A Morbid Map
In October 2009, Loydie Jerome-Majewska and her husband Jacek Majewski made a bet: which of them would be the first to identify the gene that causes Van Den Ende–Gupta Syndrome (VDEGS)? Gene mapping of four patients with the rare genetic disorder had narrowed the search to a region of chromosome 22, but the guilty gene eluded them.
“It was actually quite a race,” recalls Jerome-Majewska, a developmental geneticist at the McGill University Health Centre in Montreal. She used knowledge of the genes in the chromosomal region that she’d acquired from her genetic experiments with mice to pick likely candidates. Her husband used a powerful new technique known as exome sequencing, which takes just a fraction of the time and cost of whole-genome sequencing to sequence only the protein-coding regions—less than 5 percent of the total human genome. By January, Jerome-Majewska confirmed her suspicion that the culprit was a gene called SCARF2, expressed in the developing structures of the jaw and face. Two months later, Majewski’s sequencing studies revealed the same result—mutations in SCARF2 led to VDEGS. Jerome-Majewska had won the bet.
She enjoyed the spoils—a pint of beer at the local pub—not only because she had bested her husband, but also because the duo had successfully identified the genetic underpinnings of such a rare disorder as VDEGS. It was the first triumph of RaDiCAL (Rare Disease Consortium for Autosomal Loci), a project launched by David Rosenblatt, chair of the human genetics department at McGill, to construct what he calls a “morbid map.” He wanted to identify the genes responsible for more than 1,400 rare diseases with unknown genetic causes.
Results of RaDiCAL and similar initiatives will not only benefit afflicted families—in terms of both diagnoses and potential therapies—but may hold insights for more common diseases as well, says medical geneticist Jan Friedman of the University of British Columbia. “The genes that are involved in rare diseases often turn out to be the same genes that are involved in milder mutations in more common diseases,” he says. “By understanding that gene [involved] in a rare disease, you understand the more common disease and can provide a potential therapeutic target.”
Pinpointing the genetic roots of rare diseases may also provide insight into the basic functions of human genes, added developmental geneticist Mark Samuels of the University of Montreal. Though the entire human genome has been sequenced, less than 15 percent of the nearly 25,000 genes have a known function, he says. “One way to find out what a gene does is to figure out what happens when it’s broken.” By identifying severe phenotypes, researchers can go gene by gene, and figure out what happens if one is missing or mutated.
Download Flash player to Hear McGill University’s David Rosenblatt discuss his motivation for starting the RaDiCAL project and his goals for its future
The limiting factor for RaDiCAL’s success, Rosenblatt realized, was getting enough patients. Rare disorders are, after all, rare. They are also usually recessive, meaning that in order to develop the disease, patients must have two mutant copies. Knowing that such diseases are more common in parts of the world where interfamily marriage is common, he turned to an old friend, Ahmad Teebi, who had recently set up clinical services in Qatar. Rosenblatt wrote to Teebi, asking if he had encountered any patients with diseases that might be of interest for the project.
Sure enough, clinical morphologist Teebi of Weill Cornell Medical College’s Qatari campus had seen a handful of patients with a bizarre disorder characterized by distinctive malformations of facial and other bones. The disease turned out to be VDEGS. Teebi shipped over some DNA samples, and Majewski and his colleagues set to work.
With cheaper sequencing technology now available, many other scientists are helping to identify the genes responsible for severe phenotypes—and to annotate the entire human genome. Genome Canada and the Canadian Institutes of Health Research (CIHR), for example, recently launched a nationwide exome-sequencing effort to map the coding regions in the genomes of patients with rare diseases—an initiative that includes the McGill research institute. “There was so much enthusiasm we were able to gather hundreds of potential cases and geneticists in a very short period of time,” Friedman says. “We hope to sequence a fairly large number of rare diseases using this exome high-throughput sequencing technology.”