While the growing use of whole genome sequencing is expanding the ability to diagnose patients with rare diseases, the lack of knowledge about the mutations that underly these conditions remains a barrier to diagnosis.
Studies from the Center for Mendelian Genomics, Deciphering Developmental Disorders, and the Undiagnosed Disease Network report they have found causal variants in 20 to 40 percent of the cases they investigate. Most cases, though, remain unsolved.
Part of the problem is that some rare diseases may be so rare that there isn’t enough scientific experience with a condition to zero in on the causal variant of an individual patient. Though a given patient may have a disorder caused by a single gene, it is likely hidden in a genome containing hundreds of genetic mutations.
Researchers at European Molecular Biology Laboratory’s European Bioinformatics Institute and Queen Mary University of London have hit upon a clever approach to narrowing down culprit genes. In a study in Nature Communications, researchers report on an approach for identifying genes likely to be causal of rare diseases.
It’s much easier to find a disease-causing mutation if it has a known association with a rare condition. But in cases where the genetic variant may not be known to be disease causing, matching genotype to phenotype can be like looking for the right strand of hay in a haystack.
In the Nature study, the researchers compared knockout mice viability and phenotyping data from the International Mouse Phenotyping Consortium with human cell lines provided by the Broad Institute’s Project Achilles to create categories depending on how crucial a gene was shown to be to producing viable life.
“Loss of gene function is often referred to as a binary concept; lethal or viable,” said Violeta Muñoz-Fuentes, biologist, Mouse Informatics at European Molecular Biology Laboratory’s European Bioinformatics Institute. “In this study, we show that gene essentiality is more of a spectrum ranging from cellular lethal, developmental lethal, subviable, viable with a visible phenotype, and viable without a visible phenotype.”
The scientists categorized 3,819 genes to create an open access database that can be used to help researchers and provide clinical insight. The genes were categorized into one of five categories. The category of greatest interest to rare diseases was the one dubbed “development lethal,” which includes genes that are not essential for survival but are required for organism development.
The researchers found a strong correlation between genes necessary for mammalian development with genes associated with human disease, particularly early-onset, multi-system, autosomal dominant disorders.
“We demonstrate that the set of genes that are essential for organism development is particularly associated with known human developmental disorders,” says Damian Smedley, reader in Computational Genomics at Queen Mary University of London. “This provides candidates for undiscovered causative genes for these conditions.”
After identifying a set of genes essential for development, the researchers focused on unsolved diagnostic cases from three large rare disease sequencing programs to demonstrate their ability to identify suspect variants that correlate to undiagnosed cases.
In fact, several candidate genes identified in the study have been added to the open access resource GeneMatcher, which researchers and clinicians use to share gene information.
There’s a logic here. Essential genes tend not to be associated with human disease because mutations in them likely cause miscarriages or early embryonic death. If you want to find the cause of a developmental disorder, there’s a case to make that the best place to look for it is among genes that play a role in development. By helping to identify this set of genes and pointing a way to further identify other such genes, the researchers have provided a means to crack unsolved rare disease cases and advance patients toward a diagnosis.