Rare Genetic Disorders

William’s Mum, Pauline

Special Series: You & Your Genome

Needles in Genomic Haystacks

By David Kattenburg

Stephanie and Owen Reimer, a Mennonite couple in Steinbach, Manitoba, have been sorely challenged by something they’re striving to overcome.

Three of their boys died before or shortly after birth from a rare disorder, seemingly genetic in origin. Their one child — a boy — is healthy. They’d like to have another.

Until recently, folks like Stephanie and Owen had nothing to go by when planning a new pregnancy. The origin of disorders such as theirs defied definition; the probability of it happening again defied prediction. Prenatal testing for a putative 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.

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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, the web site 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.

An estimated 350 million people suffer from some 7000 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.

Dr. Cheryl Greenberg

Dr. Cheryl Greenberg

Such was the case Dr. Cheryl Rockman-Greenberg encountered fifteen years ago, in the form of a Winnipeg boy named William. “I remember him very well,” recalls Greenberg, head of the Department of Pediatrics and Child Health at the University of Manitoba, and Medical Director of the Child Health Program at Winnipeg’s Health Sciences Center. “I remember seeing him as an infant. “He had some unusual features, which in genetics is kind of a flag that you should do more genetic studies.”

Through Canada’s Care for Rare network, Greenberg has pursued a definitive diagnosis of young William’s condition. “If we have children with undiagnosed genetic or metabolic syndromes that we feel are likely single-gene, the ability to make a diagnosis through whole exome sequencing, or rapid throughput sequencing, will allow us to be very precise; not just what the diagnosis is, but what is the pattern of inheritance.”

William's proud mum, Pauline

William’s proud mum, Pauline

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

Dr. Michael Brudno

Dr. Michael Brudno designed the Phenome Central portal

“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.”

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.”

Dr. Patrick Frosk

Dr. Patrick Frosk

This is the sort of counseling Stephanie and Owen Reimer received, following the discovery of “their” rogue gene by Winnipeg clinical geneticist Patrick Frosk.

With the aid of Zebra fish (easy to study, because they’re transparent), Frosk isolated the recessive allele on Stephanie and Owen’s #10 chromosomes, and gave the disorder it causes a name: HARMS – a memorable acronym of its 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.

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