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Clinical Exomes Reveal Multiple Molecular Diagnoses With Surprising Frequency, Baylor Team Finds


NEW YORK (GenomeWeb) – A surprisingly large number of patients undergoing clinical whole-exome sequencing turn out to have mutations in more than one Mendelian disease gene, resulting in multiple molecular diagnoses, researchers at Baylor College of Medicine have found.

The additional diagnoses, which can have implications for the patient's clinical care, may go unnoticed with more targeted approaches such as gene panel sequencing, making the finding a strong argument in favor of exome sequencing, said Sharon Plon, a professor of molecular and human genetics and pediatrics oncology at Baylor. Plon discussed the results during a talk at the New York Genome Center yesterday.

Baylor's Whole Genome Laboratory — now part of Baylor Miraca Genetics Laboratories — has been providing clinical whole-exome sequencing since 2011 and has run about 8,000 clinical exomes in total, with multiple improvements to its sequencing and analysis pipeline over the years.

The majority of samples come from pediatric patients but Baylor has also analyzed a substantial number of adult exomes by now and introduced a prenatal trio exome last spring. Also last year, Baylor debuted a critical trio exome for patients who need a fast result for clinical decision-making, which has a reduced turnaround time of as little as three days, compared to the usual 10 to 15 weeks.

In late 2014, the Baylor team published clinical exome sequencing results from 2,000 consecutive patient cases in the Journal of the American Medical Association. That study revealed that a small percentage of patients — almost 5 percent of the 504 patients diagnosed, and 1.4 percent of all patients in the study — harbored mutations at several distinct disease loci that were relevant to their phenotype.

Since then, the researchers have further analyzed cases of patients with multiple molecular diagnoses, first presenting their results at the American Society of Human Genetics annual meeting last fall, and are preparing to submit their findings for publication, Plon told GenomeWeb.

For their latest analysis, they looked at approximately 1,400 patients diagnosed by clinical exome sequencing. Of these, about 6 percent received more than one molecular diagnosis: 74 had mutations at two disease loci, six had mutations at three loci, and two patients had four disease loci involved. Many of these had inherited a recessive disease from their parents and had an additional de novo mutation in another disease gene.

Some of the patients had a blended phenotype of two Mendelian disorders with distinct symptoms. Other patients were diagnosed with two disorders that have overlapping phenotypes and sometimes involved variants in disease genes located in the same pathway.

In the latter patients, the second diagnosis could easily be missed if, for example, a targeted panel sequencing approach finds one of the disease loci and doctors conclude that the patient has an unusual presentation of the Mendelian disorder associated with that gene. It would be interesting to sequence the exomes of patients described in the literature as unusual cases of a particular disorder, Plon suggested, and see how many of them in fact harbor mutations in a second disease gene.

Finding all disease-related mutations in a patient is important, she said, because it can affect his or her clinical management. In one patient, for example, the researchers found a mutation in the RECQL4 gene, leading to a diagnosis of Rothmund-Thomson syndrome, which is associated with a sun-sensitive skin rash, cataracts, and an increased risk of osteosarcoma. The same patient also had a mutation in the XPC gene, resulting in a diagnosis of xeroderma pigmentosum, which leads to multiple skin problems, a very high risk of skin cancer and melanoma, and eye irritation.

Patients with RTS are screened for osteosarcoma, which would not happen if this patient had only been diagnosed with XP. On the other hand, XP patients are advised to avoid all UV exposure and they receive dermatologic screening, which would not be the case if the patient had been diagnosed with an unusual form of RTS.

Given the frequency of dual diagnoses, researchers and clinicians should keep this possibility in mind, Plon said, noting that current analysis pipelines have a tendency to look for a single answer, and gene panel testing usually stops after there is a hit.