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Centogene Enters Clinical Whole-Genome Sequencing Market for Rare Disease Diagnostics

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NEW YORK (GenomeWeb) – German genetic diagnostics firm Centogene is betting on whole-genome sequencing for improving the interpretation of genetic variants in patients with rare genetic disorders.

Last week, the company said it installed Illumina's HiSeq X sequencing platform at its clinical laboratory in Rostock in the Northeast of Germany in order to provide diagnostic whole-genome sequencing services.

The driving force behind the decision to expand from clinical exome sequencing, which Centogene has been offering since 2014, to whole-genome sequencing was the potential to improve the clinical interpretation of genomic data, according to CEO Arndt Rolfs.

The same genetic variant can be pathogenic or neutral in individuals with different ethnic backgrounds, for example, and "if you take this into consideration, the more genetic information you can get, the better the interpretation in the end," he told GenomeWeb. "And the most perfect tool for genetic information is for sure the genome."  

Getting an accurate molecular diagnosis for rare genetic diseases early has become more and more important in recent years, he said, at least in certain disease areas where new treatments with orphan drugs are now available. In the past, it did not make a difference what particular gene mutation a patient had because it did not change the treatment, he said, but over the next five years or so, the number of orphan drug treatments for which the nature of a genetic mutation may be relevant is expected to grow, so "it's absolutely clear we have to diagnose the patients much earlier."

Centogene, which started in 2006 as a spinout from the University of Rostock and is privately funded, has run tens of thousands of clinical genetic and biochemical tests, and the company offers its services in more than 100 countries. Much of its business comes from the Middle East, Rolfs said, where the frequency of genetic diseases is high due to consanguinity, but it is also very active in Latin America, Canada, and Europe.

This summer, Centogene opened a small business unit in California and now offers most of its diagnostic test portfolio in the US, with the exception of a number of gene tests that are protected by US patents.

The firm has amassed genotype and phenotype data from more than 100,000 consented and anonymized patients in a database called CentoMD, which it started providing to healthcare professionals on a pay-per-use basis last year. Last month, the company published a description of CentoMD in Molecular Genetics & Genomic Medicine.

Version 3.1 of the database, which was released in September, covers more than 2,500 disease genes, and each genetic variant is linked with demographic and phenotype information from associated patients. More than half of the clinically relevant variants or variants of uncertain significance in the database are novel, according to the paper, and 3 percent of variants that had previously been called pathogenic by others were reclassified by the company as clinically irrelevant.

Because genetic and clinical data are linked in the database, it can be used to search for common genetic patterns among patients with the same clinical diagnosis, Rolfs said, adding that this could lead to the discovery of new disease genes, which is valued by pharmaceutical companies in particular.

Rolfs said that the company has applied to the US Food and Drug Administration for 510(k) clearance of CentoMD and hopes the agency will make a decision early next year.

Centogene has installed and validated the first four of an initial five HiSeq X machines that will be placed in its clinical laboratory, which is CLIA-certified and CAP-accredited. It plans to offer its clinical whole-genome sequencing test, called CentoGenome, within the next few weeks, and the plan is to bring in another five HiSeq X instruments in the spring, Rolfs said.

The main indications for CentoGenome, which will have turnaround times between 20 and 25 business days, will be heterogeneous diseases that can be caused by hundreds of genes and disorders that involve a greater-than-average number of intronic mutations, which are difficult to address by exome sequencing. Such disorders include intellectual disability, epilepsy, and cardiomyopathy, Rolfs said.

The company also plans to offer two prenatal versions of CentoGenome, which will have turnaround times of 10 business days. In addition, it intends to start offering noninvasive prenatal fetal trisomy testing in early 2017 using another Illumina platform, Rolfs said, which will mark the firm's entry into cell-free DNA testing.

In addition to inherited disease testing, Centogene plans to offer the CentoGenome test for somatic tumor profiling, starting in the first quarter of 2017.

Overall, the whole-genome sequencing test will be about three times more expensive than the firm's CentoXome exome sequencing test, which the company offered last year at prices between €1,500 ($1,600) and €4,000 ($4,200), depending on the version.

However, the diagnostic sensitivity of the genome test is expected to be about 15 to 20 percent higher than that of the exome test, Rolfs said, largely because it includes intronic and promoter mutations.

Last month, Centogene published results for 2,189 diagnostic exome sequencing tests from 1,000 families that were conducted in its laboratory in the European Journal of Human Genetics. It was able to identify pathogenic or likely pathogenic variants in 31 percent of families and variants of unknown significance in another 25 percent.

Rolfs said the company has analyzed approximately 25,000 exomes so far and hopes to sequence on the order of 20,000 genomes by the end of next year.

In addition to solving more patient cases, Centogene is interested in expanding its CentoMD database with the genome and clinical data it gleans from those patients. "The genome feeds our databank, for sure, much more efficiently than the exome or single genes," Rolfs said.

One reason why the company has hesitated up until now to expand to the US market, he added, was that it is more interested in growing its database with patients from non-European ethnicities. "The knowledge, the understanding we're gaining from 100 samples from Japan is dramatically higher than repeating what is mostly already known [from] European or Caucasian [samples]," he said.

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