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Genetic Testing for Cystic Fibrosis Dee Quinn, MS, CGC August, 2006 “Gene Testing Going Mainstream” Cystic Fibrosis Gene Test Offered By Lauran Neergaard AP Medical Writer Monday, Oct. 1, 2001; 9:53 p.m. EDT WASHINGTON –– Gene testing is going mainstream: Starting this month, tens of thousands of white Americans will be offered testing to see if they carry a gene mutation that causes cystic fibrosis even if no one in their family has the disease. CFTR Gene Identified in 1989 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) 27 exons, 250kB of genomic DNA Chromosome 7q CFTR Gene cAMP-dependent chloride channel Expressed in epithelial cells of: respiratory tract sweat and salivary glands pancreas intestine reproductive tract Clinical Phenotype Respiratory GI, pancreas Reproductive CFTR Mutations Over 1,000 mutations identified Most labs test for 25-87 mutations 13 of the identified CF mutations occur in more than 1% of CF chromosomes 72% of whites with CF are homozygous or heterozygous for 8 mutations 5 classes of CFTR mutations Genotype/phenotype correlations may not be helpful CFTR Mutations- ΔF508 Most common mutation in North America, 70-75% of the mutations Deletion of codon 508 Results in shortening of the protein product Protein product still functioning as Cl channel, but is retained in the endoplasmic reticulum ΔF508 (homozygosity): classical phenotype Epidemiology One of the most common autosomal recessive diseases in Caucasians Occurs in 1 in 3300 births 30,000 affected persons in the United States Recessive Pedigree Epidemiology Group Incidence Carrier Frequency Sensitivity Caucasians (United States) 1/3,300 1/29 80-90 Ashkenazi Jews 1/3,300 1/29 97 1/8-9,000 1/46 57 Native Americans 1/3,970-1/1,500 1/52 80-90 African Americans 1/15,300 1/60-65 69 Asian Americans 1/32,100 1/90 30 Hispanics Congenital Bilateral Absence of the Vas Deferens (CBAVD) Vas deferens – carries sperm from the epididymis to the ejaculatory ducts Absence of vas occurs in 95% of males with CF CBAVD: distinct genetic disorder which overlaps with CF and causes infertility Noncoding region of CFTR gene involved: intron 8 with thymidine tracts (5T/7T/9T) 60-70% of men with CBAVD carry one mutation in the CFTR gene. 5T reduces the number of functional Cl channels Congenital Bilateral Absence of the Vas Deferens (CBAVD) Genotype - Phenotype Correlation CFTR Genotype First Allele Second Allele Phenotypes Range of Classic (e.g., F508) Classic Classic >> nonclassic Mild (e.g., A455E) Classic or mild Nonclassic > classic R117H/5T Classic or mild Nonclassic > classic R117H/7T Classic or mild Asymptomatic female or CBAVD > nonclassic 5T/TG13 or TG12 >> Classic or mild CBAVD or nonclassic CF asymptomatic carrier 5T/TG11 Classic or mild Asymptomatic > CBAVD 7T or 9T Classic or mild Asymptomatic Newborn Screening Blood spots from infants taken within days of birth to identify infants at increased risk for a specific genetic disorders Justifications: – Early treatment of respiratory illnesses – Evidence for nutritional benefit Currently offered or in planning in many states – AZ to begin newborn screening by 9/07 Newborn Screening Initial screen tests levels of IRT (immunoreactive trypsinogen) Screening program should include: – Specific provider and patient educational materials – Protocol for addressing positive screening results Sweat chloride DNA testing – Development of systems in collaboration with specialty care providers to track short-term and long-term child outcomes and identify resources to support this activity Carrier Screening for CF 1997- NIH convened a Consensus Conference 1998- ACOG/ACMG formed Steering Committee 10/2001- “Preconception and Prenatal Carrier Screening for Cystic Fibrosis” ACOG/ACMG Recommendations Offer screening to: – Individuals with a family history of CF – Reproductive partners of individuals with CF – Couples in whom one or both are Caucasian and are planning a pregnancy or seeking prenatal care – Other individuals must be given written information ACOG/ACMG Recommendations Provider’s Role: – – – – – – Purpose of screening Voluntary nature of screening Symptoms of CF, treatment and prognosis Genetics of CF and population frequencies Meaning of positive and negative test results Factors to consider in deciding to have or not to have screening Additional Indications for Screening Echogenic bowel detected on prenatal ultrasound Infertility in males Diagnostic Prenatal Tests Testing offered when: – When both members of a couple are carriers, ie: 25% risk of having a baby with CF – When one member of a couple is carrier and other member not available for testing – Testing options: Chorionic villus sampling (CVS) – 9-11 weeks Amniocentesis – After 14 weeks Other Approaches Procedure – In vitro fertilization – One cell removed from early embryo to test for mutations which were found in parents – Cell without a CF genotype transferred to mother’s uterus Caveats – – – – Technically demanding and complex procedure Available on a limited basis Expensive: $4,000 - $12,000 Ethical implications ACOG/ACMG Recommendations Laboratory’s Role: Reports should include results of screening and an interpretation: Negative Residual risk given Positive Test other partner Limitations of CF Screening Does not detect all carriers Estimate of residual risk applies only when family history is negative and to the current pregnancy Cannot make reliable predictions for outcome based on mutations Non-paternity Genetic Counseling Various outcomes of prenatal and newborn will generate need for genetic counseling: – – – – Newly diagnosed child with CF Healthy males who carry mutations associated with infertility Identification of positive/negative couples who request additional mutational analyses or counseling to clarify residual risk Positive/positive couples Ethical, Legal, and Social Implications of CF Screening Ethical Unnecessary anxiety created Inadequate pretest information Legal Informed Consent Insurance discrimination Social Expense swell health costs Societal pressure not to bear affected offspring Resources Cystic Fibrosis Foundation http://www.cff.org http://cysticfibrosis.com GeneTests and GeneReviews http://www.genetests.org National Society of Genetic Counselors http://www.nsgc.org Mountain States Genetics Network http://www.mostgene.org Conclusions “It will be very important to see how this goes. Certainly it requires the obstetricians to become more familiar with genetics than many of them have previously had occasion to do.” -Francis Collins