Skip to main content
Premium Trial:

Request an Annual Quote

Exome Sequencing, not WGS, May ID Causative Mutations in Vast Majority of Mendelian Disease


NEW YORK (GenomeWeb) – With more than 12,200 exomes sequenced, the three Centers for Mendelian Genetics funded by the National Human Genome Research Center have identified novel genes causative of more than 200 disorders and continue to provide evidence that exome sequencing, not whole-genome sequencing, is the more efficient tool for studying Mendelian disease.

In a presentation last week, Richard Lifton, who chairs the department of genetics at Yale University, said that there are very few cases where evidence points to the causative mutation lying outside of the protein-coding region, and as such, "we'll have to be somewhat selective in how we deploy whole-genome sequencing." In addition, he said that there is evidence to suggest that each of the 22,000 human genes may be associated with a single-gene disorder.

Lifton made his remarks during a webcast presentation last week at the National Advisory Council for Human Genome Research meeting.

In 2011, the NHGRI provided $40 million in funding and the National Heart, Lung, and Blood Institute provided $8 million in funding over four years to the Mendelian Disorders Genome Centers at Yale, the University of Washington, and a combined center at Baylor College of Medicine and Johns Hopkins University.

Last year, PIs from the three centers told Clinical Sequencing News that the centers collaborate on analysis and bioinformatics strategies, and work closely to ensure that there is little overlap. The groups implemented a web portal and online repository for their collaborating researchers to input phenotyping information and link to biological materials that they want the centers to analyze.

During last week's presentation, Lifton said that the centers have thus far collaborated with more than 400 investigators from 25 countries, and the level of collaboration varies between groups. Some collaborators simply want the exome sequencing data and they do the rest of the work, Lifton said. Others are more clinically oriented with less genomics expertise and approach the center with an interesting cohort or groups of families with unique phenotypes, and the center then takes on much of the analysis and follow-up work, he added.

One major lesson that has been learned is the importance of good phenotyping, Lifton said. "People who have been successful in identifying interesting families that have novel genetic disorders are very likely to come to you with interesting [cases] that will yield interesting results," he said.

In addition, he said that the results thus far suggest a future where it may be possible to "determine the consequence of mutation in every gene in the genome."

For instance, in looking at the data from the first 2,000 cases that have been sequenced, the researchers found a new gene with a homozygous loss of function mutation in around 1 out of 18 subjects. When narrowing that analysis down to the offspring of first cousins there is a loss-of-function homozygous mutation in "almost every patient we sequence," Lifton said, illustrating that there "is clearly a path there that suggests a way to try to identify mutations in every gene in the genome."

Lifton added that while 15 percent to 30 percent of genes are thought to be embryonic lethal and as such no phenotype will ever be associated with loss of function mutations to those genes, for the remainder of the genes, the sequence data thus far suggests that a loss-of-function mutation may be associated with a specific genetic disorder and phenotype. Thus far, around 3,000 to 4,000 genes have been linked to Mendelian disorders, leaving "an awful lot of genes that have not been accounted for," he said.

"Of course, the challenge is that many of the phenotypes will only be displayed if you're in the right environment," he added. And as such, it is important to sequence the right individuals. "If you sequence healthy individuals, you're going to have a very difficult time appending a phenotype to those loss-of-function mutations should you find them. So, my personal bias is to start with individuals who have a significant medical illness, preferentially, those who are not already carrying an obvious diagnosis."

Extreme phenotypes, especially in individuals from consanguineous unions, will be especially "fertile ground" for identifying new genetic loci, he said.

The researchers are also discovering that some traits are extremely heterogeneous, Lifton said. For instance, the three centers have sequenced around 1,000 individuals with congenital malformations of the brain and have identified around 70 new genes, very few of which are recurrent.

Another important mechanism for several congenital diseases has been haploinsufficiency due to de novo mutations, Lifton said, which appears to play a role in congenital heart disease, kidney development, and autism.

Moving forward, Lifton said that exome sequencing will continue to be an important tool in identifying the cause of exome sequencing, even though some institutes are already moving into whole-genome sequencing.

For instance, both the Medical College of Wisconsin and Partners HealthCare offer clinical whole-genome sequencing. MCW's Howard Jacob has been an especially vocal proponent of whole-genome sequencing over exome sequencing. At a conference earlier this year, Jacob said that of 25 patients at MCW that had both exome and whole-genome sequencing done at 100x coverage and 40x coverage, respectively, exome sequencing missed 212 actionable variants. Whole-genome sequencing only missed three. In addition, he said that whole-genome sequencing is able to make a diagnosis 25 percent more often than exome sequencing, not only because whole-genome sequencing identifies mutations outside of the coding region, but also because exome capture often poorly covers some protein coding regions.

Lifton is not opposed to whole-genome sequencing, but said that for the time being exome sequencing is a more economical choice. At Yale, he said the total cost of exome sequencing is around $500 per exome. Nonetheless, for select cases, he is excited to move into whole-genome sequencing.

For the cases where "we think we've excluded the obvious mutations in genes and we're left with nothing, we think whole-genome sequencing is the obvious thing to do," he said.