Genome wide detection of chromosomal gains and losses greater than 7Mb by cfDNA analysis

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Roy B. Leowitz 1 , John A. Tynan 1 , Tong Liu 1 , Yijin Wu 1 , Amin R. Mazloom 1 , Eyad Almasri 1 , Grant Hogg 1 , Theresa Boomer 1 , Jenna Wardrop 1 , Ron McCollough 1 , Marcos Gonzales 1 , Mathias Ehrich 2 † 1 Sequenom Laboratories™, San Diego, CA; 2 Sequenom Inc., San Diego, CA Although only 31 events were detected in samples with a personal or family history as high risk indication, 50% of these were only detectable by MaterniT® GENOME. Investigating this set further we find that many of these positive findings are complex in nature and could be the result of an unbalanced translocation. If we compare the incidence of the complex findings between the group of patients that did not indicate personal or family history and those that did we see a 3 fold high rate of these complex events. (0.2% in patients with no FH and 0.7% in patients with FH). Sensitivity and specificity results were concordant with results from a previously performed analytical validation study. Sensitivity for the detection of sub chromosomal copy number variations exceeded 95%, while overall test specificity was maintained at >99.9%. Sensitivity Specificity Trisomy 13 [n=15] >99.9% [75%-100%] >99.9% [99.6%-100%] Trisomy 18 [n=27] >99.9% [84%-100%] >99.9% [99.6%-100%] Trisomy 21 [n=85] >99.9% [95%-100%] >99.9% [99.6%-100%] SCA [n=26] >99.9% [84%-100%] >99.9% [99.4%-100%] CNV* [n=43] 97.7% [86%-100%] >99.9% [99.4%-100%] Genome wide detection of chromosomal gains and losses greater than 7Mb by cfDNA analysis OBJECTIVE Today the most comprehensive prenatal information about the genetic health of a baby can be obtained by invasive testing combined with karyotype or microarray analysis. However, sometimes invasive testing is not available and desired. We have recently developed a genome wide cfDNA test that is sensitive and specific for the detection of trisomies as well as subchromosomal copy number variants larger than 7Mb. Here we present data from a blinded retrospective study and show the data from our first 10000 patients in the clinical laboratory. RESULTS From September 2015 to May 2016 a total of 10272 samples were submitted to the clinical laboratory for genome wide assessment of copy number variations. The gestational age at time of submission was comparable to traditional cfDNA testing with a slight but not statistically significant increase around 20 to 21 weeks. The proportion of samples submitted for AMA only shrank from around 66% in standard cfDNA testing to about 50% in genome wide cfDNA testing. This reduction was almost entirely compensated by samples that had ultrasound findings either as the sole high risk indication or as part of multiple high risk indications. Out of all positive findings 52% percent were common trisomies and 16% were sex chromosomal aneuploidies. In total 30% of all positive findings could only be obtained by genome wide assessment of cfDNA. These MaterniT® GENOME specific findings are comprised of other full chromosome trisomies (other than 13, 18 and 21) as well as isolated and complex deletions and duplications. We annotate complex deletions/ duplications in patients that present with more than one deletion and/or duplication. Often we find that these events are connected and for example could be indicative of an unbalanced translocation. Results indicating a chromsomal variation have been reported in 554 cases, resulting in a test positive rate of approximately 5.5%. These positivity rates vary greatly among patients with different indications for testing. Patients referred for cfDNA testing with abnormal ultrasound findings showed the highest positivity rate at 10%, and patients referred with abnormal serum screening results were positive in 5.7% of cases. However, patients with only advanced maternal age as a high risk indication had a 3.3% positivity rate. Next we investigated if the 30% gain of unique findings is limited to specific high risk indications. We observe a slightly higher rate of these unique results in patients with the sole indication of advanced maternal age and a slightly lower rate in samples with abnormal serum screen or ultrasound findings. However this dataset is not large enough yet to determine if these differences are statistically significant. RETROSPECTIVE STUDY A total of 1222 sample were selected from previous sample collections. The first pass rate with a single sample aliquot exceeded 95% resulting in 1166 reportable samples with clinical information (invasive testing with Karyotype or Microarray information). CONCLUSIONS Our data indicates that today genome wide cfDNA testing finds higher adoption in cases with ultrasound findings compared to standard cfDNA testing. Furthermore genome wide cfDNA testing results in 30% higher detection rate of clinically relevant copy number variations. Interestingly, the AMA (Advanced Maternal Age) population especially benefits from genome wide analysis. These findings serve as an excellent basis for future research especially in an all comers population. REFERENCES 1. Leowitz RB, Tynan JA, Liu T, Wu Y, Mazloom AR, Almasri E, Hogg G, Angkachatchai V, Zhao C, Grosu DS, McLennan G, Ehrich M. Clinical validation of a noninvasive prenatal test for genomewide detection of fetal copy number variants. Am J Obstet Gynecol. 2016 Feb 17. pii: S0002-9378(16)00318-5. doi: 10.1016/j.ajog.2016.02.030. [Epub ahead of print] PubMed PMID: 26899906. SEQUENOM®, MaterniT® and Sequenom Laboratories™ are trademarks of Sequenom, Inc. 31-41542R1.0_0616 Indications for testing are reported by ordering health care professionals and have not been verified for accuracy.

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