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ACMG Talk Spells Out Details of Medical Exome Project

NASHVILLE, Tenn. (GenomeWeb News) – Researchers from the Children's Hospital of Philadelphia, Harvard University, Massachusetts General Hospital, and Emory University School of Medicine provided additional details about their efforts to annotate and target the exome for clinical applications at the American College of Medical Genetics and Genomics annual meeting.

At a morning session here today, CHOP's Avni Santani described the so-called Medical Exome Project and detailed progress made on it so far. She explained that the effort stemmed from a desire to develop a central repository containing accurate information on medially relevant genes that have been carefully curated.

Along with those curation efforts, members of the group are also considering ways of optimizing capture approaches that target that medically relevant gene set. To that end, they have come up with an assay for targeting the gene set and started developing more targeted, ancillary tests for genes that have proven tricky to assess by exome sequencing.

At the moment, Santani noted that gene panels are often preferable for diagnosing cases in which a particular condition with known genetic contributors is suspected, since such tests offer complete coverage of candidate genes.

On the other hand, whole-exome sequencing has started to find favor for those working on complex cases that involve unclear or overlapping phenotypes, though the approach typically produces variable levels of coverage of potential disease genes.

In an effort to bolster that coverage — and the consistency of using exome sequence data in the clinic — members of the Medical Exome Project are bent on more clearly defining medically relevant genes and establishing a framework that allows new disease candidates to be curated as they're detected.

To that end, members of the team started by considering the potential clinical relevance of a wide swath of genes with proven or suspected disease associations using databases such as ClinVar, the Online Mendelian Inheritance of Man, and Human Gene Mutation Database. They are also working with collaborators at NCBI to come up with a freely available, centralized database of curated, clinically relevant genes.

On the application side, meanwhile, members of the group have developed an exome capture kit that provides enhanced coverage of the 4,631 genes with known or potential medical relevance.

As reported in Clinical Sequencing News earlier this month, the Emory Genetics laboratory has started offering clinical exome sequencing based on the enhanced medical exome targeting approach.

Santani emphasized that the Medical Exome Project is intended to complement other ongoing efforts to clinically annotate the genome and exome.

During another presentation in the same ACMG session, for example, Emory University geneticist Madhuri Hegde discussed the progress being made by members of the ClinGen consortium who are working to curate medically relevant variants in NCBI's ClinVar database.

Hegde noted that a sequence variant working group within ClinGen has been not only defining standards for classifying variants and delving into apparent disease associations, but also collaborating with NCBI to share clinically annotated variants and relevant genotype and phenotype information through ClinVar.

At the moment, ClinVar includes information from nearly 100 groups that have submitted data on some 71,000 variants. That tally is climbing regularly, according to Hegde, who said that ClinGen members are continuing to solicit labs to submit additional variants and phenotypes.

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