Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico
Andrew M. Zeiger BS
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorCorresponding Author
Meghan E. McGarry MD, MS
Department of Pediatrics, University of California San Francisco, San Francisco, California
Correspondence Meghan E. McGarry, Department of Pediatrics, University of California San Francisco, 550 16th Ave, Box 0632, San Francisco, CA 94158.
Email: [email protected]
Search for more papers by this authorAngel C. Y. Mak PhD
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorVivian Medina RN
Department of Pediatrics, Centro de Neumología Pediátrica, San Juan, Puerto Rico
Search for more papers by this authorSandra Salazar BA
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorCeleste Eng BS
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorAmy K. Liu PharmD
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorSam S. Oh PhD, MPH
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorThomas J. Nuckton MD
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorDeepti Jain PhD
Department of Biostatistics, University of Washington, Seattle, Washington
Search for more papers by this authorThomas W. Blackwell PhD
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
Search for more papers by this authorHyun Min Kang PhD
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
Search for more papers by this authorGoncalo Abecasis DPhil
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
Search for more papers by this authorLeandra Cordero Oñate MD
Department of Pediatrics, Neumología Pediátrica del Hospital Infantil Dr. Robert Reid Cabral, Santo Domingo, República Dominicana
Search for more papers by this authorMax A. Seibold PhD
Department of Pediatrics, National Jewish Health, Denver, Colorado
Search for more papers by this authorEsteban G. Burchard MD, MPH
Department of Medicine, University of California San Francisco, San Francisco, California
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California
Search for more papers by this authorJose Rodriguez-Santana MD
Department of Pediatrics, Centro de Neumología Pediátrica, San Juan, Puerto Rico
Search for more papers by this authorAndrew M. Zeiger BS
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorCorresponding Author
Meghan E. McGarry MD, MS
Department of Pediatrics, University of California San Francisco, San Francisco, California
Correspondence Meghan E. McGarry, Department of Pediatrics, University of California San Francisco, 550 16th Ave, Box 0632, San Francisco, CA 94158.
Email: [email protected]
Search for more papers by this authorAngel C. Y. Mak PhD
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorVivian Medina RN
Department of Pediatrics, Centro de Neumología Pediátrica, San Juan, Puerto Rico
Search for more papers by this authorSandra Salazar BA
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorCeleste Eng BS
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorAmy K. Liu PharmD
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorSam S. Oh PhD, MPH
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorThomas J. Nuckton MD
Department of Medicine, University of California San Francisco, San Francisco, California
Search for more papers by this authorDeepti Jain PhD
Department of Biostatistics, University of Washington, Seattle, Washington
Search for more papers by this authorThomas W. Blackwell PhD
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
Search for more papers by this authorHyun Min Kang PhD
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
Search for more papers by this authorGoncalo Abecasis DPhil
Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan
Search for more papers by this authorLeandra Cordero Oñate MD
Department of Pediatrics, Neumología Pediátrica del Hospital Infantil Dr. Robert Reid Cabral, Santo Domingo, República Dominicana
Search for more papers by this authorMax A. Seibold PhD
Department of Pediatrics, National Jewish Health, Denver, Colorado
Search for more papers by this authorEsteban G. Burchard MD, MPH
Department of Medicine, University of California San Francisco, San Francisco, California
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California
Search for more papers by this authorJose Rodriguez-Santana MD
Department of Pediatrics, Centro de Neumología Pediátrica, San Juan, Puerto Rico
Search for more papers by this authorEsteban G. Burchard and Jose Rodriguez-Santana shared senior authorship.
Andrew M. Zeiger, Meghan E. McGarry, and Angel C.Y. Mak contributed equally to this work.
Abstract
Background
In cystic fibrosis (CF), the spectrum and frequency of CFTR variants differ by geography and race/ethnicity. CFTR variants in White patients are well-described compared with Latino patients. No studies of CFTR variants have been done in patients with CF in the Dominican Republic or Puerto Rico.
Methods
CFTR was sequenced in 61 Dominican Republican patients and 21 Puerto Rican patients with CF and greater than 60 mmol/L sweat chloride. The spectrum of CFTR variants was identified and the proportion of patients with 0, 1, or 2 CFTR variants identified was determined. The functional effects of identified CFTR variants were investigated using clinical annotation databases and computational prediction tools.
Results
Our study found 10% of Dominican patients had two CFTR variants identified compared with 81% of Puerto Rican patients. No CFTR variants were identified in 69% of Dominican patients and 10% of Puerto Rican patients. In Dominican patients, there were 19 identified CFTR variants, accounting for 25 out of 122 disease alleles (20%). In Puerto Rican patients, there were 16 identified CFTR variants, accounting for 36 out of 42 disease alleles (86%) in Puerto Rican patients. Thirty CFTR variants were identified overall. The most frequent variants for Dominican patients were p.Phe508del and p.Ala559Thr and for Puerto Rican patients were p.Phe508del, p.Arg1066Cys, p.Arg334Trp, and p.I507del.
Conclusions
In this first description of the CFTR variants in patients with CF from the Dominican Republic and Puerto Rico, there was a low detection rate of two CFTR variants after full sequencing with the majority of patients from the Dominican Republic without identified variants.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
Supporting Information
| Filename | Description |
|---|---|
| ppul24549-sup-0001-Supplement_Table_Final.docx25.5 KB | Supporting information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 Cystic Fibrosis Foundation. Cystic fibrosis Foundation Patient Registry, 2017 Annual Data Report to the Center Directors. Bethesda, MD: Cystic Fibrosis Foundation; 2017.
- 2McGarry ME, Neuhaus JM, Nielson DW, Burchard E, Ly NP. Pulmonary function disparities exist and persist in Hispanic patients with cystic fibrosis: a longitudinal analysis. Pediatr Pulmonol. 2017; 52(12): 1550-1557.
- 3Rho J, Ahn C, Gao A, Sawicki GS, Keller A, Jain R. Disparities in mortality of Hispanic patients with cystic fibrosis in the United States. A national and regional cohort study. Am J Respir Crit Care Med. 2018; 198(8): 1055-1063.
- 4Watts KD, Layne B, Harris A, McColley SA. Hispanic infants with cystic fibrosis show low CFTR mutation detection rates in the Illinois newborn screening program. J Genet Couns. 2012; 21(5): 671-675.
- 5Schrijver I, Pique L, Graham S, Pearl M, Cherry A, Kharrazi M. The spectrum of CFTR variants in non-White cystic fibrosis patients. J Mol Diagn. 2016; 18(1): 39-50.
- 6Palomaki GE, FitzSimmons SC, Haddow JE. Clinical sensitivity of prenatal screening for cystic fibrosis via CFTR carrier testing in a United States panethnic population. Genet Med. 2004; 6(5): 405-414.
- 7Stewart C, Pepper MS. Cystic fibrosis in the African diaspora. Ann Am Thorac Soc. 2017; 14(1): 1-7.
- 8Moreno-Estrada A, Gravel S, Zakharia F, et al. Reconstructing the population genetic history of the Caribbean. PLoS Genet. 2013; 9(11):e1003925.
- 9Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017; 181: S4-S15.e1.
- 10Taliun D, Harris DN, Kessler MD, et al. Sequencing of 53 831 diverse genomes from the NHLBI TOPMed Program. bioRxiv. 2019; Taliun, Daniel, et al. "Sequencing of 53 831 diverse genomes from the NHLBI TOPMed Program. BioRxiv. 2019:563866.
- 11Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5): 405-423.
- 12Liu X, White S, Peng B, et al. WGSA: an annotation pipeline for human genome sequencing studies. J Med Genet. 2016; 53(2): 111-112.
- 13Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arWiv preprint. 2013; arXiv: 1303. 3997.
- 14Li H, Handsaker B, Wysoker A, et al. The sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16): 2078-2079.
- 15Abyzov A, Urban AE, Snyder M, Gerstein M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 2011; 21(6): 974-984.
- 16Layer RM, Chiang C, Quinlan AR, Hall IM. LUMPY: a probabilistic framework for structural variant discovery. Genome Biol. 2014; 15(6): R84.
- 17Loh P-R, Danecek P, Palamara PF, et al. Reference-based phasing using the haplotype reference consortium panel. Nat Genet. 2016; 48(11): 1443-1448.
- 18 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015; 526(7571): 68-74.
- 19 CFTR2@Johns Hopkins. Home page [Internet]. http://cftr2.org/. Updated March 2019.
- 20Landrum MJ, Lee JM, Benson M, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016; 44(D1): D862-D868.
- 21Nykamp K, Anderson M, Powers M, et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med. 2017; 19(10): 1105-1117.
- 22Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019; 47(D1): D886-D894.
- 23Rogers MF, Shihab HA, Mort M, Cooper DN, Gaunt TR, Campbell C. FATHMM-XF: accurate prediction of pathogenic point mutations via extended features. Bioinformatics. 2018; 34(3): 511-513.
- 24Ioannidis NM, Rothstein JH, Pejaver V, et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 2016; 99(4): 877-885.
- 25Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011; 27(21): 2987-2993.
- 26Alonso MJ, Heine-Suñer D, Calvo M, et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007; 71(2): 194-201.
- 27Sugarman EA, Rohlfs EM, Silverman LM, Allitto BA. CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations. Genet Med. 2004; 6(5): 392-399.
- 28Grebe TA, Seltzer WK, DeMarchi J, et al. Genetic analysis of Hispanic individuals with cystic fibrosis. Am J Hum Genet. 1994; 54(3): 443-446.
- 29Wong LJC, Wang J, Zhang YH, et al. Improved detection of CFTR mutations in southern California Hispanic CF patients. Hum Mutat. 2001; 18(4): 296-307.
- 30Groman JD, Cutting GR. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002; 347(6): 401-407.
- 31Mekus F, Ballmann M, Bronsveld I, et al. Cystic-fibrosis-like disease unrelated to the cystic fibrosis transmembrane conductance regulator. Hum Genet. 1998; 102(5): 582-586.
- 32Agrawal PB, Wang R, Li HL, et al. The epithelial sodium channel is a modifier of the long-term nonprogressive phenotype associated with F508del CFTR mutations. Am J Respir Cell Mol Biol. 2017; 57(6): 711-720.
- 33 Committee on Genetics. Committee opinion no. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017; 129(3): e41-e55.
- 34Leung DH, Heltshe SL, Borowitz D, et al. Effects of diagnosis by newborn screening for cystic fibrosis on weight and length in the first year of life. JAMA Pediatrics. 2017; 171(6): 546.
- 35Kharrazi M, Yang J, Bishop T, et al. Newborn screening for cystic fibrosis in California. Pediatrics. 2015; 136(6): 1062-1072.
- 36Alper M, Wong LJC, Young S, et al. Identification of novel and rare mutations in California Hispanic and African American cystic fibrosis patients. Hum Mutat. 2004; 24(4): 353.
- 37De Boeck K, Amaral MD. Progress in therapies for cystic fibrosis. Lancet Respir Med. 2016; 4(8): 662-674.
- 38McGarry ME, Ly NP. Unequal access to CFTR modulators in Hispanics. Pediatr Pulm. 2017; 52: S396-297.
- 39McGarry ME, McColley SA. Minorities are underrepresented in clinical trials of pharmaceutical agents for cystic fibrosis. Ann Am Thorac Soc. 2016; 13(10): AnnalsATS.201603-192BC.
- 40Raraigh KS, Han ST, Davis E, et al. Functional assays are essential for interpretation of missense variants associated with variable expressivity. Am J Hum Genet. 2018; 102(6): 1062-1077.
- 41Lim RM, Silver AJ, Silver MJ, et al. Targeted mutation screening panels expose systematic population bias in detection of cystic fibrosis risk. Genet Med. 2016; 18(2): 174-179.
- 42Marson FAL, Bertuzzo CS, Ribeiro JD. Classification of CFTR mutation classes. Lancet Respir Med. 2016; 4(8): 37.
Citing Literature
