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Exome sequencing can improve diagnosis and alter patient management.

ABSTRACT: The translation of "next-generation" sequencing directly to the clinic is still being assessed but has the potential for genetic diseases to reduce costs, advance accuracy, and point to unsuspected yet treatable conditions. To study its capability in the clinic, we performed whole-exome sequencing in 118 probands with a diagnosis of a pediatric-onset neurodevelopmental disease in which most known causes had been excluded. Twenty-two genes not previously identified as disease-causing were identified in this study (19% of cohort), further establishing exome sequencing as a useful tool for gene discovery. New genes identified included EXOC8 in Joubert syndrome and GFM2 in a patient with microcephaly, simplified gyral pattern, and insulin-dependent diabetes. Exome sequencing uncovered 10 probands (8% of cohort) with mutations in genes known to cause a disease different from the initial diagnosis. Upon further medical evaluation, these mutations were found to account for each proband's disease, leading to a change in diagnosis, some of which led to changes in patient management. Our data provide proof of principle that genomic strategies are useful in clarifying diagnosis in a proportion of patients with neurodevelopmental disorders.

SUBMITTER: Dixon-Salazar TJ

PROVIDER: S-EPMC4442637 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Exome sequencing can improve diagnosis and alter patient management.

Dixon-Salazar Tracy J TJ Silhavy Jennifer L JL Udpa Nitin N Schroth Jana J Bielas Stephanie S Schaffer Ashleigh E AE Olvera Jesus J Bafna Vineet V Zaki Maha S MS Abdel-Salam Ghada H GH Mansour Lobna A LA Selim Laila L Abdel-Hadi Sawsan S Marzouki Naima N Ben-Omran Tawfeg T Al-Saana Nouriya A NA Sonmez F Müjgan FM Celep Figen F Azam Matloob M Hill Kiley J KJ Collazo Adrienne A Fenstermaker Ali G AG Novarino Gaia G Akizu Naiara N Garimella Kiran V KV Sougnez Carrie C Russ Carsten C Gabriel Stacey B SB Gleeson Joseph G JG

Science translational medicine 20120601 138

The translation of "next-generation" sequencing directly to the clinic is still being assessed but has the potential for genetic diseases to reduce costs, advance accuracy, and point to unsuspected yet treatable conditions. To study its capability in the clinic, we performed whole-exome sequencing in 118 probands with a diagnosis of a pediatric-onset neurodevelopmental disease in which most known causes had been excluded. Twenty-two genes not previously identified as disease-causing were identif ...[more]

PMID: 22700954

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Project description:Introduction: Monogenic diabetes (MD) accounts for 3%-6% of all cases of diabetes. This prevalence is underestimated due to its overlapping clinical features with type 1 and type 2 diabetes. Hence, genetic testing is the most appropriate tool for obtaining an accurate diagnosis. In Tunisia, few cohorts of MD have been investigated until now. The aim of this study is to search for pathogenic variants among 11 patients suspected of having MD in Tunisia using whole-exome sequencing (WES). Materials and methods: WES was performed in 11 diabetic patients recruited from a collaborating medical center. The pathogenicity of genetic variation was assessed using combined filtering and bioinformatics prediction tools. The online ORVAL tool was used to predict the likelihood of combinations of pathogenic variations. Then, Sanger sequencing was carried out to confirm likely pathogenic predicted variants among patients and to check for familial segregation. Finally, for some variants, we performed structural modeling to study their impact on protein function. Results: We identified novel variants related to MD in Tunisia. Pathogenic variants are located in several MODY and non-MODY genes. We highlighted the presence of syndromic forms of diabetes, including the Bardet-Biedl syndrome, Alström syndrome, and severe insulin resistance, as well as the presence of isolated diabetes with significantly reduced penetrance for Wolfram syndrome-related features. Idiopathic type 1 diabetes was also identified in one patient. Conclusion: In this study, we emphasized the importance of genetic screening for MD in patients with a familial history of diabetes, mainly among admixed and under-represented populations living in low- and middle-income countries. An accurate diagnosis with molecular investigation of MD may improve the therapeutic choice for better management of patients and their families. Additional research and rigorous investigations are required to better understand the physiopathological mechanisms of MD and implement efficient therapies that take into account genomic context and other related factors.

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Exome sequencing can improve diagnosis and alter patient management.

Publications

Exome sequencing can improve diagnosis and alter patient management.

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