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China's Berry Genomics Runs More than 150K NIPT; Aims to Move into Single-Gene Disorders, PGS

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China's Berry Genomics, a genetic test developer and next-generation sequencing service provider, has evaluated over 150,000 of its noninvasive prenatal tests for fetal aneuploidy and is aiming to develop tests for fetal single-gene disorders and preimplantation genetic screening in the short term and for oncology longer term.

At the JP Morgan Healthcare Conference in San Francisco last week, Berry Genomics CEO Daixing Zhou provided an update on the company. Founded in 2010, the company now has around 600 employees and offers three genetic tests.

It began offering its main test, Bambni, for fetal aneuploidy, in late 2011. The test costs between $400 to $500 and was validated on Illumina's HiSeq 2000, but Zhou said the firm is in the process of switching to the HiSeq 2500.

Berry Genomics also offers a test for chromosomal duplications and deletions, called Chromate, which was originally developed as an invasive test to validate Bambni. Its latest test for which it only recently finished validation in a clinical trial is Chrosure, a single-cell sequencing test for preimplantation genetic diagnosis.

The need for a noninvasive prenatal aneuploidy screening tests in China is high, Zhou said. Currently, serum screening has only about a 25 percent adoption rate in China, he said, compared to 50 percent in the US. One reason for this is the lack of resources, Zhou said. For instance, in one suburban district of China that comprises 11 counties and has a population of 4 million, there is only one prenatal screening facility to cater to the approximately 80,000 new births per year. The facility's annual capacity for serum screening is less than 500, Zhou said.

Additionally, he said, even when serum screening is performed, it has a high false positive rate for aneuploidy, increasing the demand for invasive procedures.

Because the next-gen sequencing-based noninvasive method has a much lower false positive rate, Zhou said introducing such testing will help alleviate the strain on limited resources.

Berry Genomics' Bambni test uses similar shotgun whole-genome sequencing methodology as US firms Sequenom and Verinata Health, but with some key differences, Zhou said. First, the company has an exclusive partnership with Streck, which makes clinical laboratory products, to use its products for sample collection and delivery. Additionally, it has a patent pending, automated library construction method. Sequencing is done on Illumina's instruments, and it uses proprietary bioinformatics dubbed RUPA for mapping and analysis. Zhou said that RUPA enables samples to be processed in 15 seconds on a small desktop server.

Zhou described an analysis of 151,000 tests the company performed. The maternal average age was 31 years, he said. The firm offers its test only to women at high risk, Zhou said, but unlike in the US where the vast majority of women who are at an elevated risk are so because of age, in China only about one-third of women at risk are above the age of 35.

Average turnaround time for the first 50,000 tests was 4.7 days, Zhou said, while the redraw rate and no call rate were one in 573 and one in 4,010, respectively.
From 151,000 samples, 2,072 were positive. Of the positive samples, 1,142 were trisomy 21; 327 were trisomy 18; 50 were trisomy 13; 540 were a sex chromosome aneuploidies; and 13 had another indication. Sensitivity and specificity for trisomy 21, 18, and 13 were all above 99 percent.

The firm then examined its false positives and found that the main cause was mosaicism. Zhou said that the company now uses its Chromate test to analyze every positive case to try and pinpoint the cases that are being called positive due to mosaicism.

Additionally, Berry Genomics conducted an end-user survey and found that 97 percent were either satisfied or very satisfied and only .1 percent were unsatisfied with the test. Of the reasons for choosing the test, 88 percent of users said they chose it because it is safe compared to invasive procedures.

While patients must pay out of pocket for the test, insurance companies in China will provide patients a certain portion of the test's fee if it is a false negative, Zhou said. That serves to relieve some of the financial burden on the patient, while also providing liability protection to both Berry Genomics and the hospital.

Berry Genomics has built up a physician network at around 1,500 hospitals in China to offer its testing services, according to Zhou.

Aside from the Bambni test, Zhou said the company recently finished a clinical trial of Chrosure, which is similar to its duplication/deletion test, Chromate, except that it is applied to single cells, Zhou said.

For Chrosure, the firm uses whole-genome amplification kits from both Qiagen and Rubicon and has developed bioinformatics to normalize the inherent fragmentation bias as well as bias introduced from the amplification. Sequencing is performed on the Illumina MiSeq, and the firm generates between 5 million and 10 million reads per sample. Then it uses a binning approach to call aneuploidies. Each bin comprises around 20 kilobases, and there must be five contiguous bins of either over or under representation, Zhou said, giving the test a 100-kilobase resolution.

Berry Genomics has teamed up with five hospitals to provide the Chrosure test. One such hospital has used BlueGnome's microarray technology for preimplantation screening, and Berry Genomics did a retrospective study of 14 samples. Zhou said that of the 14 samples one was discordant, and it turned out to be a terminal deletion that was missed by the microarray.

Zhou said that so far Berry Genomics has tested around 100 samples with Chrosure. That test also costs between $400 and $500.

Zhou said the firm next plans to begin developing prenatal tests for severe single-gene disorders, such as neuromuscular dystrophy and thalassemia. Thalassemia in particular, is very severe in southern China, Zhou said.

The difficulty in testing for these disorders, though, is that circulating fetal DNA is highly fragmented, on average around 160 bases, Zhou said. This makes it difficult to amplify the region of interest since there is no guarantee that the region will be contained in one of those fragmented DNA pieces. To overcome this problem, Zhou said the firm developed a single-end PCR technology, to "anchor at one end, so we can cover all the molecules downstream."

The same technology can also be applied to circulating tumor DNA, Zhou said, another area Berry Genomics is looking to tap into. Within the oncology space, Zhou said the firm is developing tests that would look for specific well-known markers in patients' plasma, such as the CKIT gene in gastrointestinal cancer, or EGFR in non-small cell lung cancer.

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