A Bayesian framework for <i>de novo</i> mutation calling in parents-offspring trios

Wei, Qiang; Zhan, Xiaowei; Zhong, Xue; Liu, Yongzhuang; Han, Yujun; Chen, Wei; Li, Bingshan

doi:10.1093/bioinformatics/btu839

Cited by 93 publications

(79 citation statements)

References 26 publications

(39 reference statements)

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“…In parallel, we analyzed de novo variants in parents and healthy siblings of 1,789 autism probands from the Simons simplex collection sequenced on the same platform. Variants in both cohorts were called using the same GATK pipeline, and de novo mutations were identified using TrioDeNovo (12); the impact of missense mutations was inferred using MetaSVM (Methods).…”

Section: Resultsmentioning

confidence: 99%

“…Local realignment and quality score recalibration were performed using the GATK pipeline, after which variants were called using the GATK Haplotype Caller. A Bayesian algorithm, TrioDeNovo, was used to call de novo mutations (12). VQSR "PASS" variants with ExAC allele frequency ≤ 10 −3 sequenced to a depth of 8 or greater in the proband and 10 or greater in each parent with Phred-scaled genotype likelihood scores >30 and de novo quality scores [log 10 (Bayes factor)] >6 were considered.…”

Section: Methodsmentioning

confidence: 99%

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De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

100

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Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10 −11 ). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

100

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“…De novo SNVs were detected by four algorithms run on the default settings: TrioDeNovo 50 , DenovoGear 51 , PlinkSeq (https://atgu.mgh.harvard.edu/plinkseq/), and DenovoFlow. For de novo indels, DenovoGear was replaced with Scalpel 52 .…”

Section: Methodsmentioning

confidence: 99%

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

et al. 2018

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Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here, we present a comparable framework to evaluate rare and de novo noncoding single nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism the contribution of de novo noncoding variation is probably modest compared to de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple testing burden.

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“…To identify de novo mutations, the TrioDeNovo 23 program was used and high-stringency filters were applied as described in the Methods section. We identified two de novo mutations in this trio.…”

Section: Resultsmentioning

confidence: 99%

“…23 TrioDenovo calculates the posterior likelihood of a mutation being a bona fide de novo event and assigned a data quality (DQ) score to each variant call. De novo candidates were filtered based on the following hard filters: (1) have a minor allele frequency (MAF) ⩽5×10 −3 in ExAC, (2) pass GATK variant quality score recalibration, (3) have a minimum 10 reads total, 5 alternate allele reads and a 20% alternate allele ratio in proband, (4) have a minimum depth of 10 reference reads and alternate allele ratio <3% in parents (5) are exonic or canonical splice-site variants and (6) have a DQ⩾7 (suggested cutoff by authors of TrioDenovo).…”

Section: Methodsmentioning

confidence: 99%

Digenic mutations of human OCRL paralogs in Dent’s disease type 2 associated with Chiari I malformation

et al. 2016

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OCRL1 and its paralog INPP5B encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in OCRL1 cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in INPP5B have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression. Sequencing revealed a novel, de novo DD2-causing 462 bp deletion disrupting exon 3 of OCRL1 and a maternally inherited, extremely rare (ExAC allele frequency 8.4×10−6) damaging missense mutation in INPP5B (p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein’s critical PH domain. In silico analyses of mutation impact predicted by SIFT, PolyPhen2, MetaSVM and CADD algorithms were all highly deleterious. Together, our findings report a novel association of DD2 with Chiari I malformation and syringohydromyelia, and document the effects of digenic mutation of human OCRL paralogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP3 metabolism in this mechanism.

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A Bayesian framework for de novo mutation calling in parents-offspring trios

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 93 publications

References 26 publications

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder

Digenic mutations of human OCRL paralogs in Dent’s disease type 2 associated with Chiari I malformation

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