Genetics experts at The Children’s Hospital of Philadelphia have developed a unique test to characterize the genes that encode HLA molecules. Relying on gene sequencing to type human leukocyte antigens (HLAs) — complex proteins that are essential to immune function — the new test has the potential to improve transplantation outcomes through refined donor compatibility assessments, and will expedite the donor selection process from bone marrow registries.
“This new test addresses a sixty-year-old problem,” said Dimitri Monos, PhD, director of the Immunogenetics Laboratory in the Division of Genomic Diagnostics. “Since the discovery of HLAs in the early 1950s, it has been a challenge to accurately and thoroughly characterize HLA gene sequences. We have now used next-generation sequencing tools to significantly advance HLA typing.”
The test also provides an advanced tool for research in immunological diseases, infectious diseases, and pharmacogenomics — the field that studies the influence of genetic variations on drug efficacy and toxicity. Children’s Hospital is the first hospital to offer this new comprehensive HLA typing test.
“This is a new, disruptive technology, with the potential to transform research and clinical practice, in transplantation and other fields,” said Robert Doms, MD, PhD, CHOP’s pathologist-in-chief.
HLA genes are the most complex gene family known in the entire human genome, and their sequences are highly variable, to a degree not adequately captured by conventional typing tests. Current tests often provide ambiguous and limited results, by sequencing only segments of HLA genes and failing to distinguish among different alleles suggested by a given sequence. In addition, preliminary testing often must be followed by a second level testing, adding expense and time to the HLA typing process.
The new test, says Dr. Monos, is a single test that provides the highest resolution possible by covering the full HLA genomic region. It can currently distinguish among 10,500 different alleles of all known HLA types and can fully characterize new alleles yet to be discovered. The researchers validated the test by comparing its results against previously sequenced data from a collection of over 300 samples characterized at five different genes.
CHOP will be offering the HLA typing test for patient testing as a service to medical and academic centers. The test is faster, more precise, and costs less than existing testing procedures. The new test’s most significant short-range impact may be in typing donors in bone marrow/stem cell registries.
“This faster, more thorough technology allows us to better account for subtle genetic differences between individuals,” said Dr. Monos. “We expect this knowledge to yield clinical benefits, by facilitating more precise matches between transplant donors and recipients, and assessing the significance of mismatches in genomic regions of the HLAs that were previously uncharacterized.”