Genomics in Clinical Practice: Lessons from the Front Lines

Jacob, Howard J.; Abrams, Kelly; Bick, David; Brodie, Ken; Dimmock, David; Farrell, Michael; Geurts, Jennifer L.; Harris, Jeremy M.; Helbling, Daniel; Joers, Barbara J.; Kliegman, Robert M.; Kowalski, George; Lazar, Jozef; Margolis, David; North, Paula E.; Northup, Jill K.; Roquemore-Goins, Altheia; Scharer, Gunter; Shimoyama, Mary; Strong, Kimberly A.; Taylor, Bradley; Tsaih, Shirng Wern; Tschannen, Michael; Veith, Regan; Wendt-Andrae, Jaime; Wilk, Brandon; Worthey, Elizabeth A.

doi:10.1126/scitranslmed.3006468

Cited by 96 publications

(77 citation statements)

References 19 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This level of yield is similar to or slightly higher than those of previous reports, either in research studies 1,[5][6][7] or clinical series reported by clinical laboratories.…”

Section: Discussioncontrasting

confidence: 37%

“…The available evidence of the use of WES in a clinical setting has largely been an extension of a previous research protocol 1 or a comparison of traditional diagnostic methods and WES. 2 Here we report a series of our first 115 patients evaluated by WES as part of routine clinical care in our clinical genetic practice at a single institution.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The usefulness of whole-exome sequencing in routine clinical practice

Iglesias

Anyane‐Yeboa

Wynn

et al. 2014

Genetics in Medicine

202

191

View full text Add to dashboard Cite

“…This level of yield is similar to or slightly higher than those of previous reports, either in research studies 1,[5][6][7] or clinical series reported by clinical laboratories.…”

Section: Discussioncontrasting

confidence: 37%

Section: Introductionmentioning

confidence: 99%

The usefulness of whole-exome sequencing in routine clinical practice

Iglesias

Anyane‐Yeboa

Wynn

et al. 2014

Genetics in Medicine

202

191

View full text Add to dashboard Cite

“…Despite excellent coverage (96% of the reference genome at an average depth of 33X), the initial data assessment did not reveal a clear molecular diagnosis (19). A previously described (14) heterozygous DGKE nonsense mutation, c.966G.A (p.Trp322*), was found in patient II-1 by WGS and was subsequently confirmed by Sanger in all relatives except the mother (Supplemental Figure 4A).…”

Section: Identification Of a Second Family With The Dgke C888 +40a>gmentioning

confidence: 96%

“…Patient II-1 from family 2 underwent clinical WGS as part of the Genomics Medicine Clinic, in collaboration with Children's Hospital of Wisconsin and Froedtert Hospital (19). Twenty unrelated French patients with pediatric aHUS undergoing genetic screening in Paris were included in this study.…”

Section: Methodsmentioning

confidence: 99%

Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome

Mele¹,

Lemaire²,

Iatropoulos³

et al. 2015

Clinical Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Background and objectives Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.Design, setting, participants, & measurements Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting.Results Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A.G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS.Conclusions This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process nextgeneration sequencing data routinely exclude these regions from downstream analyses in both research and clinical settings. The results suggest that analysis of noncoding regions of aHUS-associated genes coupled with mRNA sequencing might provide a tool to explain genetically unsolved aHUS cases.

show abstract

“…This paradigm shift in molecular analysis has been fully embraced in the endocrine field, both in research and at the clinic 28 . If the use of WGS in the clinical front has been so far limited to the diagnosis of severe complex phenotypes 29 , WES is now easily available as a diagnostic test and can be very useful for obtaining a molecular diagnosis in endocrinopathies for which several candidate genes exist, such as disorders of sex development 6,30 .…”

Section: Massive Parallel Sequencingmentioning

confidence: 99%

Diagnóstico molecular na prática clínica: visão do endocrinologista

Ferraz-de-Souza¹

2015

Rev. Med. (São Paulo)

View full text Add to dashboard Cite

Endocrinology is one of several medical specialities that have been gradually transformed by a deeper understanding of the molecular bases of disorders. Genetic testing with the purposes of defining a precise molecular diagnosis has increasingly gained space in the routine assessment of patients with endocrinopathies, and the advent of massive parallel sequencing (MPS) is boosting the incorporation of molecular information in the clinic. The main benefit of genetic testing is diagnostic precision, resulting in improved and individualized care for patients and family members, and better disease prevention. However, genetic tests are not infallible and may bear several potential risks, being thus indicated when clinical suspicion is strong and the benefit of determining a molecular diagnosis is unambiguous. In this review, these evolving concepts and current indications for molecular diagnosis in endocrinology will be explored. Molecular tools will be revised and contextualised, including those aimed at identifying changes in gene dosage (karyotpe, FISH, MLPA, aCGH, SNParray) or in the DNA nucleotide sequence (allele-specific PCR, RFLP, Sanger sequencing, MPS or NGS). Finally, matters surrounding the complex attribution of biologically relevant functional impact to identified DNA variants will be explored, together with the challenges brought by high throughput molecular analysis. These are exciting times for molecular endocrinology, and hopefully soon a translation to multiple benefits for patients will be self-evident.Keywords: Genetic testing; Endocrinology; Mutation; DNA mutation analysis; Transcription, genetic; Genetic markers; Sequence analysis, DNA/methdos; Molecular sequence data. RESUMO:A endocrinologia é uma de muitas especialidades médicas que vem sendo transformada pelo maior conhecimento das bases moleculares das doenças. O teste genético com o propósito de definir o diagnóstico molecular vem ganhando espaço na avaliação rotineira de pacientes com endocrinopatias, e o advento do sequenciamento paralelelo em larga escala (SPLE) está ampliando o potencial de incorporação da informação molecular na prática clínica. O principal benefício do teste genético é a precisão diagnóstica, resultando em melhora e individualização do tratamento de pacientes e seus familiares, e da prevenção de doenças. Entretanto, testes genéticos não são infalíveis e podem trazer alguns riscos potenciais, estando portanto indicados quando a suspeita clínica é forte e o benefício do diagnóstico molecular é claro. Nesta revisão serão explorados conceitos genéticos em evolução e as atuais indicações de diagnóstico molecular em endocrinologia. Ferramentas moleculares serão revisadas, incluindo aquelas visando a identificação de alterações no número de cópias gênicas (cariótipo, FISH, MLPA, aCGH, SNParray) ou na sequencia nucleotídica do DNA (PCR alelo-específica, RFLP, sequenciamento Sanger, SPLE ou NGS). Ainda, serão discutidos os percalços da difícil atribuição de impacto funcional e relevância biológica a variantes de DN...

show abstract

Genomics in Clinical Practice: Lessons from the Front Lines

Abstract: This Commentary explores the challenges in launching a medical genomics clinic for whole genome sequencing and analysis of patient samples.

Cited by 96 publications

References 19 publications

The usefulness of whole-exome sequencing in routine clinical practice

The usefulness of whole-exome sequencing in routine clinical practice

Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome

Diagnóstico molecular na prática clínica: visão do endocrinologista

Contact Info

Product

Resources

About