Duke Health

Researchers from the Duke University Medical Center and colleagues at Johns Hopkins discovered two gene mutations that cause metachondromatosis. They combined whole-genome sequencing technology with classic genetic approaches in order to lower inherited diseases. They sequenced the entire genome of particularly just one individual.

Rare and traditionally inherited diseases were examined using a method called linkage where a small number of markers are assessed for co-inheritance with the disease. Researchers share that in many cases this method was successful but very lengthy. It has been unsuccessful in as many as 1,500 studies where the presence of a gene inherited in Mendelian fashion is alleged but not identified.

David Goldstein, PhD, director of the Center for Human Genome Variation at Duke elucidates that his team observed mutations that cause metachondromatosis; this enabled quick recognition of Mendelian genes. However this may enable to spot a lot of Mendelian genes that were difficult to examine using traditional methods.

Nara Sobreira, a graduate student in human genetics at Hopkins and a lead author of the study, mentioned to Goldstein that she was examining a family that included six individuals across four generations affected with metachondromatosis. Researchers selected one member of the family and sequenced the entire genome of the person. In order to examine areas in the genome where potentially contributing alterations were likely to be identified, they used information from partial linkage data from other family members. The analysis covered six possible regions affecting about one percent of the total genome. Goldstein suggests that sequencing this genetic material using traditional means would be a taxing job.

In order to identify a tiny string of 11 base pairs deleted from exon four of a gene called PTPN11 researchers used whole genome sequencing. All members of the family affected with metachondromatosis carried this alteration. They found an unusual change in the same gene in a second family with a history of the disease that was also identified in those with the disorder. Due to this scientist confirmed PTPN11 modification as the main cause of the disease. Both changes highlighted the inability of the body to form a protein that is useful for normal development.

Researchers sequenced exon 4 of PTPN11 that is the site of casual mutation in 469 distinct controls; however they did not observe any changes in the gene in that group. Elizabeth Cirulli, a graduate student at Duke, a lead author and a member of Goldstein’s team shares that this is the first time that irregular changes in PTPN11 have been observed in humans. They would further identify how these changes enhance the development of metachondromatosis.

Goldstein reveals, “The fact that linkage evidence was able to narrow our search for variants to just a fraction of what it might otherwise have been, cut our research time considerably. He says that one interesting feature of this research is that the initial linkage evidence was only modest, approaching the sort of linkage evidence sometimes seen in large, multiple families for common diseases. “We are therefore hopeful that this sort of family-based sequencing might have utility in the research of genetic variants involved in more common diseases.”

Molecular basis of other disease like Maffucci syndrome and Ollier’s disease may be revealed by identifying the gene that causes metachondromatosis. Similarity in physical features was observed among individuals with these diseases and those having metachondromatosis. In addition Goldstein says that this research adds to a small but significant example where whole-genome sequencing approaches have effectively observed rare, high-penetrant risk factors for disease.

Penetrance is a method of identifying how potent a mutation is in causing disease. Metachondromatosisis is a rare heritable disorder that causes bony growths particularly on hands and feet.