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Sci Transl Med. 2012 Jun 13;4(138):138ra78. doi: 10.1126/scitranslmed.3003544.

Exome sequencing can improve diagnosis and alter patient management.

Author information

Howard Hughes Medical Institute, Institute for Genomic Medicine, Rady Children's Hospital, University of California, San Diego, San Diego, CA 92093, USA.
Department of Computer Sciences, School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Cairo University Children's Hospital, Cairo 406, Egypt.
Laboratoire Génétique Moléculaire, El Razi University Hospital, Marrakech 2360, Morocco.
Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha 3050, Qatar.
Department of Pediatrics, Dhahran Health Center, Saudi Aramco Corporation, Dhahran 31311, KSA.
Child Neurology Department, Medical School of Karadeniz Technical University, Trabzon 61080, Turkey.
Medical Biology Department, Medical School of Karadeniz Technical University, Trabzon 61080, Turkey.
Department of Paediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan.
The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Contributed equally


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.

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