DeNovoGear: de novo indel and point mutation discovery and phasing

Ramu, Avinash; Noordam, Michiel J.; Schwartz, Rachel S.; Wüster, Arthur; Hurles, Matthew E.; Cartwright, Reed A.; Conrad, Donald F.

doi:10.1038/nmeth.2611

Cited by 171 publications

(186 citation statements)

References 18 publications

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“…Each affected individual has also had a high‐resolution analysis for copy number abnormalities using array‐based comparative genomic hybridization (aCGH). Putative de novo mutations were identified from exome data using DeNovoGear software [Ramu et al, 2013] and were validated using targeted Sanger sequencing.…”

Section: Methodsmentioning

confidence: 99%

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Parker

Fryer

Shears

et al. 2015

American J of Med Genetics Pt A

109

115

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De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase‐activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi‐gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss‐of‐function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate‐to‐severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide‐based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

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Section: Methodsmentioning

confidence: 99%

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Parker

Fryer

Shears

et al. 2015

American J of Med Genetics Pt A

109

115

View full text Add to dashboard Cite

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“…Putative de novo variants were identified from exome data using DeNovoGear software15 and were validated using targeted Sanger sequencing. Analysis revealed a candidate de novo variant in ERF .…”

Section: Methodsmentioning

confidence: 99%

Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in theERFgene

et al. 2016

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“…Previous estimates of the human indel mutation rate range from 0.53 to 1.5 × 10 −9 per base per generation (Kondrashov 2003;Lynch 2010;Campbell and Eichler 2013;Ramu et al 2013;Besenbacher et al 2015). The mutation rate for copy number variants was estimated to be 0.03 for CNVs larger than 500 bp ) and 0.012 for CNVs larger than 100 kbp (Itsara et al 2010) per haploid genome.…”

Section: Indel and Sv Mutation Ratesmentioning

confidence: 99%

Characteristics of de novo structural changes in the human genome

et al. 2015

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Small insertions and deletions (indels) and large structural variations (SVs) are major contributors to human genetic diversity and disease. However, mutation rates and characteristics of de novo indels and SVs in the general population have remained largely unexplored. We report 332 validated de novo structural changes identified in whole genomes of 250 families, including complex indels, retrotransposon insertions, and interchromosomal events. These data indicate a mutation rate of 2.94 indels (1-20 bp) and 0.16 SVs (>20 bp) per generation. De novo structural changes affect on average 4.1 kbp of genomic sequence and 29 coding bases per generation, which is 91 and 52 times more nucleotides than de novo substitutions, respectively. This contrasts with the equal genomic footprint of inherited SVs and substitutions. An excess of structural changes originated on paternal haplotypes. Additionally, we observed a nonuniform distribution of de novo SVs across offspring. These results reveal the importance of different mutational mechanisms to changes in human genome structure across generations.

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DeNovoGear: de novo indel and point mutation discovery and phasing

Cited by 171 publications

References 18 publications

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in theERFgene

Characteristics of de novo structural changes in the human genome

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