First steps of exome sequencing as diagnostic tool

The advent of exome sequencing over the past two years has led to an earthquake in the traditional approach of discovering new mutations involved in mendelian diseases, and it is increasingly considered as a powerful diagnostic tool for unresolved disorders. The question if exome sequencing will be soon an effective clinical diagnostic tool and if it will be succesfully fitted in the standard procedures of the clinical routine is a relevant topic well faced in a review recently published on Annals of Neurology. Exome sequencing could represent a dramatic improvement in the diagnosis of many Mendelian disorders (such as retinitis pigmentosa, Charcot-Marie-Tooth, etc.) characterized by locus heterogeneity. Sanger sequencing of all the exons of the candidate genes, is a time consuming procedures, representing a problem if a rapid molecular diagnosis is crucial for a more specific and effective care. The new NGS platforms seem to satisfy the needs of speed and accuracy, and the recent commercialization of kits for the sequening of a panel of genes involved in the main mendelian diseases is a further proof.

The possibility to sequence just a set of genes and not the entire exome is another crucial point that introduces some ethical concerns specially in those countries with a medical care based on private health insurance. A recent post on GenomeWeb by Matthew Dublin discuss the choice of UCLA to offer exome sequencing in a CLIA-certified (Clinical Laboratory Improvement Amendments) laboratory. It offers the service at $ 4.500 for an individual, $6.550 for a trio of exomes, and $2.500 for any additional exome. "There's a very large number of people with a clear Mendelian disease that do not have a molecular diagnosis" said Stan Nelson, a professor of human genetics at UCLA, "it's clearly more efficient to sequence the exome first, as the first genetic test" rather than subject a patient to a whole host of different tests, he noted. And about how to choose the patients for the exome sequencing: "Anyone with a very rare serious phenotype that's likely to be a single genetic event" would be eligible. Through exome sequencing and the bionformatic analysis of data they find a list of candidate variants, those are highlighted for further evaluation by a genomic data board. This step consist of a discussion between expert physicians, genetic counselors, bioinformaticians, medical geneticists, and the patient's primary physician. Only results that are relevant for the patient's disease are returned. The test is "explicitly to diagnose," Nelson said. Other institutes, such as the Medical College of Wisconsin and Children's Hospital, decided to be more stringent in the number of cases analysed with exome sequencing. They choose this technique only after all the other options are exhausted, but they return any relevant results that the patient's parents want, including variants that confer risk for adult-onset diseases.

A crucial point is: how will the insurance companies treat exome sequencing? UCLA has no specific and formal agreements about reimbursement of the cost of exome sequencing, but Nelson thinks the test will eventually be reimbursed, because it will ultimately save them money. But a new doubt arises: after the reimbursement will the insurance companies claim demand to know all the variants of their customers?