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Exome Sequencing Can Improve Diagnosis and Alter Patient Management

Exome sequencing of 118 patients with neurodevelopmental disorders shows that this technique is useful for identifying new pathogenic mutations and for correcting diagnosis in ~10% of cases. A Needle in a Haystack Exome sequencing enables evaluation of all protein-coding variants in an individual genome and promises to revolutionize the practice of clinical genetics as it moves from the lab into the clinic. Bringing this technology to the clinic affords the opportunity not just to identify new disease-causing mutations but also to clarify disease presentation and diagnosis. There are many challenges to implementing this technology, however, including which patients to select for analysis, how to rank and prioritize the genetic variants, and how to align the data with the clinical record. In new work, Dixon-Salazar et al. studied a cohort of 118 probands with genetic forms of neurodevelopmental disease, all derived from consanguineous unions, using exome sequencing. All patients were previously excluded for genes most likely to cause their disease. The authors analyzed the exome sequences with a standardized bioinformatic pipeline. They found mutations in known disease-causing genes that in about 10% of cases led to a change in the underlying diagnosis. In 19% of cases, they identified mutations in genes not previously linked to disease. In the remaining cases, the genetic causes remained elusive. Thus, exome sequencing may both improve diagnosis and lead to alterations in patient management in some patients with neurodevelopmental disorders. However, analysis of more than one individual will be required to increase the success rate of identifying the causative mutation in most cases. 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.