The novel CFTR haplotype E583G/F508del in CFTR-related disorder.
CFTR
CFTR-RD
Next generation sequencing
Variants of unknown significance
Journal
Molecular biology reports
ISSN: 1573-4978
Titre abrégé: Mol Biol Rep
Pays: Netherlands
ID NLM: 0403234
Informations de publication
Date de publication:
25 Jul 2024
25 Jul 2024
Historique:
received:
04
06
2024
accepted:
17
06
2024
medline:
26
7
2024
pubmed:
26
7
2024
entrez:
25
7
2024
Statut:
epublish
Résumé
CFTR-related disorder (CFTR-RD) is a clinical entity associated to complex diagnostic paths and newly upgraded standard of care. In CFTR-RD, CFTR genotyping represents a diagnostic surrogate marker. In case of novel haplotype, the diagnosis could represents an area of concern. We described the molecular evaluation of the rare CFTR variant E583G identified in trans with the F508del in a novel haplotype. An adult woman was referred to our pulmonary unit for persistent respiratory symptoms. CFTR Next Generation Sequencing was performed to evaluate full-gene mutational status. The variant identified was evaluated for its pathogenicity integrating clinical evidences with dedicated bioinformatics analyses. Clinical evaluation of patient matched with a mono-organ CFTR-RD diagnosis. Genotyping revealed the novel CFTR haplotype F508del/E583G. Multiple evidences of a deleterious effect of the CFTR E583G rare variant emerged from the bioinformatics analyses performed. Guidelines for CFTR-RD are available with the purpose of harmonizing clinical and molecular investigations. In such context, the identification of novel CFTR haplotype need to a deeper evaluation with a combination of skills. The novel E583G variant could be considered of clinical interest and overall a CFTR-RD Variants of Varying Clinical Consequences.
Sections du résumé
BACKGROUND
BACKGROUND
CFTR-related disorder (CFTR-RD) is a clinical entity associated to complex diagnostic paths and newly upgraded standard of care. In CFTR-RD, CFTR genotyping represents a diagnostic surrogate marker. In case of novel haplotype, the diagnosis could represents an area of concern. We described the molecular evaluation of the rare CFTR variant E583G identified in trans with the F508del in a novel haplotype.
METHODS AND RESULTS
RESULTS
An adult woman was referred to our pulmonary unit for persistent respiratory symptoms. CFTR Next Generation Sequencing was performed to evaluate full-gene mutational status. The variant identified was evaluated for its pathogenicity integrating clinical evidences with dedicated bioinformatics analyses. Clinical evaluation of patient matched with a mono-organ CFTR-RD diagnosis. Genotyping revealed the novel CFTR haplotype F508del/E583G. Multiple evidences of a deleterious effect of the CFTR E583G rare variant emerged from the bioinformatics analyses performed.
CONCLUSIONS
CONCLUSIONS
Guidelines for CFTR-RD are available with the purpose of harmonizing clinical and molecular investigations. In such context, the identification of novel CFTR haplotype need to a deeper evaluation with a combination of skills. The novel E583G variant could be considered of clinical interest and overall a CFTR-RD Variants of Varying Clinical Consequences.
Identifiants
pubmed: 39052151
doi: 10.1007/s11033-024-09732-x
pii: 10.1007/s11033-024-09732-x
doi:
Substances chimiques
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
CFTR protein, human
0
Types de publication
Journal Article
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
849Informations de copyright
© 2024. The Author(s).
Références
Schram CA (2012) Atypical cystic fibrosis: identification in the primary care setting. Can Family Physician Medecin De Famille Canadien 12:1341–1345
Farrell PM, White TB, Ren CL et al (2017) Diagnosis of Cystic Fibrosis: Consensus Guidelines from the Cystic Fibrosis Foundation. J Pediatr. 181S:S4-S15.e1. https://doi.org/10.1016/j.jpeds.2016.09.064
Polgreen PM, Comellas AP (2022) Clinical phenotypes of cystic fibrosis carriers. Annu Rev Med 73:563–574. https://doi.org/10.1146/annurev-med-042120-020148
doi: 10.1146/annurev-med-042120-020148
pubmed: 35084992
pmcid: 8884701
Davé S, Honney S, Raymond J, Flume PA (2005) An unusual presentation of cystic fibrosis in an adult. Am J Kidney Dis 45:e41–e44. https://doi.org/10.1053/j.ajkd.2004.11.009
doi: 10.1053/j.ajkd.2004.11.009
pubmed: 15754262
Bombieri C, Claustres M, De Boeck K et al (2011) Recommendations for the classification of diseases as CFTR-related disorders. J Cyst Fibros 10(Suppl 2):S86–S102. https://doi.org/10.1016/S1569-1993(11)60014-3
doi: 10.1016/S1569-1993(11)60014-3
pubmed: 21658649
Ziedalski TM, Kao PN, Henig NR, Jacobs SS, Ruoss SJ (2006) Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest 130:995–1002. https://doi.org/10.1378/chest.130.4.995
doi: 10.1378/chest.130.4.995
pubmed: 17035430
Gan KH, Geus WP, Bakker W, Lamers CB, Heijerman HG (1995) Genetic and clinical features of patients with cystic fibrosis diagnosed after the age of 16 years. Thorax 50:1301–1304. https://doi.org/10.1136/thx.50.12.1301
doi: 10.1136/thx.50.12.1301
pubmed: 8553305
pmcid: 1021355
Sermet-Gaudelus I, Girodon E, Vermeulen F et al (2022) ECFS standards of care on CFTR-related disorders: diagnostic criteria of CFTR dysfunction. J Cyst Fibros 21:922–936. https://doi.org/10.1016/j.jcf.2022.09.005
doi: 10.1016/j.jcf.2022.09.005
pubmed: 36207272
De Paolis E, Tilocca B, Lombardi C et al (2023) Next-generation sequencing for screening analysis of cystic fibrosis: Spectrum and Novel variants in a South-Central Italian Cohort. Genes (Basel) 14:1608. https://doi.org/10.3390/genes14081608
doi: 10.3390/genes14081608
pubmed: 37628659
Stawiński P, Płoski R (2024) Genebe.net: implementation and validation of an automatic ACMG variant pathogenicity criteria assignment. Clin Genet. https://doi.org/10.1111/cge.14516
doi: 10.1111/cge.14516
pubmed: 38440907
Li C, Zhi D, Wang K, Liu X (2022) MetaRNN: differentiating rare pathogenic and rare benign missense SNVs and InDels using deep learning. Genome Med 14:115. https://doi.org/10.1186/s13073-022-01120-z
doi: 10.1186/s13073-022-01120-z
pubmed: 36209109
pmcid: 9548151
Pejaver V, Byrne AB, Feng BJ et al (2022) Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria. Am J Hum Genet 12:2163–2177. https://doi.org/10.1016/j.ajhg.2022.10.013
doi: 10.1016/j.ajhg.2022.10.013
Kopanos C, Tsiolkas V, Kouris A et al (2019) VarSome: the human genomic variant search engine. Bioinformatics 35:1978–1980. https://doi.org/10.1093/bioinformatics/bty897
doi: 10.1093/bioinformatics/bty897
pubmed: 30376034
Ioannidis NM, Rothstein JH, Pejaver V et al (2016) REVEL: an Ensemble Method for Predicting the pathogenicity of rare missense variants. Am J Hum Genet 99:877–885. https://doi.org/10.1016/j.ajhg.2016.08.016
doi: 10.1016/j.ajhg.2016.08.016
pubmed: 27666373
pmcid: 5065685
Murakami Y, Mizuguchi K (2014) Homology-based prediction of interactions between proteins using averaged one-dependence estimators. BMC Bioinformatics 15:213. https://doi.org/10.1186/1471-2105-15-213
doi: 10.1186/1471-2105-15-213
pubmed: 24953126
pmcid: 4229973
Perovic V, Sumonja N, Gemovic B, Toska E, Roberts SG, Veljkovic N (2017) TRI_tool: a web-tool for prediction of protein-protein interactions in human transcriptional regulation. Bioinformatics 33:289–291. https://doi.org/10.1093/bioinformatics/btw590
doi: 10.1093/bioinformatics/btw590
pubmed: 27605104
Chevalier B, Hinzpeter A (2020) The influence of CFTR complex alleles on precision therapy of cystic fibrosis. J Cyst Fibros 19 Suppl 1S15–S18. https://doi.org/10.1016/j.jcf.2019.12.008
Castellani C, De Boeck K, De Wachter E et al (2022) ECFS standards of care on CFTR-related disorders: updated diagnostic criteria. J Cyst Fibros 21:908–921. https://doi.org/10.1016/j.jcf.2022.09.011
doi: 10.1016/j.jcf.2022.09.011
pubmed: 36220763
Alghisi F, Angioni A, Tomaiuolo AC et al (2008) Diagnosis of atypical CF: a case-report to reflect. J Cyst Fibros 7:292–294. https://doi.org/10.1016/j.jcf.2007.11.002
doi: 10.1016/j.jcf.2007.11.002
pubmed: 18180206
LeDoux MS (2020) Population Prevalence of Deleterious SGCE variants. Tremor Other Hyperkinet Mov (N Y 4(10):50. https://doi.org/10.5334/tohm.567
doi: 10.5334/tohm.567
Leonard RJ, Preston CC, Gucwa ME, Afeworki Y, Selya AS, Faustino RS (2020) Protein Subdomain Enrichment of NUP155 variants identify a Novel predicted pathogenic hotspot. Front Cardiovasc Med 7:8. https://doi.org/10.3389/fcvm.2020.00008
doi: 10.3389/fcvm.2020.00008
pubmed: 32118046
pmcid: 7019101
Brock DC, Wang M, Hussain HMJ, Rauch DE, Marra M et al (2024) Comparative analysis of in-silico tools in identifying pathogenic variants in dominant inherited retinal diseases. Hum Mol Genet 33(11):945–957. https://doi.org/10.1093/hmg/ddae028
doi: 10.1093/hmg/ddae028
pubmed: 38453143
Zhu E, Shu X, Xu Z, Peng Y, Xiang Y et al (2023) Screening of immune-related secretory proteins linking chronic kidney disease with calcific aortic valve disease based on comprehensive bioinformatics analysis and machine learning. J Transl Med 21(1):359. https://doi.org/10.1186/s12967-023-04171-x
doi: 10.1186/s12967-023-04171-x
pubmed: 37264340
pmcid: 10234004
Mendoza JL, Schmidt A, Li Q et al (2012) Requirements for efficient correction of ∆F508 CFTR revealed by analyses of evolved sequences. Cell 148(1–2):164–174. https://doi.org/10.1016/j.cell.2011.11.023
doi: 10.1016/j.cell.2011.11.023
pubmed: 22265409
pmcid: 3266553