PERSONALIZED GENETIC REPORT CLIENT-REPORTED DATA PURPOSE OF THE X-SCREEN TEST

Transcription

1 INCLUDED IN THIS REPORT: REVIEW OF YOUR GENETIC INFORMATION RELEVANT TO ENDOMETRIOSIS PERSONAL EDUCATIONAL INFORMATION RELEVANT TO YOUR GENES INFORMATION FOR OBTAINING YOUR ENTIRE X-SCREEN DATA FILE PERSONALIZED GENETIC REPORT REPORT GENERATED FOR...Jane Sample SAMPLE ID...XS SAMPLE COLLECTION DATE...09/25/2015 REPORT DATE...10/01/2015 CLIENT-REPORTED DATA TEST UPDATES & RESEARCH SELECTIONS PURPOSE OF THE X-SCREEN TEST UP-TO-DATE INFORMATION. FUTURE RESEARCH AND INNOVATION. You will learn how your own genetic variation may contribute to endometriosis and you will get the most accurate information available today. You will also have opportunities to update this information several times a year as knowledge expands. As a recipient of the X-Screen test, you will have the opportunity to participate in the largest endometriosis research program ever attempted. Finally, you will also have access to other health information about your genetics. Page 1 of 5

2 BACKGROUND INFORMATION: ENDOMETRIOSIS ENDOMETRIOSIS COULD AFFLICT AS MANY AS 176 MILLION WOMEN AROUND THE WORLD IT AFFECTS ONE IN 10 WOMEN OF CHILDBEARING AGE The condition is characterized by the presence of endometrial tissue (tissue that normally lines the uterus) in other parts of the body. Women living with endometriosis often suffer from debilitating pain throughout their lives. Even when symptoms are absent, endometriosis can cause infertility. Despite several advancements in diagnostic techniques, the standard for diagnosing endometriosis continues to be exploratory laparoscopic surgery. Laparoscopic exploration with biopsies is a subjective test which depends on the experience and patience of the surgeon and the pathologist. In the best scenarios, sensitivity is only 94% and specificity is 79%. Because symptoms often overlap with those of a wide variety of other conditions, doctors may be reluctant to subject a patient to such surgery before investigating other alternatives, which can unfortunately result in a delayed care. From the onset of their symptoms, affected women typically endure symptoms for over a decade before receiving a correct diagnosis. The pain caused by endometriosis can create significant interferences in an affected woman s life. Studies show that women with endometriosis often miss work, school, and social events, and it can get in the way of relationships with one s partner, friends, children, and co-workers. In the near future, DNA testing will facilitate early detection of endometriosis and prompt treatment to suppress symptoms before they adversely impact a patient s life. An earlier diagnosis will lead to earlier and more appropriate interventions, allowing women to avoid needless suffering and to preserve their fertility. ONE IN SEVEN ENDOMETRIOSIS SYMPTOMS IMPACT OVER 25 MILLION WOMEN IN THE UNITED STATES ON A REGULAR BASIS. Chronic pelvic pain lasting longer than 6 months duration impacts one in seven women. Page 2 of 5

3 ENDOMETRIOSIS IS A GENETIC CONDITION The Utah Heritability Study showed that if a woman has endometriosis, her sister is about 10 times more likely to have endometriosis, and her mother is 5 times more likely to have it. [Farrington et al, American Society of Human Genetics 2009] Endometriosis is more genetic than breast cancer or ovarian cancer (NCI data) YOUR RESULTS GENES RELEVANT TO ENDOMETRIOSIS Over 300 genes thought to play a role in endometriosis were screened in your sample. The good news is most of these genes did not have a serious variation seen in other women with endometriosis. NLRP2 The International Endogene Consortium found bad (higher stage) endometriosis was more genetically determined than mild endometriosis. While this seems logical, it doesn t tell us what the genes are doing. For instance, there could be genetic contributions to disease progression, or there could be genes that directly cause severe instead of mild disease. [Painter et al, GWAS identifies a locus at 7p15.2 associated with endometriosis. Nature Genetics 2011;43:51.] A pathogenic missense mutation was found in the NLRP2 gene (an abbreviation for NACHT, LRR and PYD domains-containing protein 2) located on the short arm of human chromosome 19. The NLRP2 protein plays a role in our body s innate immune system. The mutations seen in the women with endometriosis are likely to interfere with a women s immune system. Many scientists believe that a faulty immune system may cause endometriosis by failing to find and destroy endometrial tissue growing outside of the uterus. Women who have endometriosis are also more likely to develop autoimmune disorders in which a patient s immune system attacks her own body's tissues. The NLRP2 gene is expressed by white blood cells, by pre-implantation embryos, by female reproductive organs, and by endometriosis lesions. In most tissues, the function is unknown, and there have been no prior biologic studies in endometriosis. We know that the NLRP2 gene is one of a few hundred imprinted genes in humans. The copy of the NLRP2 gene we inherit from our fathers is silent, and only the version we inherit from our mother is an active gene producing NLRP2 proteins. Previously, mutations in the NLRP2 gene have been associated with rare imprinting and reproductive disorders. This exact DNA variant has been observed in 5% of a large study population of women with endometriosis. Page 3 of 5

4 YOUR EXOME SEQUENCE Number of variants identified 4,5556 Mean Depth of Coverage 33X Quality threshold (20X coverage) 94.2% LIMITATIONS OF OUR KNOWLEDGE Our collective scientific understanding of human DNA sequences is incomplete and the educational information provided is based on current knowledge. The results provided are not diagnostic results or treatment recommendations. The X-Screen does not evaluate every possible mutation in the genes tested. Certain DNA changes including deletions, copy number variants, intronic and regulatory mutations, mosiacism, and other important genetic variations are beyond the scope of this screening test. Chromosomal phase of recessive mutations and compound heterozygosity are not determined. The significance of some DNA variations tested may be population specific. A negative" test does not exclude the presence of a serious genetic disorder. Pathogenic variants may be present in genes or areas of genes not covered by this test and therefore would not be identified. The accuracy of DNA variant testing is NEVER 100%. Mode of inheritance, reduced penetrance, epigenetic factors, genetic heterogeneity, and other factors may reduce the clinical sensitivity of the X-Screen test. Genotyping errors will occur due to rare sequence variations that impact the assay performance for particular variants. Negative tests also do not imply that the tested individual is risk free. Non-genetic factors like diet, exercise, stress, and exposure to environmental agents may play important roles in endometriosis. OBTAIN YOUR ENTIRE X-SCREEN DATA FILE Since Predictive Rx believes that each clients owns their own genetic data, Predictive will also return all of the X-Screen raw data to clients with all of the tens-of-thousands of variants detected in the clients exome upon request. Predictive advises that a qualified genetic counselor or physician be consulted for the interpretation of exome data. Certainly, these results should not be used for medical management without appropriate confirmation and interpretation by a qualified health care provider. Raw data can be provided as a BAM file and/or VCF file. If requested, a compressed VCF file can be downloaded by clients using a secure web portal. Variant Call Format (VCF) files are the industry-standard file format for storing DNA marker and genotype data. Whole exome VCF files contain meta-information, header lines dividing the data by chromosome number, and data lines contain marker and genotype data (one variant per line). A variety of quality metrics are also included. VCF files for a X-Screen analysis are typically a < 100 MB text file and VCF files are compatible with most variant interpretation software. The X-Screen is only a screening procedure. Predictive does not provide a specific interpretation or confirmation by second test method for variants/mutations discovered during X-Screen testing. Upon request, Predictive will also send you a BAM format computer file. BAM files are the industry-standard format for storing aligned sequence data. Each BAM file contains the the actual data from a single client s sample sample aligned to a human reference genome. BAM files are large (often > 2 GB) files and these will be mailed on USB drives for an additional $100 data handling and shipping fee. Predictive can assist with referrals to qualified genetics professionals in your area. Please call for details. Page 4 of 5

5 TEST DETAILS METHODOLOGY Genomic DNA was extracted and the Life Technologies Ampliseq Exome RDY kit was used to target the exon regions as well as mitochondrial variants. These targeted regions were sequenced using the Life Technologies Proton sequencing system with 200 bp reads. DATABASES EXAMINED: CLINVAR - GENECARDS - EXAC - exac.broadinstitute.org DBSNP - PUBMED - LEIDEN OPEN VARIATION DATABASE databases.lovd.nl/ shared/variants CLINVITAE - EMVCLASS, EMORY GENETICS LABORATORY VARIANT CLASSIFICATION CATALOG - geneticslab.emory.edu/emvclass/ emvclass.php LIMITATIONS AND RECOMMENDATIONS: Some abnormalities, such as copy number changes, may not be detectable with this analysis. It is possible that the gene region where a disease causing mutation exists in the patient was not captured using the current technologies and therefore was not detected. Additionally, it is possible that a particular genetic abnormality may not be recognized as the underlying cause of the genetic disorder due to incomplete scientific knowledge about the function of all genes in the human genome and the impact of variants in those genes. Only variants thought to be potentially clinically relevant to endometriosis are discussed herein. Negative X-Screen test results do not exclude the possibility that a causative mutation not detectable by this sequencing technology exists within one of the tested genes, or within one or more genes not evaluated by the targeted gene panel. DNA based information can be hard to understand. Genetic counseling is recommended for this individual and their family to fully understand the exome sequencing results. Page 5 of 5