Webpage helps identify rare disease

Stephanie and Owen Reimer, a Mennonite couple in rural Canada, have been sorely challenged by something they’re doing their best to overcome. Three of their boys died before or shortly after birth from a rare disorder, apparently genetic in origin. Their one child is healthy. They’d like to have another.

Until recently, people like Stephanie and Owen had nothing to go by when planning to get pregnant again. The origin of disorders such as theirs defied definition, and so prenatal testing for the culprit gene was out of the question.

Now, a first-of-its kind web portal is allowing clinicians and geneticists around the world to match unusual symptoms with known mutant genes, and to provide firm counseling to patients in search of answers.

Phenome Central is a collaborative project of Care for Rare Canada and Australia, the US National lnstitute of Health’s Undiagnosed Diseases Program, and RD-Connect, in Europe. Officially launched on February 28, 2014, the web repository compiles anonymized case data on rare diseases, enabling clinicians with only their own case to go by to connect with others who’ve been dealing with something similar.

Pinpointing the gene

An estimated 350 million people suffer from some 7,000 rare genetic and metabolic disorders, many linked to a single faulty gene. Clinicians might stumble across one of these once in their lifetime, and have no idea what they’re dealing with.

To identify the origin of an apparent genetic disorder, a causative mutant gene has to be pinpointed. With the advent of ultra-rapid or “fast throughput” genome sequencing technologies, our ability to peer into a genome and pick out rogue genes has advanced by leaps and bounds.

Confirming a genetic disorder’s identity also hinges on establishing its key signs and symptoms – it’s “phenotype.” In the past, phenotypic descriptions have been hindered by the unsystematic and sloppy terminology of attending clinicians.

“We would get one line of text describing it, which was full of abbreviations, full of typos, and really impossible for a computer to understand,” recalls Dr. Michael Brudno, a University of Toronto bioinformatician who set out to compile complementary sets of genotypic and phenotypic data within a single algorithm – Phenome Central.

“As a human I could make it out, but as soon as I tried to develop an algorithm which tries to match the genotype to the phenotype, I need the computer to understand the phenotype. And having a completely nonsensical line of text does not cut it. So what we started doing is trying to figure out how can we enable clinicians to capture phenotypes precisely.”

Data matching

The solution to Brudno’s problem was an “ontology” or standardized vocabulary of phenotypes developed by a group of computational biologists at the Institute for Medical Genetics and Human Genetics in Bonn, Germany. Matched with precise gene sequence data, the institute’s Human Phenotype Ontology makes it much easier for identical cases of a genetic disorder – and their attending clinicians – to be brought together.

Improved patient counseling is another welcome outcome.

Counseling can be in the form of advice to the couple,” says Michael Brudno. “Well, if you have kids from now on, this is the likelihood that they will also develop this disease; this is the kind of testing we can offer you if you do decide to have more kids, to figure out prenatally whether your kids are going to be developing something like this, so that you can better plan your family.”

For couples like Stephanie and Owen Reimer, in Canada, counseling has brought a certain degree of closure. The disorder that affected three out of their four pregnancies now has a name: HARMS – a memorable acronym of the disorder’s four key phenotypes: hydranencephaly, renal dysplasia, multinucleated neurons and syndactily.

With any luck, Phenome Central will help identify other cases of HARMS, wherever they are in the world, for the benefit of affected families and their physicians.

For the Reimers, beating the odds on a fifth pregnancy, while reconciling technology and faith, are questions foremost in their minds.