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(April 11, 2002, Gazette)

Cause of mild hemophilia A identified
Tracking a genetic mutation

Hong Zheng (front) with Dr. Yangyang Xie

Photo by HSIMSHong Zheng, (front) a visiting scholar from Hunan Medical University, Zhengzhou, China, is working on mild hemophilia A research with Dr. Yangyang Xie, director of the Molecular Genetics Laboratory.

Dr. Yangyang Xie is a quiet man with an intense devotion to his work as a molecular geneticist. He has good reason to be proud of what he’s accomplished since arriving in St. John’s in 1998 to accept a position as director of the Molecular Genetics Lab and a faculty member in medicine. After just a year’s search, he was instrumental in identifying the genetic mutation for mild hemophilia A in a central Newfoundland population.

Hemophilia A is a bleeding disorder characterized by easy bruising, nosebleeds, bleeding into muscles and joints, delayed bleeding after surgery or dental extraction, and sometimes internal bleeding. Some carrier women are known to have a bleeding tendency as well, such as heavy periods or post-partum hemorrhage.

The high incidence of hemophilia A in central Newfoundland has long been known, and unfortunately attracted the attention of outside researchers who came in and took blood samples, but never produced any results. “The local residents and physicians were angry and refused contact with the Health Care Corporation, even though it was not that organization that took the samples,” explained Dr. Xie. “So when we went to investigate the disease we had to win over the community.”

From the beginning, Dr. Xie committed himself to presenting research results every six months. “I told people there that we are a Newfoundland team and we would convert our research findings into clinical services.” Together with hematologist Dr. Mary Frances Scully, genetic counselor David MacGregor, nurse co-ordinator Marilyn Harvey, and other support staff, that promise has been kept.

Finding the actual gene mutation for the Newfoundland variation of hemophilia A began with the hypothesis that it would be a mild mutation resulting in either reduced or abnormal gene product. “We also speculated that because of the high prevalence of hemophilia it was due to the founder’s effect and the isolated geography of the region,” said Dr. Xie, who worked on identifying the gene mutation in collaboration with Dr. David Lillicrap at Queen’s University, Kingston. “A founder effect of the identified mutation has been proved, which explains the higher prevalence of mild hemophilia A in Newfoundland.”

Based on the molecular nature of the identified mutation, Dr. Xie’s team established a simple and quick direct mutation test. “The direct mutation test has been offered as clinical service for the entire province. This enables us to make an early diagnosis for pre-symptomatic patients so that they can have early medical measures to minimize the long-term complications. It also provides a precise diagnosis for atypical patients and allows us to determine the carrier status of women in this population and offer a prenatal diagnosis service in the future.”

The high prevalence of mild hemophila A means about 44 of the 3,300 males in the region have the disease, the highest known population density in the world. Women generally do not have symptoms, but if they have the gene mutation they may pass it on to their children. Clinical histories and genetic counseling have been provided for the families with affected individuals, and family histories from these patients plus a mutation test enabled Dr. Xie and the other researchers to link all affected individuals to one very large kindred comprising more than 1,630 family members spanning 10 generations.

The population screening for the mild hemophilia A mutation had one unexpected result. “We identified another isolated population with extremely high prevalence of mild hemophilia A from rural Labrador, about 14 in 260 males. Patients from this population do not carry the mutation identified in the central Newfoundland area, so it suggests another possible causative founder effect for mild hemophilia in this province.” Dr. Xie has obtained the research funding from the Janeway Research Foundation for a study on the molecular defect of the mild hemophilia identified from the Labrador area.

Financial support for the research on mild hemophilia A in the central Newfoundland area was provided by the Aventis-Behring Canada Research Fund, the Janeway Research Foundation and the Faculty of Medicine. Dr. Xie was recently awarded $100,000 over two years from the Canadian Hemophilia Society for further scientific research.