Abstract
Cystic fibrosis (CF) is one of the most common monogenic diseases affecting Caucasians and has an incidence of approximately 1:3,300 births. Currently recommended screening panels for mutations in the responsible gene (CF transmembrane regulator gene, CFTR) do not detect all disease-associated mutations. Our laboratory offers extensive sequencing of the CFTR (ABCC7) gene (including the promoter, all exons and splice junction sites, and regions of selected introns) as a clinical test to detect mutations which are not found with conventional screening. The objective of this report is to summarize the findings of extensive CFTR sequencing from our first 157 consecutive patient samples. In most patients with classic CF symptoms (18/24, 75%), extensive CFTR sequencing confirmed the diagnosis by finding two disease-associated mutations. In contrast, only 5 of 75 (7%) patients with atypical CF had been identified with two CFTR mutations. A diagnosis of CF was confirmed in 10 of 17 (58%) newborns with either positive sweat chloride readings or positive immunoreactive trypsinogen (IRT) screen results. We ascertained ten novel sequence variants that are potentially disease-associated: two deletions (c.1641AG>T, c.2949_2853delTACTC), seven missense mutations (p.S158T, p.G451V, p.K481E, p.C491S, p.H949L, p.T1036N, p.F1099L), and one complex allele ([p.356_A357del; p.358I]). We ascertained three other apparently novel complex alleles. Finally, several patients were found to carry partial CFTR gene deletions. In summary, extensive CFTR gene sequencing can detect rare mutations which are not found with other screening and diagnostic tests, and can thus establish a definitive diagnosis in symptomatic patients with previously negative results. This enables carrier detection and prenatal diagnosis in additional family members.
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Acknowledgements
We are grateful to the patients and their families and physicians for their participation in this study. In particular, we would like to thank the following clinicians for their input on patients, clinical information and for obtaining additional family specimens: Joanne Gambo CRNP, Joan Germana MD, Eleanor Langfelder-Schwind MS CGC, Maria Santiago MD, and Laurie Varlotta MD. Finally, we gratefully acknowledge our laboratory operations staff for performing the DNA extractions and sequencing analyses for this assay. In particular, Nadia Dekov, Greg Putignani, and Jeremy Teigiser performed most of the sequencing reactions and initial sequence analyses.
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McGinniss, M.J., Chen, C., Redman, J.B. et al. Extensive Sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet 118, 331–338 (2005). https://doi.org/10.1007/s00439-005-0065-1
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DOI: https://doi.org/10.1007/s00439-005-0065-1