Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations

Howrigan, Daniel P.; Rose, Samuel A.; Samocha, Kaitlin E.; Fromer, Menachem; Cerrato, Felecia; Chen, Wei-Jen; Churchhouse, Claire; Chambert, Kimberly; Chandler, Sharon D.; Daly, Mark J.; DuMont, Ashley L.; Genovese, Giulio; Hwu, Hai-Gwo; Laird, Nan M.; Kosmicki, Jack A.; Moran, Jennifer L.; Roe, Cheryl; Singh, Tarjinder; Wang, Shi-Heng; Faraone, Stephen V.; Glatt, Stephen J.; McCarroll, Steven A.; Tsuang, Ming T.; Neale, Benjamin M.

doi:10.1038/s41593-019-0564-3

Cited by 144 publications

(134 citation statements)

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“…In one patient with COS, we identified a heterozygous missense VUS in SHANK2 (Table 1, Table S2, available online), which codes for a postsynaptic density protein highly expressed in glutamatergic synapses [Peykov et al, 2015]. SHANK2 missense variants have been linked to schizophrenia in case-control and family studies [Homann et al, 2016], but was not identified as a schizophrenia risk gene in a recent, large trio ES study [Howrigan et al, 2020]. The father was unavailable for testing, so we were unable to conclude if it was de novo or paternally inherited, making it more difficult to conclude pathogenicity.…”

Section: Genetic Test Resultsmentioning

confidence: 99%

The Feasibility and Outcomes of Genetic Testing for Autism and Neurodevelopmental Disorders on an Inpatient Child and Adolescent Psychiatry Service

et al. 2020

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Diagnostic genetic testing is recommended for children with autism spectrum disorder and other neurodevelopmental disorders. One approach to improve access to genetic testing is to offer it on the inpatient child and adolescent psychiatry (CAP) service. We provided medical genetics education to CAP fellows and retrospectively compared the genetic testing rates and diagnostic yield pre‐ and post‐education. We compared demographics to similar patients who received testing on other clinical services and assessed rates of outpatient genetics follow‐up post‐discharge. The genetic testing rate on the inpatient CAP service was 1.6% before the educational intervention and 10.7% afterward. Genetic risk factors were identified in 4.3% of inpatients. However, 34.8% had variants of unknown significance. 39.1% of patients who received genetic testing while inpatients were underrepresented minorities, compared to 7.7% of inpatients who received genetic testing from other clinical services. 43.5% of patients were lost to outpatient genetics follow‐up. We have demonstrated that it is feasible to provide medical genetics education to CAP fellows on an inpatient service, which may improve genetic testing rates. This preliminary evidence also suggests that genetic testing for inpatients may identify variants of unknown significance instead of well‐known neurodevelopmental disorder risk variants. Genetic testing on an inpatient CAP service may also improve access to genetic services for underrepresented minorities, but assuring outpatient follow‐up can be challenging. Lay Summary Genetic testing is recommended for children with autism and related developmental conditions. We provided genetic testing to a group of these children who were in a psychiatric hospital by teaching their doctors how it can be helpful. We identified a genetic risk factor in a small percentage of children and a possible genetic risk factor in a large percentage of children. However, many children did not end up receiving their genetic test results once they left the hospital. These results tell us that the psychiatric hospital may be a good place for children with autism and behavioral problems to get genetic testing, but that it is really important that doctors assure follow‐up is feasible for all patients to receive their genetic test results once they leave the hospital. Autism Res 2020, 13: 1450–1464. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

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Section: Genetic Test Resultsmentioning

confidence: 99%

The Feasibility and Outcomes of Genetic Testing for Autism and Neurodevelopmental Disorders on an Inpatient Child and Adolescent Psychiatry Service

et al. 2020

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“…Common risk alleles collectively contribute to around a third of the genetic liability 2,3 , and at least 8 rare copy number variants have been identified as risk factors 4,5 . Exome-sequencing studies have also shown a contribution to risk from ultra-rare protein-coding variants; the de novo mutation rate is modestly elevated above the expected population rate, and there is an excess of ultra-rare damaging coding variants (frequency < 0.0001 in population) in genes with evidence for strong selective constraint against protein-truncating variants (PTVs) [6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

Rees

Creeth

Hwu

et al. 2020

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Genes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

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“…Liability to disease through common variants (allele frequency ≥ 1%) ranges from 10-25% for psychiatric disorders including major depressive disorder (MDD) (1)(2)(3) and schizophrenia (1,4). Rare variants have likewise been shown to confer disease risk, particularly in neurodevelopmental and psychotic (5,6) domains. While loci containing both types of variants have been associated with neuropsychiatric phenotypes, two major hurdles have prevented use of this knowledge to better understand disease mechanisms: 1) a large volume of GWAS associations and rare variant discoveries to test for functionality/causality; and 2) the lack of means to predict a variant's functional consequences.…”

Section: Introductionmentioning

confidence: 99%

The Oft-Overlooked Massively Parallel Reporter Assay: Where, When, and Which Psychiatric Genetic Variants are Functional?

Mulvey¹,

Lagunas²,

Dougherty³

2020

Preprint

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Neuropsychiatric phenotypes have been long known to be influenced by heritable risk factors. The past decade of genetic studies have confirmed this directly, revealing specific common and rare genetic variants enriched in disease cohorts. However, the early hope for these studies-that only a small set of genes would be responsible for a given disorder-proved false. The picture that has emerged is far more complex: a given disorder may be influenced by myriad coding and noncoding variants of small effect size, and/or by rare but severe variants of large effect size, many de novo.Noncoding genomic sequences harbor a large portion of these variants, the molecular functions of which cannot usually be inferred from sequence alone. This creates a substantial barrier to understanding the higher-order molecular and biological systems underlying disease risk. Fortunately, a proliferation of genetic technologies-namely, scalable oligonucleotide synthesis, high-throughput RNA sequencing, CRISPR, and CRISPR derivatives-have opened novel avenues to experimentally identify biologically significant variants en masse. These advances have yielded an especially versatile technique adaptable to large-scale functional assays of variation in both untranscribed and untranslated regulatory features: Massively Parallel Reporter Assays (MPRAs). MPRAs are powerful molecular genetic tools that can be used to screen tens of thousands of predefined sequences for functional effects in a single experiment. This approach has several ideal features for psychiatric genetics, but remains underutilized in the field to date. To emphasize the opportunities MPRA holds for dissecting psychiatric polygenicity, we review here its applications in the literature, discuss its ability to test several biological variables implicated in psychiatric disorders, illustrate this flexibility with a proof-of-principle, in vivo cell-type specific implementation of the assay, and envision future outcomes of applying MPRA to both computational and experimental neurogenetics.

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Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations

Cited by 144 publications

References 50 publications

The Feasibility and Outcomes of Genetic Testing for Autism and Neurodevelopmental Disorders on an Inpatient Child and Adolescent Psychiatry Service

The Feasibility and Outcomes of Genetic Testing for Autism and Neurodevelopmental Disorders on an Inpatient Child and Adolescent Psychiatry Service

Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

The Oft-Overlooked Massively Parallel Reporter Assay: Where, When, and Which Psychiatric Genetic Variants are Functional?

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