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. 2013 Oct;45(10):1160-7.
doi: 10.1038/ng.2745. Epub 2013 Aug 25.

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

Patrick R Sosnay  1 , Karen R Siklosi, Fredrick Van Goor, Kyle Kaniecki, Haihui Yu, Neeraj Sharma, Anabela S Ramalho, Margarida D Amaral, Ruslan Dorfman, Julian Zielenski, David L Masica, Rachel Karchin, Linda Millen, Philip J Thomas, George P Patrinos, Mary Corey, Michelle H Lewis, Johanna M Rommens, Carlo Castellani, Christopher M Penland, Garry R Cutting
Affiliations

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

Patrick R Sosnay et al. Nat Genet. 2013 Oct.

Abstract

Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of ł0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.

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Figures

Figure 1
Figure 1. Data collected for the CFTR2 project
The 159 variants seen in 9 or more alleles with an allele frequency of ≥0.01% in CFTR2 were prioritized for further analysis. *Incomplete clinical information available from submitting registry at the time of analysis. aSweat chloride data was not reported for 10,170 patients. 236 patients had sweat chloride values outside physiologic range (>150 mmol/L or <5 mmol/L) and were excluded. bLung function data was not reported for 10,197 patients. 5,633 patients were under the age of 6 years and were excluded, if measurements were present. 46 patients had lung function measurements outside physiologic range (<3% or >150% predicted) and were excluded. cPancreatic status was characterized as sufficient (PS) or insufficient (PI). Data was not reported on 5,083 patients.
Figure 2
Figure 2. The process used to assign CFTR variants as cystic fibrosis-causing based on a biochemical measure
The mean sweat chloride concentration was evaluated for patients with a given variant in trans with a known cystic fibrosis-causing variant (16 commonly occurring pancreatic insufficient variants among the 23 originally identified as cystic fibrosis-causing in the ACMG panel). Five variants did not have sufficient sweat chloride values from patients with the variant of interest in trans with a cystic fibrosis-causing variant.
Figure 3
Figure 3. The process used to assign CFTR variants as cystic fibrosis-causing based on functional analysis
Variants were sorted by their predicted effect. Those expected to disrupt the amount or quality of RNA included variants that cause a premature termination codon (PTC) and therefore no protein (introduction of a stop codon, variants that affect splice donor-acceptor sites, insertion or deletion changes that introduce a frameshift) and variants predicted to result in altered mRNA splicing efficiency and therefore reduced full-length CFTR protein produced. Variants predicted to produce full-length CFTR protein, but with an amino acid substitution, insertion, or deletion (missense and insertion or deletion changes that do not introduce a frameshift) were evaluated to determine protein level (defined as percentage of mature protein present) or function (defined as percentage of chloride current). Variants were considered disease-causing if they resulted in less than 10% of the level of WT-CFTR mRNA transcript, WT-CFTR protein or WT-CFTR chloride current. aTwo common variants in intron 9 that have a complex effect upon the cystic fibrosis phenotype and have been extensively studied were excluded from further analysis (see text). b Variants known to cause additional consequences include: c.1393-1G>A (legacy name 1525-1G->A), which skips an in-frame exon; p.Glu831X, which results in an alternatively spliced mRNA in addition to synthesis of a truncated protein; and p.Glu1418ArgfsX14 in which the deletion in the final exon would not be expected to cause nonsense mediated decay (NMD). Each of these variants is associated with a mean sweat chloride concentration above 60mmol/L (Supplementary Figure 2). cFive variants previously reported in the literature to have aberrant splicing; four variants found to have aberrant splicing by minigene analysis. dVariants p.[Gln359Lys;Thr360Lys], p.Leu558Ser, and p.Arg1070Gln.
Figure 4
Figure 4. Assignment of disease liability to the 159 most frequent CFTR variants using three criteria
127 variants deemed cystic fibrosis-causing met clinical and functional criteria and had no evidence of non-penetrance. Of 19 variants meeting clinical or functional criteria but not both, 14 had no evidence of non-penetrance and were classified as indeterminate; 5 variants were seen on the non-transmitted CFTR allele in fathers of cystic fibrosis offspring and were classified as non-cystic fibrosis causing. Thirteen remaining variants met neither clinical nor functional criteria, 7 of which were observed to be non-penetrant and were classified as non-cystic fibrosis causing. The remaining 6 variants had no evidence of non-penetrance but insufficient evidence to be classified as non cystic fibrosis-causing and so were classified as indeterminate. CVariants that met clinical criteria but not functional criteria. FVariants that met functional criteria but not clinical criteria. †Variant known to be part of a complex allele or found in cis with another variant.
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