SAMPLE LAB REPORTS - inqaba biotecSAMPLE LAB REPORTS FOR PRENATAL LABORATORY-DEVELOPED TESTING SERVICES ... 3 ohn Hopins Court San Diego CA 2121 Tel: .21.266 CLIA : D2136 CAP : 213

SAMPLE LAB REPORTSFOR PRENATAL LABORATORY-DEVELOPED TESTING SERVICES

Noninvasive prenatal test for genome-wide fetal chromosomal abnormalities

QUALITY OF SCIENCE™

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Lab Reports GENOME

TABLE OF CONTENTS

PAGE

1. NEGATIVE REPORT: NORMAL FEMALE 2

2. POSITIVE REPORT: T21 SINGLE FINDING 5

3. POSITIVE REPORT: LOSS OF 22Q 9

4. NEGATIVE REPORT: UNINFORMATIVE FOR 22Q 13

5. POSITIVE REPORT: GAIN / DUPLICATION 16

6. POSITIVE REPORT: T7 SINGLE FINDING 20

File name: 34-40500R1.0-MaterniT-GENOME-Lab-Reports-082715

MaterniT™ GENOME Lab Report Page 1 of 3 Sample, Jane Order ID: ORD12345-01234

Sequenom Laboratories 3595 John Hopkins Court, San Diego, CA 92121 Tel: 877.821.7266 CLIA #: 05D2015356 CAP #: 7527138 FINAL REPORT

Ordering Provider: Doe, John, MD Patient: Sample, JaneProvider Location: Grand Rapids DOB: 09/13/1970Provider Phone: 555-555-5555 Patient ID: 12345-01234Date Ordered: 06/28/2015 Specimen: 1035600024Date Collected: 06/29/2015 Referral Clinician: Smith, Jane, GCDate Received: 06/30/2015 Lab Director: Nilesh Dharajiya, MDOrder ID: ORD12345-01234 Date Reported: 07/07/2015 6:00 PM PT

Lab Report GENOME

Sequenom® and MaterniT™ are trademarks of Sequenom. © 2015 Sequenom Laboratories. 34-40500R1.0 0715

Test Result Negative Fetal sex consistent with female

Laboratory Director’s Comments Genome-wide analysis of this specimen did not detect gains or losses of chromosomal material suggestive of whole chromosome aneuploidies, subchromosomal duplications or deletions ≥7 Mb, or select microdeletions ranging in size below 7Mb. A negative result does not ensure an unaffected pregnancy. Please refer to the “Performance” and “Limitations of the Test” sections of this laboratory report for additional information.

Result Table

Content ResultAUTOSOMAL ANEUPLOIDIES

Trisomy 21 (Down syndrome) Negative

Trisomy 18 (Edwards syndrome) Negative

Trisomy 13 (Patau syndrome) Negative

Other autosomal aneuploidies Negative

SEX CHROMOSOME ANEUPLOIDIESFetal sex Consistent with female

Monosomy X (Turner syndrome) Negative

XYY (Jacobs syndrome) Negative

XXY (Klinefelter syndrome) Negative

XXX (Triple X syndrome) Negative

GENOME-WIDE COPY NUMBER VARIANTS ≥7 MbGains/Losses ≥7 Mb Negative

SELECT MICRODELETIONS22q11 deletion (associated with DiGeorge syndrome) Negative

15q11 deletion (associated with Prader-Willi / Angelman syndrome) Negative

11q23 deletion (associated with Jacobsen syndrome) Negative

8q24 deletion (associated with Langer-Giedion syndrome) Negative

5p15 deletion (associated with Cri-du-chat syndrome) Negative

4p16 deletion (associated with Wolf-Hirschhorn syndrome) Negative

1p36 deletion syndrome Negative




Lab Report GENOME

Sequenom® and MaterniT™ are trademarks of Sequenom. © 2015 Sequenom Laboratories.

About the TestThe MaterniT GENOME laboratory-developed test analyzes the relative amount of chromosomal material across the genome in circulating cell-free DNA from a maternal blood sample. The test is indicated for use in pregnant women with singleton pregnancies at risk of fetal chromosomal and/or subchromosomal abnormalities.

Test MethodCirculating cell-free DNA was purified from the plasma component of anti-coagulated maternal whole blood. A genomic DNA library was prepared to determine chromosomal representation by massively parallel sequencing.1 Gain or loss of chromosomal material ≥7 Mb was evaluated across the entire genome. Select chromosomal regions (1p, 4p, 5p, 8q, 11q, 15q, and 22q) associated with known syndromes were also evaluated. Fetal sex was assessed by Y chromosome representation.

PerformanceThe MaterniT™ GENOME test utilizes the same proprietary technology as the MaterniT21® PLUS test, with deeper sequencing. In a clinical study using 448 patient samples to evaluate concordance, the MaterniT GENOME test was equivalent in performance, for the analysis of trisomy 21, trisomy 18, trisomy 13, sex chromosome aneuploidies and fetal sex classification, to the MaterniT21 PLUS test.2 The MaterniT21 PLUS test performance has previously been validated and published extensively.1, 3-6

The MaterniT GENOME test performance characteristics for the detection of genome-wide gain or loss events ≥7 Mb, and select microdeletions below 7 Mb, were established using in silico analytic methods, and validated using test samples comprised of genomic DNA mixed with plasma from non-pregnant females.2 Sensitivity for genome-wide events ≥7 Mb was determined to be 95.9%. Sensitivities for select microdeletions varied by size of the event and fetal fraction. Specificity for genome-wide events and select microdeletions was established using 1060 maternal plasma DNA samples and was determined to be >99.9%. Additional details can be found in the table below, and at sequenom.com/genome/performance.

Performance Characteristics

Region (Associated Syndrome)Size Range*

(Mb)Median Size*

(Mb)Reportable Fetal

Fraction Threshold Sensitivity** SpecificityGenome-wide events ≥7 Mb NA NA ≥4% 95.9% (61->99%) >99.9%

22q11.2 (DiGeorge) 0.8-3.6 2.6 ≥8% 53.9% (28-91%) >99.9%

15q11.2 (Prader-Willi & Angelman) 1.2-15.8 5.1 ≥4% 59.2% (16-74%) >99.9%

11q23 (Jacobsen) 1.3-15.7 9.0 ≥4% 86.7% (57->99%) >99.9%

8q24.11-q24.13 (Langer-Giedion) 7.6-8.8 7.9 ≥4% 97.2% (80->99%) >99.9%

5p15.3 (Cri du chat) 1.5-17.8 6.0 ≥4% 83.1% (48-96%) >99.9%

4p16.3 (Wolf-Hirschhorn) 1.1-17.3 4.2 ≥4% 72.9% (37-91%) >99.9%

1p36 (1p36 deletion syndrome) 1.6-13.3 3.8 ≥4% 50.7% (13-81%) >99.9%

* As reported in ISCA database nstd37 [http://dbsearch.clinicalgenome.org/search/]

** Sensitivity estimated across the observed size distribution of each syndrome [per ISCA database nstd37] and across the range of fetal fractions observed in routine clinical NIPT. Figures in parentheses indicate upper and lower estimates for sensitivity at the reportable fetal fraction threshold and at fetal fraction >20%, respectively. Actual sensitivity can also be influenced by other factors such as the size of the event, total sequence counts, amplification bias, or sequence bias.

34-40500R1.0 0715




Lab Report GENOME


Limitations of the Test While the results of the MaterniT GENOME test are highly accurate, discordant results, including inaccurate fetal sex prediction, may occur due to placental, maternal, or fetal mosaicism, or other causes. Cell-free DNA (cfDNA) testing does not replace the accuracy and precision of prenatal diagnosis with CVS or amniocentesis. A patient with a positive MaterniT GENOME test result should be referred for genetic counseling and offered invasive prenatal diagnosis for confirmation of test results. A negative MaterniT GENOME result does not ensure an unaffected pregnancy. An uninformative result may be reported, the causes of which may include, but are not limited to, insufficient sequencing coverage, sequencing noise or artifacts, amplification bias, or insufficient fetal fraction. The MaterniT GENOME test is not intended to identify pregnancies at risk for neural tube defects or ventral wall defects. cfDNA testing for whole chromosome abnormalities (including sex chromosomes) and for subchromosomal abnormalities could lead to the potential discovery of both fetal and maternal genomic abnormalities that could have minor, or no, clinical significance. Evaluating the significance of a positive or a non-reportable test result may involve both invasive testing and additional studies on the pregnant woman. Such studies may lead to a diagnosis of whole or partial chromosomal abnormalities in the pregnant woman, which on occasion could be associated with benign or malignant neoplasms. cfDNA testing may not accurately identify fetal triploidy, balanced rearrangements, or the precise location of subchromosomal duplications or deletions; these may be detected by prenatal diagnosis with CVS or amniocentesis. The ability to report results may be impacted by maternal BMI, maternal weight, and/or maternal systemic lupus erythematosus (SLE). The results of this testing, including the benefits and limitations, should be discussed with a qualified health care provider. Management decisions, including termination of the pregnancy, should not be based on the results of this test alone.

NoteThis laboratory-developed test was developed and its performance characteristics determined by Sequenom Laboratories. It has not been cleared or approved by the U.S. FDA. This test is used for clinical purposes. It should not be regarded as investigational or for research. Although laboratory-developed tests to date have not been subject to U.S. FDA regulation, certification of the laboratory is required under the Clinical Laboratory Improvement Amendments (CLIA) to ensure the quality and validity of the tests. This laboratory is certified under CLIA to perform high complexity clinical laboratory testing and accredited by the College of American Pathologists (CAP).

References1. Palomaki GE, et al. Genet Med. 2011;13(11):913-920. 2. Tynan J, et al. Karyotype-level noninvasive prenatal testing by sequencing of circulating cell-free DNA from maternal plasma. Poster presented at the

International Society of Prenatal Diagnosis Annual Meeting. July 2015.3. Palomaki GE, et al. Genet Med. 2012;14(3):296-305.4. Mazloom AR, et al. Prenat Diag. 2013;33(6):591-597.5. Mazloom AR, et al. American Society of Human Genetics. November 2012.6. Zhao C, et al. Clin Chem. 2015 Apr;61(4):608-616.

Nilesh Dharajiya, MDLaboratory Director, Sequenom Laboratoriesxx/xx/2015

34-40500R1.0 0715




Lab Report GENOME


Test Result Positive Trisomy 21

Laboratory Director’s Comments This specimen showed an increased representation of chromosome 21 (trisomy 21), suggestive of Down syndrome. Genetic counseling and clinical correlation are recommended. Confirmatory testing is required if fetal confirmation and clinical interpretation of the suspected event are desired. Please refer to the “Performance” and “Limitations of the Test” sections of this laboratory report for additional information.

Description: An approximate 35 Mb gain of chromosome 21 material was observed, suggestive of trisomy 21.

34-40500R1.0 0715

p13

p12

p11.

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p11.

1

q11.

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q11.

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q21.

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q22.

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q22.

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q22.

3

Chr21 Duplication




Lab Report GENOME


Result Table


Trisomy 21 (Down syndrome) Positive

















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Lab Report GENOME








(Mb)Median Size*



22q11.2 (DiGeorge) 0.8-3.6 2.6 ≥8% 53.9% (28-91%) >99.9%


11q23 (Jacobsen) 1.3-15.7 9.0 ≥4% 86.7% (57->99%) >99.9%


5p15.3 (Cri du chat) 1.5-17.8 6.0 ≥4% 83.1% (48-96%) >99.9%








Lab Report GENOME










Lab Report GENOME


Test Result PositiveLoss of chromosome 22(q11.2) material

Laboratory Director’s CommentsA loss of chromosome 22 material was observed. It is estimated to be 2.6 Mb in size and is suggestive of a deletion in the region 22q11.2, which is associated with DiGeorge syndrome. Genetic counseling and clinical correlation are recommended. Confirmatory testing is required if fetal confirmation and clinical interpretation of the suspected event are desired. Please refer to the “Performance” and “Limitations of the Test” sections of this laboratory report for additional information.

Description: An approximate 2.6 Mb loss of chromosome 22 material was observed, suggestive of a deletion in the region q11.2, associated with DiGeorge syndrome.

34-40500R1.0 0715

p13

p12

p11.

2

p11.

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q11.

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q11.

2

q12.

1

q12.

2

q12.

3

q13.

1

q13.

2

q13.

3

Chr22 Deletion




Lab Report GENOME


Result Table






SEX CHROMOSOME ANEUPLOIDIESFetal sex Negative

Monosomy X (Turner syndrome)

XYY (Jacobs syndrome) Consistent with female





SELECT MICRODELETION REGIONS22q11 deletion (associated with DiGeorge syndrome) Positive







34-40500R1.0 0715




Lab Report GENOME








(Mb)Median Size*



22q11.2 (DiGeorge) 0.8-3.6 2.6 ≥8% 53.9% (28-91%) >99.9%


11q23 (Jacobsen) 1.3-15.7 9.0 ≥4% 86.7% (57->99%) >99.9%


5p15.3 (Cri du chat) 1.5-17.8 6.0 ≥4% 83.1% (48-96%) >99.9%








Lab Report GENOME










Lab Report GENOME


Test Result Negative

Fetal sex consistent with female Uninformative for 22q11.2

Laboratory Director’s Comments Genome-wide analysis of this specimen did not identify copy number variants ≥7 Mb. The fetal fraction in this sample (<8%) was insufficient to reliably detect a loss of chromosomal material in region 22q11, in the size range associated with DiGeorge syndrome (0.8-3.6 Mb). Clinical correlation is suggested. Ultrasound evaluation and/or prenatal diagnostic procedures should be considered. Please refer to the “Performance” and “Limitations of the Test” sections of this laboratory report for additional information.

Result Table












SELECT MICRODELETION REGIONS22q11 deletion (associated with DiGeorge syndrome) Uninformative







34-40500R1.0 0715




Lab Report GENOME








(Mb)Median Size*



22q11.2 (DiGeorge) 0.8-3.6 2.6 ≥8% 53.9% (28-91%) >99.9%


11q23 (Jacobsen) 1.3-15.7 9.0 ≥4% 86.7% (57->99%) >99.9%


5p15.3 (Cri du chat) 1.5-17.8 6.0 ≥4% 83.1% (48-96%) >99.9%








Lab Report GENOME







34-40500R1.0 0715




Lab Report GENOME


Test Result Positive Gain of chromosome 1 (p36.3-p36.1) material

Laboratory Director’s CommentsA gain of chromosome 1 material was observed. It is estimated to be 15.3 Mb in size and is suggestive of a duplication in the region 1p36.3-p36.1. This region may contain one or more clinically significant genes. Genetic counseling and clinical correlation are recommended. Confirmatory testing is required if fetal confirmation and clinical interpretation of the suspected event are desired. Please refer to the “Performance” and “Limitations of the Test” sections of this laboratory report for additional information.

Description: An approximate 15.3 Mb gain of chromosome 1 material was observed, suggestive of a duplication in the region p36.3-p36.1.

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Lab Report GENOME


Result Table











GENOME-WIDE COPY NUMBER VARIANTS ≥7 MbGains/Losses ≥7 Mb Positive








34-40500R1.0 0715




Lab Report GENOME








(Mb)Median Size*



22q11.2 (DiGeorge) 0.8-3.6 2.6 ≥8% 53.9% (28-91%) >99.9%


11q23 (Jacobsen) 1.3-15.7 9.0 ≥4% 86.7% (57->99%) >99.9%


5p15.3 (Cri du chat) 1.5-17.8 6.0 ≥4% 83.1% (48-96%) >99.9%








Lab Report GENOME










Lab Report GENOME


Test Result Positive Trisomy 7

Laboratory Director’s Comments This specimen showed an increased representation of chromosome 7, suggestive of trisomy 7. Genetic counseling and clinical correlation are recommended. Trisomy 7 mosaicsm is commonly reported. Confined placental mosaicism (CPM) is likely. Chromosome 7 is known to be imprinted. Therefore, subsequent trisomy rescue in fetal tissue carries residual risk for UPD. Confirmatory testing is required if fetal confirmation and clinical interpretation of the suspected event are desired. Please refer to the “Performance” and “Limitations of the Test” sections of this laboratory report for additional information.

Description: An approximate 135 Mb gain of chromosome 7 material was observed, suggestive of trisomy 7.

p22

p21

p15.

3p1

5.2

p15.

1

p14

p13

p12

p11.

2p1

1.1

q11.

1q1

1.21

q11.

22

q11.

23

q21.

1

q21.

2q2

1.3

q22

q31.

1

q31.

2

q31.

3

q32

q33

q34

q35

q36

Chr7 Trisomy

34-40500R1.0 0715

Chr7 Duplication




Lab Report GENOME


Result Table





Other autosomal aneuploidies Positive














34-40500R1.0 0715




Lab Report GENOME








(Mb)Median Size*



22q11.2 (DiGeorge) 0.8-3.6 2.6 ≥8% 53.9% (28-91%) >99.9%


11q23 (Jacobsen) 1.3-15.7 9.0 ≥4% 86.7% (57->99%) >99.9%


5p15.3 (Cri du chat) 1.5-17.8 6.0 ≥4% 83.1% (48-96%) >99.9%








Lab Report GENOME







ABOUT THE COMPANY

Sequenom Laboratories, a wholly owned subsidiary of Sequenom, Inc., is a CAP-accredited and Clinical Laboratory Improvement Amendment (CLIA) certified molecular diagnostics laboratory dedicated to improving

revolutionary laboratory-developed tests for a variety of prenatal conditions. Sequenom Laboratories pioneered NIPT with the launch of its MaterniT21 PLUS

broad menu of prenatal tests.

SEQUENOM®, MaterniT™, and Sequenom Laboratories™ are trademarks of Sequenom, Inc. All other trademarks are the property of their respective owners.

©2015 Sequenom Laboratories. All rights reserved.

ABOUT THE TEST

The MaterniT GENOME test is a laboratory-developed test that was developed, validated and performed exclusively by Sequenom Laboratories. The test has not been cleared or approved by the US Food and Drug Administration (FDA). Although laboratory-developed tests to date have not been subject to US FDA regulation, certification of the laboratory is required under the Clinical Laboratory Improvement Amendments (CLIA) to ensure the quality and validity of the test. Sequenom Laboratories is certified under CLIA as qualified to perform high complexity clinical laboratory testing and is accredited by the College of American Pathologists.

No test is perfect. While the results of the MaterniT GENOME test are highly accurate, discordant results, including inaccurate fetal sex prediction, may occur due to: placental, maternal, or fetal mosaicism or neoplasm; vanishing twin; prior maternal organ transplant; or other causes. Cell-free DNA (cfDNA) testing does not replace the accuracy and precision of prenatal diagnosis with CVS or amniocentesis. A patient with a positive MaterniT

invasive prenatal diagnosis for confirmation of test results. A negative

locus. The MaterniT GENOME test is not intended to identify pregnancies at risk for neural tube defects. cfDNA testing for whole chromosome abnormalities (including sex chromosomes) and for subchromosomal abnormalities could lead to the potential discovery of both fetal and maternal genomic abnormalities that could have minor, or no, clinical significance. Evaluating the significance of a positive or a non-reportable test result may involve both invasive prenatal testing and additional studies on the mother. Such investigations may lead to a diagnosis of maternal chromosomal or subchromosomal abnormalities, which on occasion may be associated with benign or malignant maternal neoplasms. cfDNA testing may not accurately identify fetal triploidy, balanced rearrangements, or the precise location of subchromosomal duplications or deletions; these may be detected by prenatal diagnosis with CVS or amniocentesis. The ability to report results may be impacted by maternal BMI, maternal weight, and/or maternal systemic lupus erythematosus (SLE). The results of this testing, including the benefits and limitations, should be discussed. Management decisions, including termination of the pregnancy, should not be based on the results of this test alone.

REFERENCES

1. Di Gregorio E, et al. Large cryptic genomic rearrangements with apparently normal karyotypes detected by array-CGH. Mol Cytogenet. 2014;7(82).

2. Zhao C, et al. Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from maternal plasma. Clin Chem. 2015 Apr;61(4):608-616.



Sequenom Laboratories 3595 John Hopkins Court San Diego, CA 92121

[email protected] sequenom.com/laboratories

Toll Free (within the US) at

877.821.7266

34-40500R1.0 0815

SAMPLE LAB REPORTS - inqaba biotecSAMPLE LAB REPORTS FOR PRENATAL LABORATORY-DEVELOPED TESTING SERVICES ... 3 ohn Hopins Court San Diego CA 2121 Tel: .21.266 CLIA : D2136 CAP : 213

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