A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders

Stark, Zornitza; Tan, Tiong Yang; Chong, Belinda; Brett, Gemma R; Yap, Patrick; Walsh, Maie; Yeung, Alison; Peters, Heidi; Mordaunt, Dylan; Cowie, Shannon; Amor, David J.; Savarirayan, Ravi; McGillivray, George; Downie, Lilian; Ekert, Paul G.; Theda, Christiane; James, Paul; Yaplito‐Lee, Joy; Ryan, Monique M.; Leventer, Richard J.; Creed, Emma; Macciocca, Ivan; Bell, Katrina M.; Oshlack, Alicia; Sadedin, Simon; Georgeson, Peter; Anderson, Charlotte; Thorne, Natalie; Gaff, Clara; White, Susan

doi:10.1038/gim.2016.1

Cited by 339 publications

(378 citation statements)

References 36 publications

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“…WES has been available for several years, but its usefulness as a routine clinical diagnostic tool is only now beginning to emerge [26, 27]. WES has particular value in diagnosing the cause of rare conditions with unclear phenotypes [28] or with an atypical presentation [29] as found in our index case.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

et al. 2017

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BackgroundTrichohepatoenteric syndrome (THE-S) or phenotypic diarrhoea of infancy is a rare autosomal recessive disorder characterised by severe infantile diarrhoea, facial dysmorphism, immunodeficiency and woolly hair. It was first described in 1982 in two infants with intractable diarrhoea, liver cirrhosis and abnormal hair structure on microscopy. We report on two siblings from a consanguineous family of Somali descent who, despite extensive clinical investigation, remained undiagnosed until their demise. The index patient died of fulminant cytomegalovirus pneumonitis at 3 months of age.MethodsWhole exome sequencing (WES) was performed on a premortem DNA sample from the index case. Variants in a homozygous recessive state or compound heterozygous state were prioritized as potential candidate variants using TAPER™. Sanger sequencing was done to genotype the parents, unaffected sibling and a deceased sibling for the variant of interest.ResultsExome sequencing identified a novel homozygous mutation (c.4507C > T, rs200067423) in TTC37 which was confirmed by Sanger sequencing in the index case. The identification of this mutation led to the diagnosis of THE-S in the proband and the same homozygous variant was confirmed in a male sibling who died 4 years earlier with severe chronic diarrhoea of infancy. The unaffected parents and sister were heterozygous for the identified variant.ConclusionsWES permitted definitive genetic diagnosis despite an atypical presentation in the index case and suggests that severe infection, likely secondary to immunodeficiency, may be a presenting feature. In addition definitive molecular diagnosis allows for genetic counseling and future prenatal diagnosis, and demonstrates the value of WES for post-mortem diagnosis of disorders with a non-specific clinical presentation in which a Mendelian cause is suspected.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0388-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

et al. 2017

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“…These techniques have not only proven to be promising tools in studying the genetics underlying rare Mendelian disorders (12)(13)(14), but have also been shown to be valuable diagnostic tools in genetic diseases (3,8,(15)(16)(17)(18)(19). A recent review showed that although several studies on the cost-effectiveness of NGS applications have been performed, a complete and valid cost overview is currently lacking (20 ).…”

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confidence: 99%

Is the $1000 Genome as Near as We Think? A Cost Analysis of Next-Generation Sequencing

Nimwegen¹,

et al. 2016

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BACKGROUND:The substantial technological advancements in next-generation sequencing (NGS), combined with dropping costs, have allowed for a swift diffusion of NGS applications in clinical settings. Although several commercial parties report to have broken the $1000 barrier for sequencing an entire human genome, a valid cost overview for NGS is currently lacking. This study provides a complete, transparent and up-to-date overview of the total costs of different NGS applications.

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“…While gene discovery research is ongoing, translational research is the next necessary step in determining the utility of genomics. Translational studies are now demonstrating the cost-effectiveness and utility of exome sequencing as a first-line diagnostic test for eligible families [26,27] . Not all results are returned, but of those that are, not all will be validated in an accredited laboratory.…”

Section: Concerns Around the Current Policy Climatementioning

confidence: 99%

Genetics and Insurance in Australia: Concerns around a Self-Regulated Industry

Newson

Tiller

Keogh

et al. 2017

Public Health Genomics

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Background: Regulating the use of genetic information in insurance is an issue of ongoing international debate. In Australia, providers of life and other mutually rated insurance products can request applicants to disclose all results from any genetic test. Insurers can then use this information to adjust premiums and make policy decisions. The Australian Financial Services Council (FSC; an industry body) developed and maintains the relevant industry standard, which was updated in late 2016. Aims/Objective: To review the 2016 FSC Standard in light of relevant research and determine the legitimacy of the Australian regulatory environment regarding use of genetic information by insurers. Results: We identified five concerns arising from the 2016 FSC Standard: (1) use of results obtained from research; (2) the requirement for an applicant to disclose whether they are “considering” a genetic test; (3) failure to account for genome sequencing and other technology developments; (4) limited evidence regarding adverse selection; and (5) the inappropriateness of industry self-regulation. Conclusion: Industry self-regulation of the use of genetic information by life insurers, combined with a lack of government oversight, is inappropriate and threatens to impede the progress of genomic medicine in Australia. At this critical time, Australia requires closer government oversight of the use of genetic information in insurance.

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A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders

Cited by 339 publications

References 36 publications

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

Exome sequencing identifies a novel TTC37 mutation in the first reported case of Trichohepatoenteric syndrome (THE-S) in South Africa

Is the $1000 Genome as Near as We Think? A Cost Analysis of Next-Generation Sequencing

Genetics and Insurance in Australia: Concerns around a Self-Regulated Industry

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