Aiming to provide more personalized treatment options for patients with monogenic diabetes, the University of Chicago Genetics Services Laboratory has launched a next-gen-sequencing-based gene panel to diagnose the disease.
Monogenic diabetes represents an estimated 1 to 2 percent of all diabetes mellitus cases. To date, more than 30 genes, which are highly expressed in pancreatic beta cells, have been implicated in the disease, a list that keeps growing.
Several phenotypes suggest the presence of monogenic diabetes, including neonatal diabetes; maturity-onset diabetes of the young, or MODY; and rare diabetes-associated syndromes.
According to Daniela Del Gaudio, associate director of the Clinical Molecular Genetics Laboratory at the University of Chicago, who helped develop the panel, it has been a challenge to provide patients with molecular diagnoses because the disease is genetically so heterogeneous. However, determining the exact gene defect is important "as it can have a dramatic effect on the treatment a patient should receive."
For example, the most common causes of neonatal diabetes are mutations in one of two potassium channel genes, and patients that have these "can be effectively treated with oral sulfonylurea drugs rather than insulin, resulting in dramatically improved quality of life and control of diabetes," she said.
Also, MODY patients with mutations in certain genes respond to oral sulfonylurea, as well, so they can avoid having to inject insulin. Moreover, some forms of MODY are mild and only come to light during routine check-ups, and if a specific gene is found to be mutated, doctors may recommend no treatment at all, or just changes in diet.
Finally, if the mutation is inherited, a molecular diagnosis can help provide genetic counseling to the family.
The gene panel, which Del Gaudio presented at Hanson Wade's NGS Translate conference in Cambridge, Mass., last week, has been available since May 15 and includes 31 genes, of which 26 are analyzed routinely, and five are only looked at if patients are suspected to have a syndromic form of diabetes.
The lab did not include the four most common genes involved in monogenic MODY – HNF1A, HNF1B, HNF4A, and GCK – "due to restrictive licensing conditions imposed for testing on these genes," according to the information sheet describing the test.
Athena Diagnostics holds patents to these genes, and Del Gaudio said it is up to physicians to have patients tested for them first and then refer them to her lab for the panel if the results are negative. As the patents expire – starting this June – the lab plans to add them to its test, along with other genes that may prove to be causative for the disease.
Other labs have apparently taken a license to Athena's MODY genes: for example, GeneDx offers a next-gen sequencing panel for the four genes, as well as one other gene. That test also includes targeted array CGH analysis of the HNF1B gene.
According to Del Gaudio, genetic testing for monogenic diabetes is currently only available for the most common forms of MODY and neonatal diabetes, and only from a few diagnostic laboratories in the US, most of which offer Sanger-based gene-by-gene testing. "The current testing is really not comprehensive," she said.
Her lab's test, called Neonatal Diabetes Mellitus and Maturity-Onset Diabetes of the Young Sequencing Panel, has a list price of $3,900 and a turnaround time of 8 to 10 weeks. The lab also offers an 11-gene panel for lipodystrophies, a somewhat related condition that comes with a loss of adipose tissue and insulin resistance, which has a list price of $3,500 and the same turnaround time.
The lab does not currently bill insurance for these tests – Del Gaudio said they are either covered "under institutional billing" or patients pay out of pocket.
The tests use Agilent's HaloPlex target enrichment system to capture and amplify the coding regions and splice junctions of the genes, which are then sequenced on Illumina's MiSeq and analyzed using an in-house-developed and validated bioinformatics pipeline.
All novel or potentially pathogenic variants are confirmed by Sanger sequencing, and regions that are found to be covered at less than 15x by HaloPlex/Illumina are also filled in with Sanger. Variants are manually reviewed and interpreted prior to reporting.
So far, the lab has tested about 20 patient samples and plans to add another 20 for a study of the clinical utility of the test, which it hopes to complete by the end of this year.
While the panel is not the first next-gen sequencing test offered by the laboratory – it also provides NGS tests to diagnose several pediatric neurologic diseases, brain malformation syndromes, and intellectual disability – it is the first that uses the HaloPlex enrichment method.
Del Gaudio said the lab is currently evaluating whole-exome sequencing for clinical testing. However, for relatively small panels like the one for monogenic diabetes, "we feel that a more focused, targeted approach represents a better testing option since it offers the advantage of achieving complete sequence coverage of all regions of interest as opposed to whole-exome sequencing where sequence coverage of the genes of interest will inevitably remain incomplete," she said.