The mutational constraint spectrum quantified from variation in 141,456 humans

Karczewski, Konrad J.; Francioli, Laurent C.; Tiao, Grace; Cummings, Beryl B.; Alföldi, Jessica; Wang, Qingbo; Collins, Ryan L.; Laricchia, Kristen M.; Ganna, Andrea; Birnbaum, Daniel; Gauthier, Laura D.; Brand, Harrison; Solomonson, Matthew; Watts, Nicholas A.; Rhodes, Daniel R.; Singer-Berk, Moriel; England, Eleina; Seaby, Eleanor G.; Kosmicki, Jack A.; Walters, Raymond; Tashman, Katherine; Farjoun, Yossi; Banks, Eric; Poterba, Timothy; Wang, Arcturus; Seed, Cotton; Whiffin, Nicola; Chong, Jessica X.; Samocha, Kaitlin E.; Pierce‐Hoffman, Emma; Zappala, Zachary; O’Donnell-Luria, Anne; Minikel, Eric Vallabh; Weisburd, Ben; Lek, Monkol; Ware, James S.; Vittal, Christopher; Armean, Irina M.; Bergelson, Louis; Cibulskis, Kristian; Connolly, Kristen M.; Covarrubias, Miguel; Donnelly, Stacey; Ferriera, Steven; Gabriel, Stacey; Gentry, Jeff; Gupta, Namrata; Jeandet, Thibault; Kaplan, Diane; Llanwarne, Christopher; Munshi, Ruchi; Novod, Sam; Petrillo, Nikelle; Roazen, David; Ruano-Rubio, Valentín; Saltzman, Andrea; Schleicher, Molly; Soto, José María Satizábal; Tibbetts, Kathleen; Tolonen, Charlotte; Wade, Gordon; Talkowski, Michael E.; Neale, Benjamin M.; Daly, Mark J.; MacArthur, Daniel G.

doi:10.1038/s41586-020-2308-7

Cited by 7,383 publications

(6,685 citation statements)

References 53 publications

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“…In 2007, these changes were proposed by Bassuk et al as possibly pathogenic in cis in a symptomatic mother and daughter. 5,6 In our patient's family, the father was asymptomatic and was shown not to have the two cis changes and the patient's mother's estrangement meant her genetic profile and phenotype are not known.…”

Section: Discussionmentioning

confidence: 86%

Biallelic Mutation of SETX and Additional Likely “In Cis” SETX Sequence Change in Ataxia with Oculomotor Apraxia Type 2

et al. 2020

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Ataxia with oculomotor apraxia type 2 (AOA2) is a slowly progressive, autosomal recessive disease characterized by the triad of ataxia, oculomotor apraxia, and sensorimotor neuropathy. The genetic basis of AOA2 is biallelic mutation of the SETX gene, resulting in reduced or absent senataxin, a DNA/RNA repair protein essential for genomic stability.In this report, we describe a case of AOA2 with two clear pathogenic SETX mutations, one of which is novel. We then discuss two further likely in cis SETX sequence changes, previously reported in the literature as pathogenic, and present the case that they are likely benign polymorphisms.

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Section: Discussionmentioning

confidence: 86%

Biallelic Mutation of SETX and Additional Likely “In Cis” SETX Sequence Change in Ataxia with Oculomotor Apraxia Type 2

et al. 2020

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“…1). These two nonsynonymous variants were present among 20 TMPRSS2 exonic variants with global AF of >1% from gnomAD 23 . Thirteen of these were in 3′ UTR and ve were synonymous ( Supplementary Fig.…”

Section: Correlation Of Nonsynonymous Tmprss2 Allele Frequencies Withmentioning

confidence: 96%

Ethnicity-dependent allele frequencies are correlated with COVID-19 case fatality rate

Jeon

Blažytė

Yoon

et al. 2020

Preprint

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Coronavirus disease (COVID-19), caused by SARS-CoV-2, has a higher case fatality rate (CFR) in European ethnic groups than in others, especially East Asians. One explanation to this phenomenon might be TMPRSS2, a key processing enzyme essential for viral infection. Here, we analyzed the allele frequencies of two nonsynonymous variants rs12329760 (V197M) and rs75603675 (G8V) in the TMPRSS2 gene using over 200,000 present-day and ancient genomic samples. We found a significant association between the CFR of COVID-19 and the allele frequencies of the two variants. Interestingly, they had opposing effects on the CFR: inverse correlation by V197, proportional correlation by G8V. East Asians have higher V197M and lower G8V allele frequencies than Europeans, possibly endowing resistance against SARS-CoV-2. Structural and energy calculation analysis of the V197M amino acid change showed that it destabilizes the TMPRSS2 protein, possibly affecting its ACE2 and viral spike protein processing negatively, ultimately resulting in reduced SARS-CoV-2 infection efficiency and CFR in East Asian ethnic groups.

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“…'NDD phenotype' indicates whether the variant was reported in a developmental disorder (DD) trio or an autism spectrum disorder (ASD) trio 13,20 . pathogenicity score 21 ; pLi = "probability of loss-of-function intolerance" 22 .…”

Section: Allelic Pleiotropymentioning

confidence: 99%

“…We divided these variants into primary and negative control sets. The primary set contains variants with characteristics known to be associated with pathogenicity for NDDs 13,41 , namely PTVs in loss-of-function intolerant genes (genes with gnomAD pLi scores ≥ 0.9 22 ) and missense variants with MPC scores ≥ 2 21 . The negative control set contained all remaining variants (PTVs in genes with pLi scores < 0.9, missense variants with MPC scores < 2 and all synonymous variants), properties that do not predict NDD pathogenicity.…”

Section: Statisticsmentioning

confidence: 99%

“…To test for an excess burden of NDD variants in cases compared with controls, a one-tailed Firth's penalized-likelihood logistic regression model was used, correcting for the rst 10 principal components derived from the sequencing data, and for the exome-wide burden of synonymous variants, sequencing platform and sex. To focus the case-control analysis on ultra-rare alleles, as those are more likely to be pathogenic, we excluded variants with an allele count > 5 in gnomAD 22 . Frameshift variants were included in the case-control analysis.…”

Section: Statisticsmentioning

confidence: 99%

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

Rees

Creeth

Hwu

et al. 2020

Preprint

Self Cite

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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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The mutational constraint spectrum quantified from variation in 141,456 humans

Abstract: As this was an opportunistic secondary use study, we did not recruit any participants.

Cited by 7,383 publications

References 53 publications

Biallelic Mutation of SETX and Additional Likely “In Cis” SETX Sequence Change in Ataxia with Oculomotor Apraxia Type 2

Biallelic Mutation of SETX and Additional Likely “In Cis” SETX Sequence Change in Ataxia with Oculomotor Apraxia Type 2

Ethnicity-dependent allele frequencies are correlated with COVID-19 case fatality rate

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

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