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ACMG: Initial Exome Analysis Does Not Always Yield Right Answer, Emory Researchers Find

SALT LAKE CITY (GenomeWeb) – The initial analysis of exome sequencing data does not always provide the correct diagnosis and the exome is "always worth a second look," according to researchers from Emory Genetics Laboratory.

During a talk at the American Society of Medical Genetics and Genomics annual meeting here yesterday, Madhuri Hegde, a professor at Emory University School of Medicine and the executive director of its genetics lab, reported two case studies that illustrate how researchers can initially be led astray in their interpretation — for example, by relying on incorrect data from the literature, or because a patient is mosaic for a disease-causing mutation — but eventually find the true pathogenic mutation by using different test methods or repeating the exome test in a different sample.

Careful reanalysis and reinterpretation of exome data can also improve the diagnostic yield of exome sequencing beyond the current yield of less than 30 percent, she said.

The first case she described involved a 12-year-old girl with retinal dystrophy, diminished cognitive functions and other symptoms who underwent exome sequencing at Emory Genetics Laboratory. The data revealed a likely pathogenic variant in exon 3 of the ARID1B gene, which was reported because other pathogenic mutations in this gene had been reported before. However, it turned out that the patient's mother carried the same change in exon 3 without having the disease, and that the published transcript of the ARID1B gene used by clinical laboratories for interpretation was probably incorrect. A subsequent microarray identified a deletion involving exons 7 and 8 in the CLN3 gene, and going back to the exome data, the researchers found that these exons actually had poor coverage but the deletion was hard to pick up.

The second case Hegde presented was that of an 11-year-old boy with developmental delay, hydrocephalus, and other symptoms. Exome sequencing identified a variant of unknown significance in the L1CAM gene, which had been reported as likely disease-causing in another patient and had not been found in the general population. However, the mutation did not explain all the clinical symptoms, and the researchers suspected that the patient may be mosaic for another mutation, so they proceeded to sequence his exome in DNA from a skin biopsy sample. Indeed, they found a known pathogenic mutation in the PIK3CA gene that was present in a fraction of the skin sample. The same mutation could not be detected in the original exome, which was obtained from a blood DNA sample, or in any family member.

While the original exome did not yield the correct answer in these two cases, in others a reanalysis of the exome data can lead to the right diagnosis because new disease-causing variants are constantly being published, Hegde said. Her laboratory reanalyzes all exome cases on a monthly basis, checking them against a list of newly published pathogenic variants, she said, or in response to physicians asking them to re-evaluate certain variants in light of new evidence.

Interactions between the clinical team and the analytical team is "extremely important" for these reanalyses, she added.