A Transparent Approach to Calculate Detection Rate and Residual Risk for Carrier Screening

Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself. Herein, we provide a detailed approach for calculating DR and RR. DR was calculated on the basis of the sum of disease allele frequencies (DAFs) of pathogenic variants found in published literature. As a proof of concept, DAF data for cystic fibrosis were compared with society guidelines. The DAF data calculated by this method were consistent with the published cystic fibrosis guideline. In addition, we compared DAF for four genes (ABCC8, ASPA, GAA, and MMUT) across three laboratories, and outlined the likely reasons for discrepancies between these laboratories. The utility of carrier screening is to support couples with information while making reproductive choices. Accurate development of DR and RR is therefore critical. The method described herein provides an unbiased and transparent process to collect, calculate, and report these data. Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself. Herein, we provide a detailed approach for calculating DR and RR. DR was calculated on the basis of the sum of disease allele frequencies (DAFs) of pathogenic variants found in published literature. As a proof of concept, DAF data for cystic fibrosis were compared with society guidelines. The DAF data calculated by this method were consistent with the published cystic fibrosis guideline. In addition, we compared DAF for four genes (ABCC8, ASPA, GAA, and MMUT) across three laboratories, and outlined the likely reasons for discrepancies between these laboratories. The utility of carrier screening is to support couples with information while making reproductive choices. Accurate development of DR and RR is therefore critical. The method described herein provides an unbiased and transparent process to collect, calculate, and report these data. Carrier screening (CS) is a genetic test performed on healthy individuals to assess their carrier status of recessive disorders and, thus, their risk of having affected children.1Committee on GeneticsCommittee opinion no. 691: carrier screening for genetic conditions.Obstet Gynecol. 2017; 129: e41-e55Crossref PubMed Scopus (143) Google Scholar, 2Monaghan K.G. Lyon E. Spector E.B. American College of Medical Genetics and GenomicsACMG standards and guidelines for fragile X testing: a revision to the disease-specific supplements to the standards and guidelines for clinical genetics laboratories of the American College of Medical Genetics and Genomics.Genet Med. 2013; 15: 575-586Crossref PubMed Scopus (92) Google Scholar, 3Prior T.W. Professional P. Guidelines C. Carrier screening for spinal muscular atrophy.Genet Med. 2008; 10: 840-842Crossref PubMed Scopus (158) Google Scholar, 4Watson 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 (346) Google Scholar In addition to the prevalent conditions, such as cystic fibrosis (CF) and spinal muscular atrophy, many testing laboratories now have expanded CS panels that can include hundreds of conditions.5Henneman L. Borry P. Chokoshvili D. Cornel M.C. van El C.G. Forzano F. Hall A. Howard H.C. Janssens S. Kayserili H. Lakeman P. Lucassen A. Metcalfe S.A. Vidmar L. de Wert G. Dondorp W.J. Peterlin B. Responsible implementation of expanded carrier screening.Eur J Hum Genet. 2016; 24: e1-e12Crossref PubMed Scopus (137) Google Scholar Recent studies have focused on determining the criteria for appropriate selection of genetic conditions for a pan-ethnic CS approach but fail to discuss how to generate metrics, like disease prevalence, ethnic carrier frequency, detection rate (DR), or residual risk (RR).6Johansen Taber K.A. Beauchamp K.A. Lazarin G.A. Muzzey D. Arjunan A. Goldberg J.D. Clinical utility of expanded carrier screening: results-guided actionability and outcomes.Genet Med. 2019; 21: 1041-1048Crossref PubMed Scopus (22) Google Scholar, 7Ben-Shachar R. Svenson A. Goldberg J.D. Muzzey D. A data-driven evaluation of the size and content of expanded carrier screening panels.Genet Med. 2019; 21: 1931-1939Crossref PubMed Scopus (14) Google Scholar, 8Beauchamp K.A. Johansen Taber K.A. Grauman P.V. Spurka L. Lim-Harashima J. Svenson A. Goldberg J.D. Muzzey D. Sequencing as a first-line methodology for cystic fibrosis carrier screening.Genet Med. 2019; 21: 2569-2576Crossref PubMed Scopus (13) Google Scholar, 9Beauchamp K.A. Muzzey D. Wong K.K. Hogan G.J. Karimi K. Candille S.I. Mehta N. Mar-Heyming R. Kaseniit K.E. Kang H.P. Evans E.A. Goldberg J.D. Lazarin G.A. Haque I.S. Systematic design and comparison of expanded carrier screening panels.Genet Med. 2018; 20: 55-63Crossref PubMed Scopus (25) Google Scholar, 10Committee on GeneticsCommittee opinion no. 690: carrier screening in the age of genomic medicine.Obstet Gynecol. 2017; 129: e35-e40Crossref PubMed Scopus (105) Google Scholar, 11Haque I.S. Lazarin G.A. Kang H.P. Evans E.A. Goldberg J.D. Wapner R.J. Modeled fetal risk of genetic diseases identified by expanded carrier screening.JAMA. 2016; 316: 734-742Crossref PubMed Scopus (100) Google Scholar Because an individual who tests negative for a specific condition still carries a nonzero possibility (referred to as RR) of being a carrier for a pathogenic variant not detected by the assay, providing the transparent summary in the derivation of and supporting evidence behind these metrics is important. Despite the importance of DR and RR for the utility of CS results, there have not been any recommendations for a standardized approach for calculation or mechanisms to transparently report the evidence for a laboratory's methods. Multiple laboratories with similar gene/variant content can have different numbers. Also, the associated evidence and methods used to calculate the respective carrier frequencies and DR are not readily available; this presents challenges for ordering providers to conduct objective comparisons between multiple laboratories offering similar tests. This study presents one suggested method of calculating these metrics across four autosomal recessive genes/conditions (ABCC8, ASPA, GAA, and MMUT), using CF as a proof of concept.4Watson 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 (346) Google Scholar We then demonstrate the variability of DR for these conditions across multiple laboratories and explore the possible reasons behind these nuances. Carrier frequency is the proportion of individuals who carry a single heterozygous pathogenic variant for a recessive genetic condition in a given population. Mimicking the categories used in CF guidelines, carrier frequencies for five ethnicities [Ashkenazi Jewish (AJ), white, African American, Hispanic, and Asian] were obtained and grouped from published studies and guidelines as well as public databases like Orphanet (https://www.orpha.net/consor/www/cgi-bin/OC_Exp.php?lng=EN&Expert=293355, last accessed December 7, 2020) and GeneReviews (Supplemental Table S1).12Glaser B. Blech I. Krakinovsky Y. Ekstein J. Gillis D. Mazor-Aronovitch K. Landau H. Abeliovich D. ABCC8 mutation allele frequency in the Ashkenazi Jewish population and risk of focal hyperinsulinemic hypoglycemia.Genet Med. 2011; 13: 891-894Crossref PubMed Scopus (20) Google Scholar, 13Nestorowicz A. Wilson B.A. Schoor K.P. Inoue H. Glaser B. Landau H. Stanley C.A. Thornton P.S. Clement JPt Bryan J. Aguilar-Bryan L. 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Professional Practice and Guidelines CommitteeCarrier screening in individuals of Ashkenazi Jewish descent.Genet Med. 2008; 10: 54-56Crossref PubMed Scopus (147) Google Scholar, 17Kaul R. Gao G.P. Aloya M. Balamurugan K. Petrosky A. Michals K. Matalon R. Canavan disease: mutations among Jewish and non-Jewish patients.Am J Hum Genet. 1994; 55: 34-41PubMed Google Scholar, 18Elpeleg O.N. Shaag A. The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients.J Inherit Metab Dis. 1999; 22: 531-534Crossref PubMed Scopus (41) Google Scholar, 19Leslie N. Bailey L. Pompe disease.in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J.H. Stephens K. Amemiya A. GeneReviews [Internet]. Copyright University of Washington, Seattle1993Google Scholar, 20Pittis M.G. Donnarumma M. Montalvo A.L. Dominissini S. Kroos M. Rosano C. Stroppiano M. Bianco M.G. Donati M.A. Parenti G. D'Amico A. Ciana G. Di Rocco M. Reuser A. Bembi B. Filocamo M. 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Mutation and haplotype analyses of the MUT gene in Japanese patients with methylmalonic acidemia.J Hum Genet. 2007; 52: 48-55Crossref PubMed Scopus (24) Google Scholar Alternatively, if no specific carrier frequencies were listed, they were derived on the basis of the disease prevalence using the Hardy-Weinberg equation.30Mayo O. A century of Hardy-Weinberg equilibrium.Twin Res Hum Genet. 2008; 11: 249-256Crossref PubMed Scopus (66) Google Scholar If neither were available, a default value of 1 in 500 carrier frequency (which is equivalent to the prevalence rate of 1 in 1,000,000) was used for rare disorders. White data were used for AJ individuals unless a specific prevalence was reported for the AJ population. An other category was generated for patients who did not fit into one of the five ethnicities or would report a mixed ethnicity. To be conservative, the numbers used in this category were to be the highest found across the five ethnicities unless a general population frequency had been found in the literature. Carrier frequency denominators were rounded to the nearest whole number. In this study, DR is defined as the sum of disease allele frequencies (DAFs) for a given disease gene that could be detected by a specific molecular screening method. To calculate DR, Online Mendelian Inheritance in Man, GeneReviews, and PubMed were examined for publications that provided the relevant DAF information in affected individuals from different ethnicities for a given gene/syndrome. Studies in which cohorts were selected on the basis of clinical diagnosis of a specific syndrome and had at least ≥10 patients (≥20 patient alleles) were used. For each variant, the DAF in the affected population was noted. For multiple articles describing the same ethnicity and variant, an average was taken to determine the final ethnic-specific DAF. Cohorts that include consanguineous families or the same individuals described in multiple studies were excluded. The final DR for each ethnicity was the sum of all disease variants' DAF listed for the gene and corresponding syndrome. The following rules were applied for calculating DR extracted from the literature: i) Subethnicity or country-specific data on DR were grouped into one of five ethnicities. ii) Similar to carrier frequency calculations, unless the DAF information was specified for AJ ethnicity, white data were used for the DR of AJ individuals. iii) The data for other were either based on general population if data were stated or were conservatively listed as the lowest specified DR for any ethnicity. iv) The lowest and highest possible DR values were set at 10% and 99%, respectively. v) DR values were rounded to the nearest whole number (percentage). Finally, RR was calculated as the carrier frequency multiplied by one minus the DR, and the denominator was rounded to the nearest whole number.31Dungan J. Expanded carrier screening: what the reproductive endocrinologist needs to know.Fertil Steril. 2018; 109: 183-189Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The American College of Medical Genetics and Genomics (ACMG) has previously published guidelines on CF testing in 2002 and 2004.4Watson 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 (346) Google Scholar,32Richards C.S. Bradley L.A. Amos J. Allitto B. Grody W.W. Maddalena A. McGinnis M.J. Prior T.W. Popovich B.W. Watson M.S. Palomaki G.E. Standards and guidelines for CFTR mutation testing.Genet Med. 2002; 4: 379-391Crossref PubMed Scopus (102) Google Scholar It presents a panel of 23 pathogenic variants, each of which is present in >0.1% of the CF affected population. The guideline lists ethnic-specific DAF for each of the 23 variants, as determined from a total of >400,000 CF patients. Taken together, the panel detects 49% to 94% of CF alleles, depending on the ethnicity.4Watson 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 (346) Google Scholar,32Richards C.S. Bradley L.A. Amos J. Allitto B. Grody W.W. Maddalena A. McGinnis M.J. Prior T.W. Popovich B.W. Watson M.S. Palomaki G.E. Standards and guidelines for CFTR mutation testing.Genet Med. 2002; 4: 379-391Crossref PubMed Scopus (102) Google Scholar As a proof of concept to test the validity of our approach, the proposed literature-based method for DAF calculation was compared with the data described in the widely accepted ACMG guideline. A literature search was performed for the DAF for each of the 23 variants for each ethnicity per our criteria (Table 1).33Macek Jr., M. Mackova A. Hamosh A. Hilman B.C. Selden R.F. Lucotte G. Friedman K.J. Knowles M.R. Rosenstein B.J. Cutting G.R. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.Am J Hum Genet. 1997; 60: 1122-1127PubMed Google Scholar, 34Grebe T.A. Seltzer W.K. DeMarchi J. Silva D.K. Doane W.W. Gozal D. Richter S.F. Bowman C.M. Norman R.A. Rhodes S.N. Hernried L.S. Murphy S. Harwood I.R. Accurso K.J. Jain K.D. Genetic analysis of Hispanic individuals with cystic fibrosis.Am J Hum Genet. 1994; 54: 443-446PubMed Google Scholar, 35Casals T. Ramos M.D. Gimenez J. Larriba S. Nunes V. Estivill X. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes.Hum Genet. 1997; 101: 365-370Crossref PubMed Scopus (68) Google Scholar, 36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 37Lerer I. Sagi M. Cutting G.R. Abeliovich D. Cystic fibrosis mutations delta F508 and G542X in Jewish patients.J Med Genet. 1992; 29: 131-133Crossref PubMed Google Scholar, 38Abeliovich D. Lavon I.P. Lerer I. Cohen T. Springer C. Avital A. Cutting G.R. Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population.Am J Hum Genet. 1992; 51: 951-956PubMed Google Scholar, 39McColley S.A. Rosenstein B.J. Cutting G.R. Differences in expression of cystic fibrosis in blacks and whites.Am J Dis Child. 1991; 145: 94-97PubMed Google Scholar, 40Mei-Zahav M. Durie P. Zielenski J. Solomon M. Tullis E. Tsui L.C. Corey M. The prevalence and clinical characteristics of cystic fibrosis in South Asian Canadian immigrants.Arch Dis Child. 2005; 90: 675-679Crossref PubMed Scopus (23) Google Scholar, 41Padoa C. Goldman A. Jenkins T. Ramsay M. Cystic fibrosis carrier frequencies in populations of African origin.J Med Genet. 1999; 36: 41-44PubMed Google Scholar The DAF values were consistent (<±5%) with the original ACMG data for these 23 variants, which were based on the internal data of >400,000 individuals screened for CFTR variants (Table 1).4Watson 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 (346) Google ScholarTable 1DAFs for the 23 ACMG-Defined CFTR Pathogenic VariantsVariant frequencies among individuals with cystic fibrosis, %HGVS cDNAHGVS pDNAAlternative nomenclatureWhiteHAAASAJReferencesfor data in columns 4-8, DAF (PMID)c.1000C>Tp.Arg334TrpNA0.11.680.52.4NAWhite = 0.1 (9150159)33Macek Jr., M. Mackova A. Hamosh A. Hilman B.C. Selden R.F. Lucotte G. Friedman K.J. Knowles M.R. Rosenstein B.J. Cutting G.R. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.Am J Hum Genet. 1997; 60: 1122-1127PubMed Google ScholarH = 1.6 (7509564)34Grebe T.A. Seltzer W.K. DeMarchi J. Silva D.K. Doane W.W. Gozal D. Richter S.F. Bowman C.M. Norman R.A. Rhodes S.N. Hernried L.S. Murphy S. Harwood I.R. Accurso K.J. Jain K.D. Genetic analysis of Hispanic individuals with cystic fibrosis.Am J Hum Genet. 1994; 54: 443-446PubMed Google Scholar; 1.64 (9439669)35Casals T. Ramos M.D. Gimenez J. Larriba S. Nunes V. Estivill X. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes.Hum Genet. 1997; 101: 365-370Crossref PubMed Scopus (68) Google Scholar; 1.8 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar (AVG = 1.68)AA = 0.7 (9150159)33Macek Jr., M. Mackova A. Hamosh A. Hilman B.C. Selden R.F. Lucotte G. Friedman K.J. Knowles M.R. Rosenstein B.J. Cutting G.R. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.Am J Hum Genet. 1997; 60: 1122-1127PubMed Google Scholar; 0.3 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar (AVG = 0.5)AS = 2.4 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholarc.1040G>Cp.Arg347ProNA0.30.23NANANAWhite = 0.3 (9150159)33Macek Jr., M. Mackova A. Hamosh A. Hilman B.C. Selden R.F. Lucotte G. Friedman K.J. Knowles M.R. Rosenstein B.J. Cutting G.R. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.Am J Hum Genet. 1997; 60: 1122-1127PubMed Google Scholar; 0.3 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar (AVG = 0.3)H = 0.23 (9439669)35Casals T. Ramos M.D. Gimenez J. Larriba S. Nunes V. Estivill X. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes.Hum Genet. 1997; 101: 365-370Crossref PubMed Scopus (68) Google Scholarc.1364C>Ap.Ala455GluNA0.2NANA0.8NAWhite = 0.1 (9150159)33Macek Jr., M. Mackova A. Hamosh A. Hilman B.C. Selden R.F. Lucotte G. Friedman K.J. Knowles M.R. Rosenstein B.J. Cutting G.R. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.Am J Hum Genet. 1997; 60: 1122-1127PubMed Google Scholar; 0.3 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar (AVG = 0.2)AS = 0.8 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholarc.1519_1521delATCp.Ile507delΔI507del0.251.040.5NANAWhite = 0.1 (9150159)33Macek Jr., M. Mackova A. Hamosh A. Hilman B.C. Selden R.F. Lucotte G. Friedman K.J. Knowles M.R. Rosenstein B.J. Cutting G.R. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.Am J Hum Genet. 1997; 60: 1122-1127PubMed Google Scholar; 0.4 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar (AVG = 0.25)H = 0.78 (9439669)35Casals T. Ramos M.D. Gimenez J. Larriba S. Nunes V. Estivill X. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes.Hum Genet. 1997; 101: 365-370Crossref PubMed Scopus (68) Google Scholar; 1.3 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar (AVG = 1.04)AA = 0.7 (9150159)33Macek Jr., M. Mackova A. Hamosh A. Hilman B.C. Selden R.F. Lucotte G. Friedman K.J. Knowles M.R. Rosenstein B.J. Cutting G.R. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.Am J Hum Genet. 1997; 60: 1122-1127PubMed Google Scholar; 0.4 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar (AVG = 0.5)c.1521_1523delCTTp.Phe508delΔF508del69.85143.84229.7AJ = 29.7 (1377276)37Lerer I. Sagi M. Cutting G.R. Abeliovich D. Cystic fibrosis mutations delta F508 and G542X in Jewish patients.J Med Genet. 1992; 29: 131-133Crossref PubMed Google Scholar; 29.7 (1384328)38Abeliovich D. Lavon I.P. Lerer I. Cohen T. Springer C. Avital A. Cutting G.R. Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population.Am J Hum Genet. 1992; 51: 951-956PubMed Google Scholar (AVG = 29.7)White = 66.2 (9150159)33Macek Jr., M. Mackova A. Hamosh A. Hilman B.C. Selden R.F. Lucotte G. Friedman K.J. Knowles M.R. Rosenstein B.J. Cutting G.R. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%.Am J Hum Genet. 1997; 60: 1122-1127PubMed Google Scholar; 73.4 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. The spectrum of CFTR variants in nonwhite cystic fibrosis patients: implications for molecular diagnostic testing.J Mol Diagn. 2016; 18: 39-50Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar (AVG = 69.8)H = 46 (7509564)34Grebe T.A. Seltzer W.K. DeMarchi J. Silva D.K. Doane W.W. Gozal D. Richter S.F. Bowman C.M. Norman R.A. Rhodes S.N. Hernried L.S. Murphy S. Harwood I.R. Accurso K.J. Jain K.D. Genetic analysis of Hispanic individuals with cystic fibrosis.Am J Hum Genet. 1994; 54: 443-446PubMed Google Scholar; 53.2 (9439669)35Casals T. Ramos M.D. Gimenez J. Larriba S. Nunes V. Estivill X. High heterogeneity for cystic fibrosis in Spanish families: 75 mutations account for 90% of chromosomes.Hum Genet. 1997; 101: 365-370Crossref PubMed Scopus (68) Google Scholar; 54 (26708955)36Schrijver I. Pique L. Graham S. Pearl M. Cherry A. Kharrazi M. 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