1. Welcome to the WebEx Presentation on the New Follow-up Service Introduced by the California Prenatal Screening Program Prenatal Microarray (MA) Sara Goldman, MPH Chief, Program Standards and Quality Assurance Branch Genetic Disease Screening Program (510) 412-1463 Sara.goldman@cdph.ca.gov Sara.goldman@cdph.ca.gov California Department of Public Health 1

2. Cytogenomic Microarray Analysis (CMA) CMA: Cytogenomic Microarray Analysis detects DNA copy number gains and losses associated with unbalanced chromosomal aberrations

3. Cytogenomic Microarray Analysis to replace Standard Karyotyping following prenatal diagnostic procedures as standard of care? In December 2012, Ronald Wapner, MD published an article in the NEJM showing that in the context of prenatal diagnosis, CMA identified additional, clinically significant cytogenetic results as compared to standard karyotyping In 2013, the ACMG revised their Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications. They listed the advantages and limitations of CMAs In 2013, ACOG published Committee Opinion Number 581 on the Use of Chromosomal Microarray Analysis in Prenatal Diagnosis, which included the information to share with patients before prenatal CMA California Department of Public Health 3

4. MA as an authorized service through the California Prenatal Screening (PNS) Program Between 2013 and 2015, the CA PNS Program worked with Cytogenetic Laboratory Directors to develop Standards for Cytogenetic and Cytogenomic Laboratories The CA PNS Program worked with the Reporting Work Group to develop the Cytogenomic Laboratory Application The CA PNS Program worked with the Indications Work Group to develop the second trimester indications for authorizing Prenatal Microarray In 2015, the CA PNS Program developed the requirements for authorizing Prenatal Microarray (MA) and the SIS screens for reporting results Beginning March 24, 2016, any patient referred to a state-approved Prenatal Diagnosis Center (PDC) will have a “soft” authorization for Prenatal Microarray (MA) California Department of Public Health 4

5. Indications for MA as a “Soft” Authorized Follow-up Service through the CA PNS Program Any Second Trimester referral to a state-approved PDC that is Screen Positive for Trisomy 21 (T21), Trisomy 18 (T18), Large Nuchal Translucency (NT), Neural Tube Defects (NTDs), and/or Smith-Lemli- Opitz syndrome (SCD) will have a “soft” authorization for Prenatal Microarray (MA) This includes all referrals to a PDC that are Screen Positive for T21, T18, and/or Large NT in the First Trimester and the patient is not seen until the Second Trimester This also includes all referrals to a PDC that are Screen Positive for T21, T18, and/or Large NT in the First Trimester, have Genetic Counseling in the First Trimester and then “roll” into the Second Trimester at 15 weeks 0 days California Department of Public Health 5

6. Indications for MA as a “Soft” Authorized Follow-up Service through the CA PNS Program The woman must be seen at a PDC in the Second Trimester (between 15 and 24 weeks gestation), receive Genetic Counseling, an Ultrasound performed by an approved Consultative Sonologist and consent to have an Amniocentesis provided by an approved Amniocentesis Practitioner The Second Trimester Ultrasound must find a designated fetal structural anomaly The woman must consent to Microarray in lieu of Standard Karyotyping California Department of Public Health 6

9. Cases Referred Screen in the Screening Information System (SIS) Showing MA as a “Soft” Authorization Any Second Trimester referral to a state-approved PDC that is Screen Positive for Trisomy 21 (T21), Trisomy 18 (T18), Large Nuchal Translucency (NT), Neural Tube Defects (NTDs), and/or Smith-Lemli-Opitz syndrome (SCD) will have a “soft” authorization for Prenatal Microarray (MA) California Department of Public Health 9

10. Cases Referred Screen showing “soft” authorization California Department of Public Health 10

11. Cases Referred Screen in SIS Showing MA as a “Soft” Authorization Any referral to a PDC that is Screen Positive for T21, T18, and/or Large NT in the First Trimester and the patient is not seen until the Second Trimester Any referral to a PDC that is Screen Positive for T21, T18, and/or Large NT in the First Trimester, the patient has Genetic Counseling in the First Trimester, the appointment status is “1st T Appt Kept-Dx not performed” and the case “rolls” into the Second Trimester at 15 weeks 0 days California Department of Public Health 11

12. Cases Referred Screen for Screen Positive for T21, T18 or Large NT referrals that rollover from First to Second Trimester California Department of Public Health 12

13. Special Authorization for Prenatal Microarray (MA) - In advance of providing any unauthorized MA service, contact GDSP, not a Case Coordinator, for the special authorization NIPT confirmation of a microdeletion or microduplication result may be specially authorized Karyotype findings from CVS or Amniocentesis, such as balanced translocations, deletions, inversions, markers, rings, additional unidentified material (“add”) A Second Trimester Ultrasound anomaly where MA may be requested, such as fetal demise with another fetal anomaly not associated with demise; or other heart/lung defect California Department of Public Health 13

15. Situations that will not be Specially Authorized for Prenatal Microarray (MA) NIPT confirmation of a trisomy, triploidy, sex chromosome abnormality or no results from NIPT Parental Karyotypes or studies following Prenatal Microarray Any First Trimester Ultrasound anomalies Modified Genetic Counseling or Follow-up Genetic Counseling for Prenatal Microarray results California Department of Public Health 15

16. Second Trimester Ultrasound Anomalies where MA is Authorized as an Option in Lieu of Standard Karyotyping 16 Central Nervous System Agenesis/Hypoplasia of Corpus Callosum Arnold Chiari Malformation Cerebellar Hypoplasia Dandy Walker Encephalocele Holoprosencephaly Hydrocephalus NOT with spina bifida (unknown etiology) Meckel Gruber Mega Cisterna Magna Pentalogy of Cantrell Porencephaly Ventriculomegaly Face Absent Nasal Bone Cleft Lip Cleft Lip & Palate Cleft Palate Micrognathia Neck Cystic Hygroma Nuchal Fold (> 5 mm) Heart/Lung Cardiac Defect- Abnormal Outflow Tracts Cardiac Defect- Aortic Valve Stenosis Cardiac Defect- Atrial Septal Defect (ASD) Cardiac Defect- Cardiomegaly Cardiac Defect- Coarctation of Aorta Cardiac Defect- Truncus Arteriosus Cardiac Defect- Dextrocardia/Heart on right side Cardiac Defect- Endocardial Cushion Defect/ A-V canal Cardiac Defect- Ebstein Anomaly Cardiac Defect- Enlarged Atrium Cardiac Defect- Hypoplastic Left Heart Cardiac Defect- Hypoplastic Right Ventricle Cardiac Defect- Pericardial Effusion Cardiac Defect- Pulmonary Valve Atresia/Stenosis Cardiac Defect- Tetralogy of Fallot Cardiac Defect- Total Anomalous Pulmonary Venous Return Cardiac Defect- Transposition of the Great Vessels Cardiac Finding- Tricuspid Regurgitation (TR) Cardiac Defect- Tricuspid Valve Atresia/Stenosis Cardiac Defect- Ventricular Septal Defect (VSD) Pleural Effusion

17. Second Trimester Ultrasound Anomalies where MA is Authorized as an Option in Lieu of Standard Karyotyping 17 Abdomen Absent Stomach Ascites/Anasarca/Edema Diaphragmatic Hernia Double Bubble Duodenal Obstruction Omphalocele Small Stomach Skeletal System Skeletal Dysplasia Severe Scoliosis Lower extremity- Abnormal in position or number of bones Lower extremity- Unilateral Clubfoot Lower extremity- Bilateral Clubfeet Upper extremity- Abnormal in position or number of bones Upper extremity- Absent bones Upper extremity- Arthrogryposis Multiplex Congenita Upper extremity- Clenched hands Upper extremity- Polydactyly Kidney/Urinary Bladder/Pelvis Absent Bladder Absent Kidney-Unilateral Absent Kidneys-Bilateral Dilated Urinary Bladder Echogenic kidneys Empty Urinary Bladder Enlarged kidneys Hydronephrosis Multicystic Dysplastic kidneys Pelvic cysts Potter syndrome Pyelectasis Renal cysts Size/Growth/Overall Appearance Generalized Edema Hydrops Fetalis Intrauterine Growth Retardation (IUGR) Amniotic Fluid Volume Severe Oligohydramnios Severe Polyhydramnios Umbilical Cord 2 Vessel Cord/Single Umbilical Artery

18. Second Trimester Ultrasound Anomalies where MA may be Requested as a Special Authorization 18 Fetal Demise (Special Authorization may be requested with Ultrasound Abnormality Independent of the Demise. Special authorization for amniocentesis is also required from GDSP.) Central Nervous SystemSkeletal System Other Central Nervous System Anomaly Other skeletal system problem(specify under OTHER) Heart/LungAbdomen Other Heart/Lung Defect (specify under OTHER)Limb Body Wall defect Unspecified Abdominal Wall Defect Kidney/Urinary Bladder/PelvisOther Abdominal problem (specify Other Kidney/Bladder problem (specify underunder OTHER) OTHER) Size/Growth/Overall AppearanceAmniotic Fluid Volume Multiple Congenital Anomalies (MCA)Mild/Moderate Oligohydramnios Mild/Moderate Polyhydramnios

19. PSR-Ultrasound screen 19

20. PSR-Amniocentesis screen California Department of Public Health 20

21. PSR-Other/Karyo screen* *Must indicate that karyotype was “Not Performed” California Department of Public Health 21

22. PSR-Other/Karyo screen* *Must indicate that karyotype was “Not Performed” California Department of Public Health 22 On the PSR-Other/Karyo screen: the PSR data entry must indicate that the karyotype was “Not Performed”. This is how you navigate to the PSR-Microarray screen.

23. PSR-Microarray screen 23

24. PSR-Microarray screen 24

25. New PSR Screen: “Enter PSR-Microarray” A Microarray Service Status must be entered whenever MA is authorized. The Service Statuses are: Provided Declined Not Authorized Specimen unable to be analyzed (Specify) California Department of Public Health 25

26. New PSR Screen: “Enter PSR-Microarray” The following information must be entered on the “Enter PSR-Microarray” screen for each prenatal microarray when the service status is entered as “Provided “ or “Specimen Unable to be Analyzed”: Name of Cytogenomic Lab completing study Lab Specimen Number Specimen Type: CVS, Amniotic Fluid, Fetal Tissue Specimen Preparation: Cultured, Direct Microarray Ordered Date Microarray Result Date California Department of Public Health 26

27. New PSR Screen: “Enter PSR-Microarray” In the Microarray Diagnosis section, the following information must be entered on the “Enter PSR- Microarray” screen if the Service Status is selected as “Provided”: Abnormal (including VOUS) Normal Male (Including benign variants) Normal Female (Including benign variants) Test Failure California Department of Public Health 27

28. New PSR Screen: “Enter PSR-Microarray” If the Microarray Diagnosis is abnormal, the following information must be entered on the “Enter PSR-Microarray” screen: Inheritance of Rearrangements: Maternal, Paternal, De Novo, Unknown Abnormal Microarray Results (ISCN format): Specify Interpretation Summary: Specify Clinical Significance: Known Clinical Significance, Unknown Clinical Significance Is Diagnosis part of a syndrome?: Yes (Specify), No, Unknown Be sure to “Add to grid” to enter results before leaving screen California Department of Public Health 28

29. Other Radio Buttons on the “Enter PSR-Microarray” screen Add To Grid: Add new Microarray Service record. Update: Update Microarray Service record. Cancel: Cancels current operation of Adding/Updating Microarray Service. Edit: Select the record for Editing. Delete: Delete PSR Service record. Save: Saves the data, runs the validation (inconsistencies) checks and displays feedback to the user. Back: Cancels the transaction and navigates back to previous page. Next: Navigates to next page in navigation. California Department of Public Health 29

30. Screen Validations on the “Enter PSR-Microarray” screen If no “Microarray Services” option is selected, the message is “Please select a service status to continue.” If “Microarray Services” is selected as “Specimen unable to analyze” and the text field is blank, the message is “Specify the reason for specimen unable to be analyzed.” If no option is selected in any of the required fields when “Microarray Services” is “Provided”: “Enter name of the Cytogenomic Lab completing the study. If Laboratory Name is not listed, please call GDSP.” “Enter Lab Specimen Number.” “Select a Specimen Type.” “Select a Specimen Preparation.” California Department of Public Health 30

31. Additional Screen Validations on the “Enter PSR-Microarray” screen “Microarray Ordered Date cannot be less than or equal to accession date“ “Microarray Result Date cannot be less than or equal to accession date“ “Microarray Result Date cannot be less than Microarray Ordered Date“ “Microarray Ordered Date cannot be before the Amniocentesis Provided Date" “Microarray Ordered Date cannot be before the Fetal Tissue Karyotype Date " California Department of Public Health 31

32. Additional Screen Validations on the “Enter PSR-Microarray” screen If no option is selected for Microarray Diagnosis, the message is “Select a Microarray Diagnosis“ If Microarray Diagnosis is selected as “Abnormal (Including VOUS)”, you must “Select a value for “Inheritance of Rearrangements.” If Microarray Diagnosis is selected as “Abnormal (Including VOUS)” and the Interpretation text field is blank, the message is “Specify the Interpretation Summary for the Microarray abnormality.” If “Microarray Diagnosis is selected as “Abnormal (Including VOUS)”, you must “Select a Clinical Significance.” If “Microarray Diagnosis is selected as “Abnormal (Including VOUS)”, you must “Select a value for “Is Diagnosis part of a syndrome. ” California Department of Public Health 32

33. Additional Screen Validations on the “Enter PSR-Microarray” screen If a new result with status other than “Specimen unable to be analyzed” is being added and if the status already exists for the same fetus letter, the message is “This result status already exists for Microarray Service.“ When user attempts to add an Microarray result with “Microarray Ordered Date” same as any one of previous results for the same fetus, the message is "A Microarray result with the same Microarray Ordered Date has already been entered." If Microarray is “Provided” and a Subsequent Karyotype (Amniocentesis Karyotype) results are entered and Microarray is not Specially Authorized, the message is “Karyotype results entered. Microarray cannot be provided without Special Authorization." California Department of Public Health 33

34. Enter PSR screen 34

35. PSR Status Screen California Department of Public Health 35

36. PDC Invoice with the addition of Prenatal Microarray California Department of Public Health 36

37. Questions? PSR Contacts and Special Authorizations: Jacqueline Avila(510) 412-6205 Cheryl Ikeda(510) 412-1475 Bret Hutchinson(510) 412-3939 PDC Invoicing: Nympha Valdezotto(510) 412-1479 California Department of Public Health 37

38. Any Further Questions? Contact: Sara Goldman, MPH Chief, Program Standards and Quality Assurance Branch Genetic Disease Screening Program (510) 412-1463 Sara.goldman@cdph.ca.gov Sara.goldman@cdph.ca.gov California Department of Public Health 38