Timing of De Novo Mutagenesis — A Twin Study of Sodium-Channel Mutations

Vadlamudi, Lata; Dibbens, Leanne M.; Lawrence, Kate; Iona, Xenia; McMahon, Jacinta M.; Murrell, Wayne; Mackay‐Sim, Alan; Scheffer, Ingrid E.; Berkovic, Samuel F.

doi:10.1056/nejmoa0910752

Cited by 96 publications

(73 citation statements)

References 25 publications

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“…An added level of complexity, consistent with this ‘de novo model’, could be the timing of mutational events whereby early postzygotic de novo mutations could be critically important. This is supported by the observations that somatic mosaicism has been well documented in Mendelian phenotypes,14 28 29 including monozygotic twins discordant for a given disorder,30 and by demonstration of extensive genetic variation in human tissues31 including brain 32. It will be crucial to expand genome sequencing studies to the next level of tissue or even cell type-specific interrogation to better delineate causal mutations especially in sporadic forms of Mendelian disorders.…”

Section: Discussionmentioning

confidence: 86%

Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair

et al. 2014

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Characterizing the patterns and rate of de novo mutations is crucial for our perception of evolution and genetic basis of human disease. Direct observation of de novo single nucleotide variation (SNV) rate in healthy individuals revealed a rate in a range of 0.82 -1.70 ×10 -8 base pair per generation. However, the developmental timing of the de novo mutations is unknown and thus, contribution of the early post-zygotic mutations to the human de novo SNV rate remained unknown. In an attempt to estimate the rate of de novo mutations regarding the developmental timing of mutagenesis, we sequenced the whole genomes of a healthy monozygotic twin pair and their parents with a total of 170 fold coverage. We identified the de novo SNVs through examination of the genotypes of each individual for each of the variants in a synchronous manner. Subsequent to the Sanger sequencing based validation, we conservatively characterized a total of 32 de novo SNVs. Of these 23 were shared by the twin pair, 8 were specific to twin I, and 1 was specific to twin II. We estimated the overall de novo SNV rate of 1.31 × 10 -8 for twin I and 1.01 × 10 -8 for twin II. The rate of the early post-zygotic de novo SNVs was calculated to be 0.34 × 10 -8 and 0.04 × 10 -8 for twin I and twin II, respectively. These data indicate the growing importance of genome mosaicism which might be resulted from de novo mutations of early post-zygotic origin in disease pathogenesis.

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Section: Discussionmentioning

confidence: 86%

Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair

et al. 2014

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“…Twins can access information about studies, twin resources and events, and register or update contact details. The ATR has an active (Berkovic et al, 1996(Berkovic et al, , 1998Klein et al, 2012;Vadlamudi et al, 2010). Cervical cancer Possible to measure human papilloma virus genotype from archival pap smears (Moore et al, 2012;Tabrizi et al, 2010).…”

Section: Atr Branding and Web Sitementioning

confidence: 99%

Australian Twin Registry: 30 Years of Progress

et al. 2012

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The Australian Twin Registry (ATR) is a national volunteer resource of twin pairs and higher-order multiples willing to consider participating in health, medical, and scientific research. The vision of the ATR is 'to realize the full potential of research involving twins to improve the health and well-being of all Australians'. The ATR has been funded continuously by the National Health and Medical Council for more than 30 years. Its core functions entail the recruitment and retention of twin members, the maintenance of an up-to-date database containing members' contact details and baseline information, and the promotion and provision of open access to researchers from all institutes in Australia, and their collaborators, in a fair and equitable manner. The ATR is administered by The University of Melbourne, which acts as custodian. Since the late 1970s the ATR has enrolled more than 40,000 twin pairs of all zygosities and facilitated more than 500 studies that have produced at least 700 peer-reviewed publications from classical twin studies, co-twin control studies, within-pair comparisons, twin family studies, longitudinal twin studies, randomized controlled trials, and epigenetics studies, as well as studies of issues specific to twins. New initiatives include: a Health and Life Style Questionnaire; data collection, management, and archiving using a secure online software program (The Ark); and the International Network of Twin Registries. The ATR's expertise and 30 years of experience in providing services to national and international twin studies has made it an important resource for research across a broad range of disciplines.

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“…The importance of germline and somatic mosaicism is well established in a broad range of diseases, including DS (Vadlamudi et al. 2010), and highlights the usefulness of high coverage NGS techniques for mosaic mutation detection. A major weakness of NGS on the other hand is the sequencing of stretches of the same nucleotide, which can lead to homopolymer‐associated insertion and deletion errors due to the nonlinear light response generated by the nucleotide stretches (patient 22).…”

Section: Discussionmentioning

confidence: 99%

Pitfalls in genetic testing: the story of missed SCN1A mutations

Djémié

Weckhuysen

Spiczak

et al. 2016

Molec Gen & Gen Med

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BackgroundSanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next‐generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations.MethodsWe sent out a survey to 16 genetic centers performing SCN1A testing.ResultsWe collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation‐negative, both due to technical limitations and human errors.ConclusionWe illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.

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Timing of De Novo Mutagenesis — A Twin Study of Sodium-Channel Mutations

Cited by 96 publications

References 25 publications

Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair

Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair

Australian Twin Registry: 30 Years of Progress

Pitfalls in genetic testing: the story of missed SCN1A mutations

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