Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples

By J. Kosmicki, Kaitlin E. Samocha, D. Howrigan, Stephan J Sanders, Kamil Slowikowski, M. Lek, Konrad J. Karczewski, David J. Cutler, B. Devlin, Kathryn Roeder and 6 more. 2016

373 citations recorded by the source corpus.

Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo–affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.

Subfields: Genetics

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Citations in the corpus

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2019, methodology): “Samocha et al. (2017) recently introduced the MPC score, a missense deleteriousness metric composed of ‘‘Missense badness,’’ PolyPhen-2 (Adzhubei et al., 2010), and Constraint.”
Variant interpretation using population databases: lessons from gnomAD (2021, methodology): “The gnomAD database has also aided in the discovery of genes associated with many diseases, including neurodevelopmental and congenital heart disorders (The Deciphering Developmental Disorders Study 2015; Jin et al., 2017; Kaplanis et al., 2020; Kosmicki et al., 2017).”
Evaluating drug targets through human loss-of-function genetic variation (2019, neutral): “…gene essentiality, as demonstrated by agreement with cell culture and mouse knockout experiments 7 , by overlap with human disease genes 7,10 and genes depleted for structural variation 15 , and by the power of constraint to enrich for deleterious variants in neurodevelopmental disorders 7,16 .”
Regional missense constraint improves variant deleteriousness prediction (2017, methodology): “As an example, Kosmicki and colleagues found that the overall 2.6-fold excess for de novo PTVs in patients with neurodevelopmental disorders (when compared to controls) is explained almost entirely by a small subset of variants, specifically those de novo PTVs, absent from individuals in ExAC, which”