New mutational scanning method advances genetic understanding of Hemophilia B

According to the World Federation of Hemophilia, Hemophilia B affects nearly 40,000 people worldwide. This condition is a monogenetic disorder, meaning it is caused by a single gene—the Factor 9 gene—which is responsible for producing the protein needed to properly clot blood. 

For decades, physicians and researchers have been trying to answer the question, "What are the DNA changes in the gene that cause Hemophilia B?”

Dr. Jill Johnsen, professor (Hematology and Oncology) is one of those physicians.

“Answering that question has been really hard technically,” she said. “How are we going to interrogate this gene for all the different ways DNA changes might change the protein?”

The rarity of the disorder, one case in 20,000 male births she said, adds to difficulty.

“It’s a rare disorder and often when we do genetic testing, we find a gene change no one has seen before, or a gene change only in seen only a few people,” said Johnsen. “We didn’t have additional evidence, other than identifying a gene that could cause Hemophilia B. These are actionable test results. We really care.”

To help answer these questions, Johnsen and colleagues at the Brotman Bay Institute (BBI) created the first mutational scanning method aimed at secreted human proteins: MultiSTEP. This method allows researchers to examine the protein outside the cell that made it.

“We will be able to tell – with confidence – if this protein is directly related to the DNA change in that cell,” Johnsen said. “This has never been done before to be able to test a lot of changes at once. This is the innovative part.”

That innovation is expected to become a standard for other researchers. The NIH-funded Clinical Genome Resource (ClinGEN), a centralized system regarding the clinical relevance of genes and variants, is expected to incorporate a way to use evidence from Multi-STEP into its rules.