Portal de Periódicos da CAPES

Cystic Fibrosis

2015; Elsevier BV; Volume: 18; Issue: 1 Linguagem: Inglês

10.1016/j.jmoldx.2015.06.010

1943-7811

Marie‐Luise Brennan, Iris Schrijver,

Tracheal and airway disorders

Cystic fibrosis (CF) is an autosomal recessive disease with significant associated morbidity and mortality. It is now appreciated that the broad phenotypic CF spectrum is not explained by obvious genotype-phenotype correlations, suggesting that CF transmembrane conductance regulator (CFTR)–related disease may occur because of multiple additive effects. These contributing effects include complex CFTR alleles, modifier genes, mutations in alternative genes that produce CF-like phenotypes, epigenetic factors, and environmental influences. Most patients in the United States are now diagnosed through newborn screening and use of molecular testing methods. We review the molecular testing approaches and laboratory guidelines for carrier screening, prenatal testing, newborn screening, and clinical diagnostic testing, as well as recent developments in CF treatment, and reasons for the lack of a molecular diagnosis in some patients. Cystic fibrosis (CF) is an autosomal recessive disease with significant associated morbidity and mortality. It is now appreciated that the broad phenotypic CF spectrum is not explained by obvious genotype-phenotype correlations, suggesting that CF transmembrane conductance regulator (CFTR)–related disease may occur because of multiple additive effects. These contributing effects include complex CFTR alleles, modifier genes, mutations in alternative genes that produce CF-like phenotypes, epigenetic factors, and environmental influences. Most patients in the United States are now diagnosed through newborn screening and use of molecular testing methods. We review the molecular testing approaches and laboratory guidelines for carrier screening, prenatal testing, newborn screening, and clinical diagnostic testing, as well as recent developments in CF treatment, and reasons for the lack of a molecular diagnosis in some patients. CME Accreditation Statement: This activity ("JMD 2016 CME Program in Molecular Diagnostics") has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity ("JMD 2016 CME Program in Molecular Diagnostics") for a maximum of 36 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. CME Accreditation Statement: This activity ("JMD 2016 CME Program in Molecular Diagnostics") has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity ("JMD 2016 CME Program in Molecular Diagnostics") for a maximum of 36 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Although some genetic conditions already highlight the potential of precision medicine, much is yet to be learned. In this review, we discuss the current understanding and complexity of cystic fibrosis (CF) genetics. CF is a relatively common, autosomal recessive, and frequently lethal condition caused by mutations in the CF transmembrane conductance regulator gene (CFTR). CFTR consists of 27 exons, spanning approximately 250 kb on 7q31.2.1Welsh MJ, Ramsey BW, Accurso F, Cutting GR: Cystic fibrosis. Metabolic and Molecular Bases of Inherited Disease, 8th Edition, Volume 3. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York, McGraw-Hill, 2013, pp 5121–5188Google Scholar CFTR is a member of the ATP-binding cassette transporter family and encodes an anion transporter protein in the epithelium with five domains. Two membrane-spanning domains form a chloride channel pore that plays a role in chlorine and bicarbonate transport and have secondary effects on sodium transport. CFTR protein dysfunction leads to increased salt concentration in sweat and thickened secretions in various organ systems. Numerous genetic mutations have been identified; their characterization and contribution to disease pathogenesis are discussed below. The clinical presentation ranges from multiorgan symptoms, such as chronic respiratory tract infections, failure to thrive, and pancreatic insufficiency starting in infancy, to single-organ manifestations, such as male infertility or chronic sinusitis in adulthood.1Welsh MJ, Ramsey BW, Accurso F, Cutting GR: Cystic fibrosis. Metabolic and Molecular Bases of Inherited Disease, 8th Edition, Volume 3. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York, McGraw-Hill, 2013, pp 5121–5188Google Scholar The broad phenotypic spectrum is not fully explained by genotype-phenotype correlations. CFTR-related disease may arise because of multiple combining effects, such as complex alleles, modifier genes, mutations in genes that can mimic CF phenotypes, and additional effects, such as those influenced by epigenetic and environmental factors. Birth prevalence of CF approximates 1:2300 for non-Hispanic whites, 1:13,500 for Hispanic whites, 1:2270 for Ashkenazi Jews, 1:15,100 for African Americans, and 1:35,100 for Asian Americans.2Palomaki G.E. FitzSimmons S.C. Haddow J.E. Clinical sensitivity of prenatal screening for cystic fibrosis via CFTR carrier testing in a United States panethnic population.Genet Med. 2004; 6: 405-414Crossref PubMed Scopus (77) Google Scholar The consequences of CFTR dysfunction often commence before birth. Effects of CFTR dysfunction include incomplete embryologic formation of the Wolffian structures, causing congenital bilateral absence of the vas deferens (CBAVD), which causes infertility in virtually all males with CF. Females do not have structural abnormalities, but may face fertility issues as a result of thickened cervical secretions. Fetal ultrasonographic findings of hyperechogenic bowel with or without meconium peritonitis, bowel dilation, or an undetectable gallbladder are concerning for CF. Meconium ileus occurs in up to 20% of CF-affected newborns and is strongly correlated with CF (90% of such cases occur in CF patients).1Welsh MJ, Ramsey BW, Accurso F, Cutting GR: Cystic fibrosis. Metabolic and Molecular Bases of Inherited Disease, 8th Edition, Volume 3. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York, McGraw-Hill, 2013, pp 5121–5188Google Scholar The analogous condition in children and adults with thickened intestinal secretions is distal intestinal obstructive syndrome (10% to 47% of patients). Pancreatic insufficiency is a manifestation in 85% of patients, and fat malabsorption can be measured in 90% of affected infants by 1 year of age. Pancreatic dysfunction contributes to generalized malnutrition, failure to thrive, and suboptimal bone mineral content. CF-related diabetes (25% by the age of 20 years; 50% in adulthood) and pancreatitis are other manifestations.3Katkin JP, Schultz K. Cystic fibrosis: overview of gastrointestinal disease in UpToDate, Post TW (Ed), In UpToDate [Internet]. Copyright Wolters Kluwer, Waltham, MA. Available at http://www.uptodate.com/contents/cystic-fibrosis-overview-of-gastrointestinal-disease, last revised July 15, 2015Google Scholar As the infant grows, additional symptoms present. Some, such as the CF hallmark of failure to thrive, are non-specific. High temperatures risk electrolyte abnormalities because of excess losses in sweat. Respiratory tract symptoms are highly variable and can look non-specific but are the most recognized complication. Most patients develop sinus opacification, and up to 30% will have nasal polyps. Impaired pulmonary function is an early finding in some.4Pillarisetti N. Williamson E. Linnane B. Skoric B. Robertson C.F. Robinson P. Massie J. Hall G.L. Sly P. Stick S. Ranganathan S. Australian Respiratory Early Surveillance Team for Cystic FibrosisInfection, inflammation, and lung function decline in infants with cystic fibrosis.Am J Respir Crit Care Med. 2011; 184: 75-81Crossref PubMed Scopus (223) Google Scholar Bronchiectasis, mucus plugging, and air trapping have been documented by 6 to 12 months. The CF respiratory phenotype progresses because of static mucus and chronic bacterial colonization, infection, and inflammation, with progressively deteriorating lung function. Over the years, significant improvements have been made in diagnosis, delivery of care, and treatment modalities, such that the median life expectancy is now 36.8 years.5Cystic Fibrosis Foundation Patient Registry: Annual Data Report to the Center Directors. Bethesda, MD, 2011Google Scholar With the increasing life span, however, hepatobiliary dysfunction is becoming increasingly prevalent.3Katkin JP, Schultz K. Cystic fibrosis: overview of gastrointestinal disease in UpToDate, Post TW (Ed), In UpToDate [Internet]. Copyright Wolters Kluwer, Waltham, MA. Available at http://www.uptodate.com/contents/cystic-fibrosis-overview-of-gastrointestinal-disease, last revised July 15, 2015Google Scholar The diagnosis of CF is on the basis of characteristic symptoms in addition to evidence of CFTR dysfunction (Table 1).6Farrell P.M. Rosenstein B.J. White T.B. Accurso F.J. Castellani C. Cutting G.R. Durie P.R. Legrys V.A. Massie J. Parad R.B. Rock M.J. Campbell P.W. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.J Pediatr. 2008; 153: S4-S14Abstract Full Text Full Text PDF PubMed Scopus (815) Google Scholar Historically, it was on the basis of presenting clinical symptoms with sweat test verification. Over time, however, increasingly the diagnosis is solidified by molecular testing that identifies both symptomatic and presymptomatic patients. In this transition toward more frequent identification through screening and molecular analysis, several observations have emerged.Table 1Diagnostic Criteria for CFCriteria are met in the presence of (at least one):Organ system symptoms consistent with CF, such as the followingChronic sinopulmonary diseaseCharacteristic gastrointestinal and nutritional abnormalitiesSalt loss syndromesObstructive azoospermiaSibling with CFPositive newborn screening resultCriteria are met in combination with (at least one)CFTR dysfunction indicated by elevated sweat chloride levels (≥60 mmol/L, performed in accord with practice guidelines and adjusted for age) on two testsNasal potential difference consistent with CFPresence of two pathogenic CFTR mutations on different allelesCF, cystic fibrosis; CFTR, CF transmembrane conductance regulator. Open table in a new tab CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator. First, within the CF spectrum, a variety of symptoms and sweat chloride levels can be seen. Symptoms range from single-system (eg, CBAVD) to multiple-system involvement. As evidenced in approximately 2% of patients who meet diagnostic criteria, even in individuals with clinical CF, sweat chloride values can be normal (≤29 mmol/L) or indeterminate (30 to 59 mmol/L).7Borowitz D. Parad R.B. Sharp J.K. Sabadosa K.A. Robinson K.A. Rock M.J. Farrell P.M. Sontag M.K. Rosenfeld M. Davis S.D. Marshall B.C. Accurso F.J. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond.J Pediatr. 2009; 155: S106-S116Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar Such values only become a diagnostic conundrum when patients who are clinically suspected to have CF do not meet diagnostic criteria. These cases have long puzzled clinicians and have been variably designated as atypical, non-classic, non-traditional, or mild variant CF.8Groman J.D. Meyer M.E. Wilmott R.W. Zeitlin P.L. Cutting G.R. Variant cystic fibrosis phenotypes in the absence of CFTR mutations.N Engl J Med. 2002; 347: 401-407Crossref PubMed Scopus (158) Google Scholar Second, CFTR dysfunction encompasses the spectrum of CF, CFTR-related diseases, and CFTR-related metabolic syndrome. Individuals with CFTR-related disease (including chronic rhinosinusitis, idiopathic bronchiectasis, allergic bronchopulmonary aspergillosis, and chronic idiopathic pancreatitis) and CFTR-related metabolic syndrome have come to medical attention for clinical signs or screening results but have indeterminate sweat chloride or nasal potential difference values and do not meet diagnostic criteria. CFTR-related metabolic syndrome is a designation given with an initial positive CF newborn screen (CFNBS) but no symptoms on follow-up and either normal sweat chloride results and two CFTR mutations, with at least one being a variant of uncertain clinical relevance,7Borowitz D. Parad R.B. Sharp J.K. Sabadosa K.A. Robinson K.A. Rock M.J. Farrell P.M. Sontag M.K. Rosenfeld M. Davis S.D. Marshall B.C. Accurso F.J. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond.J Pediatr. 2009; 155: S106-S116Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar or an intermediate sweat result and one or zero CFTR mutations.7Borowitz D. Parad R.B. Sharp J.K. Sabadosa K.A. Robinson K.A. Rock M.J. Farrell P.M. Sontag M.K. Rosenfeld M. Davis S.D. Marshall B.C. Accurso F.J. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond.J Pediatr. 2009; 155: S106-S116Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 8Groman J.D. Meyer M.E. Wilmott R.W. Zeitlin P.L. Cutting G.R. Variant cystic fibrosis phenotypes in the absence of CFTR mutations.N Engl J Med. 2002; 347: 401-407Crossref PubMed Scopus (158) Google Scholar On longitudinal assessment, most of these children will not develop symptoms. In the past, children with CFTR-related metabolic syndrome who developed CF symptoms might have fallen into the atypical or mild variant CF diagnostic classes. Such categories remain relatively vague because they lack strict criteria and, therefore, these terms are used inconsistently or interchangeably. Nevertheless, regular evaluation remains important.9Mayell S.J. Munck A. Craig J.V. Sermet I. Brownlee K.G. Schwarz M.J. Castellani C. Southern K.W. European Cystic Fibrosis Society Neonatal Screening Working GroupA European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis.J Cyst Fibros. 2009; 8: 71-78Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Last, although CFTR mutations are identified in 95% of CF patients, genotype-phenotype correlations are as yet limited. CF and CFTR-related disorders exhibit varied clinical manifestations for the same CFTR genotypes, even within families. CF carrier frequency is highest in non-Hispanic whites and Ashkenazi Jews (1:29 for each), followed by Hispanic Americans (1:46), African Americans (1:65), and Asian Americans (1:90).10Lebo R.V. Grody W.W. Testing and reporting ACMG cystic fibrosis mutation panel results.Genet Test. 2007; 11: 11-31Crossref PubMed Scopus (21) Google Scholar As expected, most parents who have a child with CF have no family history. The American College of Medical Genetics and Genomics (ACMG),11Watson M.S. Cutting G.R. Desnick R.J. Driscoll D.A. Klinger K. Mennuti M. Palomaki G.E. Popovich B.W. Pratt V.M. Rohlfs E.M. Strom C.M. Richards C.S. Witt D.R. Grody W.W. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.Genet Med. 2004; 6: 387-391Crossref PubMed Scopus (366) Google Scholar American College of Obstetricians and Gynecologists,12American College of Obstetrics, Gynecologists Committee on GeneticsACOG Committee Opinion No. 486: update on carrier screening for cystic fibrosis.Obstet Gynecol. 2011; 117: 1028-1031Crossref PubMed Scopus (151) Google Scholar and Human Genetics Society of Australia13Grody W.W. Cutting G.R. Klinger K.W. Richards C.S. Watson M.S. Desnick R.J. Subcommittee on Cystic Fibrosis Screening Accreditation of Genetic Services Committee, ACMG, American College of Medical GeneticsLaboratory standards and guidelines for population-based cystic fibrosis carrier screening.Genet Med. 2001; 3: 149-154Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar recommend molecular carrier screening for CF be offered to inform prospective parents of their risk of having a child with CF (http://www.hgsa.org.au/about/hgsa-committees/genetic-services-committee, last accessed June 22, 2015).14Delatycki M, Burke J, Cristie L, Collines F, Gabbet M, George P, Haan E, Ioannou L, Massie J, McKenzie F, O'Leary P, Scoble-Williams N, Turner G, Human Genetics Society of Australia Genetic Services Committee. [Internet] Position statement. Population based carrier screening for cystic fibrosis. Copyright Human Genetics Society of Australasia, Sydney, Australia. Available at documents/item/1282, last revised October 2013Google Scholar A European consensus statement has also been published.15Castellani C. Macek Jr., M. Cassiman J.J. Duff A. Massie J. ten Kate L.P. Barton D. Cutting G. Dallapiccola B. Dequeker E. Girodon E. Grody W. Highsmith E.W. Kaariainen H. Kruip S. Morris M. Pignatti P.F. Pypops U. Schwarz M. Soller M. Stuhrman M. Cuppens H. Benchmarks for cystic fibrosis carrier screening: a European consensus document.J Cyst Fibros. 2010; 9: 165-178Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar Carrier screening16Grody W.W. Thompson B.H. Gregg A.R. Bean L.H. Monaghan K.G. Schneider A. Lebo R.V. ACMG position statement on prenatal/preconception expanded carrier screening.Genet Med. 2013; 15: 482-483Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar can be pursued by screening the female, or by sequential or direct couples-based testing. The approach to pursue is influenced by personal preference, time frame, privacy, and economic considerations. If testing is not obtained before conception, parental carrier screening can be performed during pregnancy, with reflex testing to prenatal diagnostic testing of fetal cells by means of chorionic villus sampling or amniocentesis, if indicated. The mutation panel recommended by the ACMG in 2001 included 25 CFTR mutations on the basis of an allele frequency of ≥0.1% in CF patients in the United States. The updated 2004 guidelines recommended that 23 mutations continue to be included11Watson M.S. Cutting G.R. Desnick R.J. Driscoll D.A. Klinger K. Mennuti M. Palomaki G.E. Popovich B.W. Pratt V.M. Rohlfs E.M. Strom C.M. Richards C.S. Witt D.R. Grody W.W. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.Genet Med. 2004; 6: 387-391Crossref PubMed Scopus (366) Google Scholar (Table 2). The 1078delT (c.948delT; p.Phe316fs) mutation was removed because it was found to occur in only 0.03% of CF patients, and thus it did not meet the allele frequency threshold. I148T (c.443T>C; p.Ile148Thr) was removed because it was present at >100-fold frequency in the general population compared with CF patients, and is itself not associated with CF.11Watson M.S. Cutting G.R. Desnick R.J. Driscoll D.A. Klinger K. Mennuti M. Palomaki G.E. Popovich B.W. Pratt V.M. Rohlfs E.M. Strom C.M. Richards C.S. Witt D.R. Grody W.W. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.Genet Med. 2004; 6: 387-391Crossref PubMed Scopus (366) Google Scholar, 17Monaghan K.G. Highsmith W.E. Amos J. Pratt V.M. Roa B. Friez M. Pike-Buchanan L.L. Buyse I.M. Redman J.B. Strom C.M. Young A.L. Sun W. Genotype-phenotype correlation and frequency of the 3199del6 cystic fibrosis mutation among I148T carriers: results from a collaborative study.Genet Med. 2004; 6: 421-425Crossref PubMed Scopus (31) Google Scholar I148T is in linkage disequilibrium with 3199del6 (c.3067_3072delATAGTG), which is a rare mutation seen in A; p.Arg117His) mutation and should only be offered as a reflex test, given that CF carrier screening aims to identify the risk of classic CF.11Watson M.S. Cutting G.R. Desnick R.J. Driscoll D.A. Klinger K. Mennuti M. Palomaki G.E. Popovich B.W. Pratt V.M. Rohlfs E.M. Strom C.M. Richards C.S. Witt D.R. Grody W.W. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.Genet Med. 2004; 6: 387-391Crossref PubMed Scopus (366) Google ScholarTable 2CFTR Mutation Frequency in CF Patients by Ethnic Group and in a Panethnic US PopulationAdapted and modified from Watson et al,11Watson M.S. Cutting G.R. Desnick R.J. Driscoll D.A. Klinger K. Mennuti M. Palomaki G.E. Popovich B.W. Pratt V.M. Rohlfs E.M. Strom C.M. Richards C.S. Witt D.R. Grody W.W. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.Genet Med. 2004; 6: 387-391Crossref PubMed Scopus (366) Google Scholar with permission from Nature Publishing Group (Genetics in Medicine, copyright 2004).Legacy/cDNA name/HGVS proteinNon-Hispanic whiteHispanic whiteAfrican AmericanAsian AmericanAshkenazi JewishPanethnicDelF508/c.1521_1523delCTT/p.Phe508del72.4254.3844.0738.9531.4166.31G542X/c.1624G>T/p.Gly542*2.285.101.450.007.552.64G551D/c.1652G>A/p.Gly551Asp2.250.561.213.150.221.93621+1G>T/c.489+1G>T/-1.570.261.110.000.001.30W1282X/c.3846G>A/p.Trp1282*1.500.630.240.0045.922.20N1303K/c.3909C>G/p.Asn1303Lys1.271.660.350.762.781.27DelI507/c.1519_1521delATC/p.Ile507del0.880.681.870.000.220.90R553X/c.1657C>T/p.Arg553*0.872.812.320.760.001.21R117H/c.350G>A/p.Arg117His0.700.110.060.000.000.543849+10kbC>T/c.3718-2477C>T/-0.581.570.175.314.770.851717-1G>A/c.1585-1G>A/-0.480.270.370.000.670.442789+5G>A/c.2657+5G>A/-0.480.160.000.000.100.38R347P/c.1040G>C/p.Arg347Pro0.450.160.060.000.000.36711+1G>T/c.579+1G>T/-0.430.230.000.000.100.35R560T/c.1679G>C/p.Arg560Thr0.380.000.170.000.000.303659delC/c.3528delC/p.Lys1177Serfs0.340.130.060.000.000.28A455E/c.1364C>A/p.Ala455Glu0.340.050.000.000.000.26G85E/c.254G>A/p.Gly85Glu0.290.230.120.000.000.26R1162X/c.3484C>T/p.Arg1162*0.230.580.660.000.000.302184delA/c.2052delA/p.Lys684Asnfs0.170.160.050.000.100.151898+1G>A/c.1766+1G>A/-0.160.050.060.000.100.13R334W/c.1000C>T/p.Arg334Trp0.141.780.490.000.000.373120+1G>A/c.2988+1G>A/-0.080.169.570.000.100.86Total88.4071.9064.5148.9394.1484.00CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; HGVS, Human Gene Variation Society; -, not applicable. Open table in a new tab CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; HGVS, Human Gene Variation Society; -, not applicable. A normal carrier screening result in someone with a family history of CF renders a higher residual risk than would be the case for an individual without it, unless the mutations in the relative were included in the screen.10Lebo R.V. Grody W.W. Testing and reporting ACMG cystic fibrosis mutation panel results.Genet Test. 2007; 11: 11-31Crossref PubMed Scopus (21) Google Scholar, 18Langfelder-Schwind E. Karczeski B. Strecker M.N. Redman J. Sugarman E.A. Zaleski C. Brown T. Keiles S. Powers A. Ghate S. Darrah R. Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors.J Genet Couns. 2014; 23: 5-15Crossref PubMed Scopus (26) Google Scholar Bayesian risk calculations can be applied to convey the most accurate information.10Lebo R.V. Grody W.W. Testing and reporting ACMG cystic fibrosis mutation panel results.Genet Test. 2007; 11: 11-31Crossref PubMed Scopus (21) Google Scholar, 19Ogino S. Wilson R.B. Gold B. Hawley P. Grody W.W. Bayesian analysis for cystic fibrosis risks in prenatal and carrier screening.Genet Med. 2004; 6: 439-449PubMed Scopus (14) Google Scholar The risk of having an affected child after testing negative with the 23-mutation panel with a negative family history and with a negative test result in the partner is approximately 1 in 44,100 for Hispanic whites, 1 in 57,600 for Asian Americans (estimated, with further studies required), 1 in 171,396 for African Americans, 1 in 3,489,424 for Ashkenazi Jews, and 1 in 78,400 in US whites(when origin is not further specified)10Lebo R.V. Grody W.W. Testing and reporting ACMG cystic fibrosis mutation panel results.Genet Test. 2007; 11: 11-31Crossref PubMed Scopus (21) Google Scholar (Table 3).Table 3Risk of Having a Child with CF in an Asymptomatic Mother with a Negative ACMG Carrier Screening Panel Result, Listed by Ethnic GroupBirth prevalenceNon-Hispanic white∗Approximate values available for US whites (origin unspecified) and European whites.Hispanic whiteAfrican AmericanAsian AmericanAshkenazi Jewish1:23001:13,5001:15,1001:35,1001:2270Carrier risk (pre test)1:291:461:651:901:29Carrier detection rate (%)72–9057692597Carrier risk (post test/neg test)1:100–1:2801:1051:2071:1201:934Fetal risk (neg mother, untested partner)1:11,600–1:32,4801:19,3201:53,8201:43,2001:108,344Fetal risk (neg test, both partners)1:40,000–1:313,6001:44,1001:171,3961:57,6001:3,489,424Adapted and modified from Lebo and Grody,10Lebo R.V. Grody W.W. Testing and reporting ACMG cystic fibrosis mutation panel results.Genet Test. 2007; 11: 11-31Crossref PubMed Scopus (21) Google Scholar with permission from the publisher, Mary Ann Liebert, Inc.ACMG, American College of Medical Genetics and Genomics; CF, cystic fibrosis; neg, negative.∗ Approximate values available for US whites (origin unspecified) and European whites. Open table in a new tab Adapted and modified from Lebo and Grody,10Lebo R.V. Grody W.W. Testing and reporting ACMG cystic fibrosis mutation panel results.Genet Test. 2007; 11: 11-31Crossref PubMed Scopus (21) Google Scholar with permission from the publisher, Mary Ann Liebert, Inc. ACMG, American College of Medical Genetics and Genomics; CF, cystic fibrosis; neg, negative. The limited mutation detection rate (clinical sensitivity) in certain ethnic groups2Palomaki G.E. FitzSimmons S.C. Haddow J.E. Clinical sensitivity of prenatal screening for cystic fibrosis via CFTR carrier testing in a United States panethnic population.Genet Med. 2004; 6: 405-414Crossref PubMed Scopus (77) Google Scholar and the high US frequency of mixed ethnicities has led to development of expanded mutation panels and other mutation detection approaches. The issues with such panels include potentially conveying a false sense of security with normal results, and a false sense of danger with identified variants of uncertain clinical significance. This is compounded by uncertain allele frequencies, admixture of one or more ethnic backgrounds, and arbitrary selection of rare variants that often do not have genotype-phenotype correlation data. With an increasing number of mutations thus selected, minimal improvement in sensitivity is achieved.20Grody W.W. Cutting G.R. Watson M.S. The Cystic Fibrosis mutation "arms race": when less is more.Genet Med. 2007; 9: 739-744Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar In addition, the mutation spectrum is still not well characterized for several ethnic groups. Until the mutation spectrum is better characterized, clinicians can consider CF in these ethnic groups as a genetic disorder that is not sufficiently screened by existing common frequency mutation panels. Examination of sensitivity and specificity combined with family history and ethnicity are key to assessing which test(s) to pursue and to providing targeted, informative, and cost-effective carrier screening care on a population scale. For the individual with a family history of CF, general carrier screening is not the appropriate workup because sequencing and/or deletion or duplication analysis may be appropriate next steps. When the affected individual in a family does not have a known molecular diagnosis and when the individual with a family history of CF has a partner who is a carrier, sequencing and/or deletion or duplication analysis may be wanted and referral to a genetics professional for assessment and genetic counseling is warranted. When familial mutations are known, preimplantation genetic diagnosis or screening is an option. Preimplantation genetic diagnosis for CF allows couples to avoid decisions regarding continuation of an affected pregnancy. However, insurance coverage for in vitro fertilization and preimplantation genetic diagnosis varies, and there are often significant associated personal costs. After conception, prenatal CF testing can be performed on chorionic villus sampling specimens at 10 to 12 weeks and on amniocentesis samples at 16 to 18 weeks. Cell-free fetal DNA testi