

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“…Though we observe lower IQ among probands that carry de novo frameshift indels, compared to probands without any de novo LoF mutations, the difference is small (6.3 IQ points), accounts for only a fraction of the variance in IQ (R 2 =0.004), and the distribution of IQ is similar to that of other probands (Figure 3B). Moreover, given an emerging picture of shared risks for de novo SNVs among a wide range of neurodevelopmental syndromes (Allen et al, 2013; Fromer et al, 2014; Moreno-De-Luca et al, 2014), the most parsimonious explanation is that a subset of highly disruptive risk mutations are associated with a range of phenotypic outcomes that includes, but is not limited to, ID, ASD, schizophrenia, and epilepsy.…”

Section: Discussionmentioning

confidence: 99%

De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

et al. 2014

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SUMMARY Whole-exome sequencing (WES) studies have demonstrated the contribution of de novo loss-of-function single nucleotide variants to autism spectrum disorders (ASD). However, challenges in the reliable detection of de novo insertions and deletions (indels) have limited inclusion of these variants in prior analyses. Through the application of a robust indel detection method to WES data from 787 ASD families (2,963 individuals), we demonstrate that de novo frameshift indels contribute to ASD risk (OR=1.6; 95%CI=1.0-2.7; p=0.03), are more common in female probands (p=0.02), are enriched among genes encoding FMRP targets (p=6×10−9), and arise predominantly on the paternal chromosome (p<0.001). Based on mutation rates in probands versus unaffected siblings, de novo frameshift indels contribute to risk in approximately 3.0% of individuals with ASD. Finally, through observing clustering of mutations in unrelated probands, we report two novel ASD-associated genes: KMT2E (MLL5), a chromatin regulator, and RIMS1, a regulator of synaptic vesicle release.

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Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci

Cited by 25 publications

References 84 publications

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Identification of Developmental and Behavioral Markers Associated With Genetic Abnormalities in Autism Spectrum Disorder

De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder

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