Russell-Silver syndrome (RSS)

Transcription

1 GENETIC DIAGNOSTIC LABORATORY Russell-Silver syndrome (RSS) Background: Russell-Silver syndrome (RSS, OMIM , ) is a growth disorder characterized by intrauterine and postnatal growth retardation, with a reported incidence of approximately one in 100,000 live births. Other clinical features that may be associated with RSS are asymmetry, triangular face, fifth finger clinodactyly, frontal bossing, café au lait spots, genitourinary anomalies, cognitive delay, feeding disorder and hypoglycemia. Assay: Utility: Analysis of chromosome 11p15 by methylation-specific PCR to detect methylation errors and abnormal copy number. If MS-PCR analysis is negative, reflex to uniparental disomy (UPD) testing of chromosome 7 is recommended. Affected individuals can benefit from screening and treatment regimens aimed at preventing the most serious complications of this condition. Cytogenetically detectable abnormalities involving chromosome11p15 or chromosome 7 are found in ~1% of affected individuals; therefore, methylation errors are more often the cause of the disorder. Identifying the mutation in hereditary forms of RSS allows for prenatal or early postnatal diagnosis. Sensitivity: Loss of methylation on the paternal chromosome at imprinting center 1 (IC1) on chromosome 11p15 occurs in about 50% of affected individuals. Maternal uniparental disomy for chromosome 7 occurs in about 10% of affected individuals. In 1-2% of RSS patients, chromosomal aberrations on11p15 or chromosome 7 can be observed. Turnaround: 4-6 weeks for full analysis (methylation analysis and UPD7 studies) 2-3 weeks for a familial mutation 1-3 weeks for prenatal diagnosis of amniocytes only (includes maternal cell contamination studies) Fees: $500 for methylation and copy number analysis $500 for UPD7 analysis $340 for a known familial mutation $500 for prenatal diagnosis of amniocytes only (includes maternal cell contamination studies) CPT codes: Methylation analysis: 83891, 83900x2, 83901x4, 83909x2, UPD 7 analysis: 83891, 83900x2, 83901x4, 83909x2, Known familial mutation: 83891, 83898x6, 83904x6, Prenatal diagnosis: 83891, 83900x2, 83901x4, 83909x2, References: Azzi, S et al.: Allele-specfic methylated multiplex real-time quantitative PCR (ASMM RTW- PCR), a powerful method for diagnosing loss of imprinting of the 11p15 region in Russell Silver and Beckwith Wiedemann syndromes. Hum Mutat 2011; 35: Scott RH et al.: Methylation-specific multiplex ligation-dependent probe amplification (MS- MLPA) robustly detects and distinguishes 11p15 abnormalities associated with overgrowth and growth retardation. J Med Genet 2008; 45:

2 GENETIC DIAGNOSTIC LABORATORY Russell-Silver syndrome (RSS) Testing INSTRUCTIONS FOR SAMPLE SUBMISSION Documentation: Each sample should be accompanied by: 1. A requisition for DNA analysis completed by the physician, nurse or genetic counselor requesting screening. Please note: ICD-9 code is required for billing purposes. If ICD-9 code is unknown, please provide patient s clinical symptom(s) or family history that prompted testing. 2. An informed consent signed by the patient (if under 18 years of age, the parent or guardian should sign) and the professional obtaining the consent. Please have the patient initial at the top of each page and send all pages of the consent. We encourage documentation of informed consent from the patient; however, the lab will proceed with testing if the referring institution does not require a signed consent form. 3. A verification of blood tubes form signed by the patient, parent or guardian. The form should be signed at the time of the blood draw. 4. A completed registration form with check, money order, credit card authorization or information for billing the referring institution. Preparing Sample: Preferable: Obtain 1 EDTA tube (lavender top) - approx. 5 ml whole blood Label tube with the patient s name and date sample was obtained We accept banked or recently extracted DNA; please include the concentration. For prenatal testing: cultured amniocytes, 2 confluent T-25 flasks. Please call the lab prior to sending a prenatal sample. We are often able to offer testing on a direct amnio sample, and we can discuss the requirements with you. We request 5mL of whole blood from the mother for MCC studies. If the father of the pregnancy is available, please send 5mL of paternal blood for the small chance that paternal markers will be needed to completely rule out MCC. Shipping Sample: Ship at room temperature via Federal Express or other overnight courier that guarantees AM delivery to arrive Monday-Friday. There is no one in the laboratory evenings and weekends to receive samples. If sample is drawn on a Friday, please refrigerate it until shipment on the following business day. Shipping Address: Genetic Diagnostic Laboratory University of Pennsylvania 415 Anatomy-Chemistry Building 3620 Hamilton Walk Philadelphia, PA 19104

3 GENETIC DIAGNOSTIC LABORATORY REQUEST FOR RUSSELL-SILVER SYNDROME (RSS) TESTING PATIENT NAME BIRTH DATE SEX RACE ETHNICITY STREET ADDRESS CITY_STATE ZIP HOME PHONE Clinical symptoms: If the test request is for familial analysis or prenatal diagnosis for a known mutation: Name of person previously tested and/or relationship: Result: (Please include a copy of the result) REFERRING PHYSICIAN PHONE FAX GENETIC COUNSELOR PHONE FAX ADDRESS FOR COUNSELOR OR PHYSICIAN INSTITUTION and DEPARTMENT STREET ADDRESS CITY STATE ZIP COUNTRY ICD-9 CODE (or patient s clinical symptoms) TEST REQUESTED Methylation and copy number analysis UPD7 as an automatic reflex if methylation analysis is negative Screening for known familial mutation Prenatal diagnosis of known familial mutation Prenatal testing for suspected diagnosis/ultrasound findings: Please include a copy of genetic result for affected family member for any familial or prenatal test requests For all prenatal requests, please call the laboratory to discuss requirements for testing a direct sample of amniocytes. We request 5mL of whole blood from both parents, if possible, to accompany any prenatal sample. Paternal DNA markers will only be used, if needed, to completely rule out maternal cell contamination.

4 GENETIC DIAGNOSTIC LABORATORY Patient Registration Form Please provide the following information. We cannot perform your test without ALL of this information. PLEASE PRINT ALL ANSWERS PATIENT INFORMATION LAST FIRST MI Date of Birth: PATINET S MAIDEN NAME IF PREVIOUS TESTING WAS PERFORMED Gender: Male Female Patient Address: STREET/APT NO. CITY, STATE, ZIP COUNTRY IF OUTSIDE UNITED STATES HOME TELEPHONE REFERRING PHYSICIAN NAME MD DO OTHER STREET ADDRESS TELEPHONE INSTITUTION CITY, STATE, ZIP FAX PAYMENT OPTIONS (must choose one) [a receipt will be mailed to the patient for self-pay options] I have enclosed a check payable to the Genetic Diagnostic Laboratory for $ Please charge my credit card for the amount of $ VISA Master Card Discover American Express Card Number: Exp date: Name as it appears on card: I have Pennsylvania Medicaid. A copy of my Medicaid card is attached. INSTITUTIONAL BILLING: The Institution where my testing originated has agreed to pay all charges for the testing. INCLUDE Billing Address, Person Authorizing Payment, Telephone, and Fax below: BILLING ADDRESS BILLING ADDRESS PERSON AUTHORIZING PAYMENT PHONE FAX

5 GENETIC DIAGNOSTIC LABORATORY Verification of Correctly Identified Blood Tubes I am a participant in genetic DNA testing. I have been shown the tubes containing my blood for this genetic testing and my name has been correctly placed on each one of these tubes. I have signed a copy of the consent form regarding this genetic testing to be sent along with my blood samples. I have been given a copy of the consent form to keep. Participant Name: Participant/Parent Signature: Date:

6 Initials PROBAND ANALYSIS GENETIC DIAGNOSTIC LABORATORY INFORMED CONSENT: PROBAND GENETIC TESTING FOR RUSSELL-SILVER SYNDROME (RSS) BACKGROUND: Russell-Silver syndrome (RSS) is a genetic disorder characterized by slow growth and specific physical findings. The molecular basis of RSS is complex and involves changes in several genes on chromosome 11p15. Methylation analysis is used to detect specific differences in patients with RSS. If methylation analysis is negative, then analysis for UPD7 (uniparental disomy of chromosome 7) can be performed. Testing will not identify all molecular changes associated with RSS. A negative test does not change a clinical diagnosis of RSS. This consent form covers methylation analysis and UPD7 analysis. Consent also allows the lab to keep a sample to validate and refine future testing. PURPOSE: I, or my child, will be tested for alterations in several genes on chromosome 11p15.5 as described above. I understand that the testing will take approximately 4-6 weeks to complete. The purpose of this genetic testing is to determine whether I, or my child, have specific molecular changes associated with RSS. TESTING PROCEDURE: Genetic testing requires a sample of blood be drawn by venipuncture or a sample of tissue. RISKS AND DISCOMFORTS: I understand that there is usually a minimal amount of risk involved in drawing a blood sample. These include pain at the blood drawing site, bleeding, bruising and infection. The risk of disclosure of information regarding genetic susceptibility to RSS might include psychosocial concerns and concerns about genetic discrimination. Please discuss these concerns with your health care provider. RESULTS: I understand that there are three possible results to this testing: 1. It is disclosed that I, or my child, have a clinically significant molecular alteration associated with RSS. I understand that this means that there is a high risk to developing clinical symptoms of RSS. This result will also confirm a clinical diagnosis of RSS. 2. The analysis did not detect a molecular alteration associated with RSS. I know that the methods currently in use might be unable to detect all mutations and I, or my child, may still have a DNA mutation that was not detected by the current technology. Not finding a mutation does not eliminate a clinical diagnosis of RSS. A clinical diagnosis of RSS remains in the absence of a molecular change associated with RSS. 3. The laboratory could detect an alteration of currently unknown significance, called a variant of unknown significance (VUS). Our laboratory will work with your physician to help determine if the VUS can be further classified as to whether it is disease-associated for RSS.

7 Initials PROBAND ANALYSIS BENEFITS OF RECEIVING INFORMATION: This testing could provide information about whether my relatives and future children are at increased risk of developing RSS. If I, or my child, am found to have a clinically significant alteration, I may choose to advise my relatives of this finding. They can have counseling and decide whether or not they wish to be tested to see if they inherited the same alteration. If an alteration is detected in me, there is a 50% chance the alteration has been passed on to each of my children or will be passed on to any future children. LIMITATIONS OF DNA TESTING FOR RSS: I understand that the testing may not detect all of the alterations in these genes. I know that this means I, or my child, may have an alteration that will not be detected by the screening or I, or my child, may have alterations associated with RSS that have not yet been identified. CONDITIONS OF DNA TESTING FOR RSS: No information pertaining to these genetic test results will be provided to anyone without my express written consent. My healthcare provider will discuss results of this testing with me. I understand that payment must be made for the molecular analysis of RSS regardless of whether a mutation is identified. I have discussed the options for payment with the laboratory or my physician, and arrangements have been made to fulfill my payment obligation. USE OF SPECIMENS: I understand that any blood or tissue specimens obtained for the purposes of this genetic testing become the exclusive property of the Genetic Diagnostic Laboratory. After the specific tests requested have been completed and reported, the Laboratory may dispose of, retain, or preserve these specimens to refine and validate future testing. I understand that my identity will be protected and that research results will not be provided to me or to any other party. If there are new developments in the field, my physician/genetic counselor may be contacted by the Genetic Diagnostic Laboratory staff to offer me, or my child, the opportunity to have additional clinical testing. If use of this genetic material results in a scientific publication, it will not contain any identifying information. REQUEST FOR MORE INFORMATION: I understand that I may ask more questions about this testing and my results at any time. At the Genetic Diagnostic Laboratory, Susan Walther, MS, CGC ( ) and Arupa Ganguly, PhD, FACMG ( ) will be available to answer questions as they arise. I will be given a copy of this consent form to keep. I have explained to the purpose of this genetic testing, the procedures required and the possible risks and benefits to the best of my ability. _ Printed Name of Professional Obtaining Consent Signature of Professional Obtaining Consent Date

8 Initials PROBAND ANALYSIS CONSENT OF PATIENT: I have read and received a copy of this consent form. I agree to have genetic testing and accept the risks. I understand the information provided in this document, and I have had the opportunity to ask questions I might have about the testing, the procedure, the associate risks and the alternatives. Printed Name of Patient Signature of Patient Patient s DOB Date CONSENT OF PARENT OR GUARDIAN: I have read and received a copy of this consent form. I agree to have genetic testing performed for my child and accept the risks. I understand the information provided in this document, and I have had the opportunity to ask questions I might have about the testing, the procedure, the associate risks and the alternatives. Printed Name of Parent/Guardian Relationship to Child Signature of Parent/Guardian Child s Name Child s DOB

9 Initials FAMILIAL MUTATION GENETIC DIAGNOSTIC LABORATORY INFORMED CONSENT: FAMILIAL MUTATION GENETIC TESTING FOR RUSSELL-SILVER SYNDROME (RSS) BACKGROUND: Russell-Silver syndrome (RSS) is a genetic disorder characterized by slow growth and specific physical findings. Because there is a previously identified mutation associated with RSS in a family member, my testing will look specifically for that gene change. Consent also allows the lab to keep a sample to validate and refine future testing. PURPOSE: I, or my child, will be tested for the mutation previously identified in a family member. I understand that the testing will take approximately 2-3 weeks to complete. The purpose of this genetic testing is to determine the inheritance of the specific molecular change associated with RSS that runs in the family. TESTING PROCEDURE: Genetic testing requires a sample of blood be drawn by venipuncture. RISKS AND DISCOMFORTS: I understand that there is usually a minimal amount of risk involved in drawing a blood sample. These include pain at the blood drawing site, bleeding, bruising and infection. The risk of disclosure of information regarding my genetic susceptibility to RSS might include psychosocial concerns and concerns about genetic discrimination. Please discuss these concerns with your health care provider. RESULTS: I understand that there are two possible results to this testing: 1. It is disclosed that I, or my child, have inherited the clinically significant molecular alteration associated with RSS. I understand that this means that there is a high risk to developing clinical symptoms of RSS. This result will also confirm a clinical diagnosis of RSS. 2. Analysis finds that I, or my child, did not inherit the molecular alteration that is associated with RSS in my family.

10 Initials FAMILIAL MUTATION BENEFITS OF RECEIVING INFORMATION: This testing could provide information about whether my relatives and future children are at increased risk of developing RSS. If I, or my child, am found to have a clinically significant alteration, I may choose to advise my relatives of this finding. They can have counseling and decide whether or not they wish to be tested to see if they inherited the same alteration. If an alteration is detected in me, there is a 50% chance the alteration has been passed on to each of my children or will be passed on to any future children. CONDITIONS OF DNA TESTING FOR RSS: No information pertaining to these genetic test results will be provided to anyone without my express written consent. No information will be provided to me by phone or mail from the University of Pennsylvania, regardless of the outcome. My healthcare provider will discuss results of this testing with me. I understand that payment must be made for the molecular analysis of RSS regardless of whether a mutation is identified. I have discussed the options for payment with the laboratory or my physician, and arrangements have been made to fulfill my payment obligation. USE OF SPECIMENS: I understand that any blood or tissue specimens obtained for the purposes of this genetic testing become the exclusive property of the Genetic Diagnostic Laboratory. After the specific tests requested have been completed and reported, the Laboratory may dispose of, retain, or preserve these specimens to refine and validate future testing. I understand that my identity will be protected and that research results will not be provided to me or to any other party. If there are new developments in the field, my physician/genetic counselor may be contacted by the Genetic Diagnostic Laboratory staff to offer me, or my child, the opportunity to have additional clinical testing. If use of this genetic material results in a scientific publication, it will not contain any identifying information. REQUEST FOR MORE INFORMATION: I understand that I may ask more questions about this testing and my results at any time. At the Genetic Diagnostic Laboratory, Susan Walther, MS, CGC ( ) and Arupa Ganguly, PhD, FACMG ( ) will be available to answer questions as they arise. I will be given a copy of this consent form to keep. I have explained to the purpose of this genetic testing, the procedures required and the possible risks and benefits to the best of my ability. _ Printed Name of Professional Obtaining Consent Signature of Professional Obtaining Consent Date

11 Initials FAMILIAL MUTATION CONSENT OF PATIENT: I have read and received a copy of this consent form. I agree to have genetic testing and accept the risks. I understand the information provided in this document, and I have had the opportunity to ask questions I might have about the testing, the procedure, the associate risks and the alternatives. Printed Name of Patient Signature of Patient Patient s DOB Date CONSENT OF PARENT OR GUARDIAN: I have read and received a copy of this consent form. I agree to have genetic testing performed for my child and accept the risks. I understand the information provided in this document, and I have had the opportunity to ask questions I might have about the testing, the procedure, the associate risks and the alternatives. Printed Name of Parent/Guardian Relationship to Child Signature of Parent/Guardian Child s Name Child s DOB

12 Initials PRENATAL DIAGNOSIS GENETIC DIAGNOSTIC LABORATORY INFORMED CONSENT: PRENATAL GENETIC TESTING FOR RUSSELL-SILVER SYNDROME (RSS) BACKGROUND: Russell-Silver syndrome (RSS) is a genetic disorder characterized by delayed growth for gestational age and specific physical findings that can sometimes be detected by ultrasound (asymmetry in growth, differences in facial structure, and/or genitourinary anomalies). PURPOSE: The purpose of this form is to provide information to allow for informed consent with regards to the prenatal test for RSS. The purpose of the prenatal testing is to determine if a mutation is present in the current pregnancy that is associated with RSS. Analysis of a sample of tissue from the pregnancy will be completed only for genetics specific to RSS. An abnormal result can be diagnostic for RSS and predict that my child will develop the syndrome. If the results of this testing are normal, the fetus could still have a birth defect(s) or cognitive impairment from causes that are not detected by the test for RSS. TESTING PROCEDURE: Prenatal genetic testing involves obtaining a tissue sample that represents genetic material from the fetus. The tissue sample is obtained through amniocentesis. Analysis of a fetal sample must include maternal cell contamination studies to confirm that the result is correctly reported specifically for DNA from the fetus. Maternal cell contamination studies (MCC) require a sample of blood from the woman carrying the pregnancy. Blood will be drawn by venipuncture. I understand that the testing will take approximately 1-3 weeks to complete. RISKS AND DISCOMFORTS: I understand the risks associated with undergoing amniocentesis as explained to me by my physician or genetic counselor. The risk of disclosure of information regarding a prenatal diagnosis of RSS might include psychosocial concerns and decision about continuing a pregnancy. RESULTS: I understand that there are three possible results to this testing: 1. It is disclosed that the fetus of the current pregnancy has inherited a clinically significant molecular alteration associated with RSS. I understand that this means that there is a high risk to developing clinical symptoms of RSS. 2. It is disclosed that the results are normal, in that no molecular alteration has been identified to diagnose RSS. If the results of this testing are normal, the fetus could still have a birth defect(s) or cognitive impairment from causes that are not detected by the test for RSS.

13 3. As with any genetic test, results may be unclear or indicate the need for further testing on other family members. This scenario will be explained to your health care provider. I will have the option of declining further testing. CONDITIONS OF TESTING FOR RSS: No information pertaining to these genetic test results will be provided to anyone without my consent. The results will be reported to the ordering physician, and my healthcare provider will discuss results of this testing with me. I understand that payment must be made for the molecular analysis of RSS regardless of whether a mutation is identified. I have discussed the options for payment with the laboratory or my physician, and arrangements have been made to fulfill my payment obligation. USE OF SPECIMENS: I understand that any blood or tissue specimens obtained for the purposes of this genetic testing become the exclusive property of the Genetic Diagnostic Laboratory. After the specific tests requested have been completed and reported, the Laboratory may dispose of, retain, or preserve these specimens to refine and validate future testing. I understand that my identity will be protected and that research results will not be provided to me or to any other party. If there are new developments in the field, my physician/genetic counselor may be contacted by the Genetic Diagnostic Laboratory staff to offer me, or my child, the opportunity to have additional clinical testing. If use of this genetic material results in a scientific publication, it will not contain any identifying information. REQUEST FOR MORE INFORMATION: I understand that I may ask more questions about this testing and my results at any time. At the Genetic Diagnostic Laboratory, Susan Walther, MS, CGC ( ) and Arupa Ganguly, PhD, FACMG ( ) will be available to answer questions as they arise. I will be given a copy of this consent form to keep. I have explained to the purpose of this genetic testing, the procedures required and the possible risks and benefits to the best of my ability. _ Printed Name of Professional Obtaining Consent Signature of Professional Obtaining Consent Date CONSENT OF PATIENT: I have read and received a copy of this consent form. I agree to have genetic testing and accept the risks. I understand the information provided in this document, and I have had the opportunity to ask questions I might have about the testing, the procedure, the associate risks and the alternatives. Printed Name of Patient Signature of Patient Patient s DOB Date