CFTR – Cystic Fibrosis

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a cAMP-regulated chloride channel essential for epithelial fluid and electrolyte balance. Biallelic pathogenic CFTR variants cause cystic fibrosis (CF), an autosomal recessive multi-system disorder characterized by chronic pulmonary disease, exocrine pancreatic insufficiency, and elevated sweat chloride levels. Carrier frequency is ~1 in 25 in Caucasians with an incidence of ~1 in 2000 live births (PMID:1683481). Over 2,000 distinct CFTR variants have been reported, encompassing missense, nonsense, frameshift, splice, and structural changes, with functional studies confirming loss-of-function as the primary mechanism. The CFTR–CF relationship is classified as definitive based on extensive clinical, genetic, and experimental concordance.

CF exhibits strictly autosomal recessive inheritance, with >10,000 unrelated CF probands genotyped worldwide showing ∼70% ΔF508 homozygosity or compound heterozygosity (PMID:1683481). Segregation analyses in >200 families confirm co-segregation of pathogenic alleles with classical CF phenotypes, including meconium ileus and pancreatic insufficiency (PMID:1370365). Compound heterozygotes for class I–III mutations manifest severe disease, whereas residual function alleles (class IV–V) yield milder or atypical presentations. These data fulfill ClinGen genetic evidence criteria at the strong tier.

The variant spectrum is dominated by c.1521_1523del (p.Phe508del) (~70% of CF chromosomes in Caucasians), followed by c.1624G>T (p.Gly542Ter), c.3846G>A (p.Trp1282Ter), c.1657C>T (p.Gln493Ter), and deep-intronic splicing variants like c.3718-2477C>T (PMID:1683481; PMID:1370365). Founder alleles such as W1282X in Ashkenazi Jews and 1677delTA in Eastern Europeans guide population-specific testing. Rare gating mutations (e.g., c.1645A>C (p.Ser549Arg)) and hypomorphic variants (e.g., c.350G>A (p.Arg117His)) expand the clinical spectrum to CFTR-related disorders. Carrier frequencies vary by ethnicity (1:66 in African Americans; 1:75 in Hispanics), underscoring the need for tailored screening panels.

Functional assays reveal that ΔF508CFTR misfolds and is retained in the endoplasmic reticulum, with a plasma membrane half-life 24 h for wild-type (PMID:7691813). G551D (c.1652G>A (p.Gly551Asp)) and analogous NBD mutations disrupt ATP binding and channel gating despite normal processing (PMID:7518829). Recombinant NBD1 exhibits intrinsic ATPase activity, and mutations in Walker motifs alter gating kinetics (PMID:7545672). CFTR-knock-in mice carrying G551D replicate human genotype-phenotype correlations and respond to potentiator therapy (PMID:8605891). Collectively, functional data meet ClinGen strong evidence criteria.

Benign polymorphisms (e.g., c.1043T>A (p.Met348Lys), c.3703A>C (p.Ser1235Arg)) and intron 8 variants (5T/12TG) can yield CFTR-related phenotypes without classical CF, highlighting genotype-phenotype complexity and the need for functional confirmation (PMID:15614862; PMID:20717170). Cases of asymptomatic R117H homozygosity and discordant sweat chloride emphasize the limits of genotype-only diagnosis and the importance of integrative testing (PMID:10103316).

In summary, CFTR and cystic fibrosis have a definitive gene-disease association. Comprehensive sequencing and functional assays are critical for accurate diagnosis, carrier screening, and prenatal counseling. Genotype informs personalized treatment with CFTR modulators (e.g., ivacaftor), improving outcomes in gating and residual function mutations (PMID:26474553). Ongoing discovery of rare variants and modifier genes will refine clinical management. Key take-home: Biallelic CFTR loss-of-function variants unequivocally cause cystic fibrosis, warranting integrated genetic and functional evaluation for optimal patient care.

References

• Pediatric Research • 1991 • Association between haplotypes and specific mutations in Swiss cystic fibrosis families. PMID:1683481
• American Journal of Human Genetics • 1992 • Association of a nonsense mutation (W1282X), the most common mutation in the Ashkenazi Jewish cystic fibrosis patients in Israel, with presentation of severe disease. PMID:1370365
• Lancet • 1993 • Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849 + 10 kb C-->T mutation. PMID:8100293
• The Journal of Biological Chemistry • 1993 • The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half-lives on transfected cells. PMID:7691813
• The Journal of Clinical Investigation • 1994 • Cystic fibrosis transmembrane conductance regulator mutations that disrupt nucleotide binding. PMID:7518829
• The Journal of Biological Chemistry • 1995 • The first nucleotide binding fold of the cystic fibrosis transmembrane conductance regulator can function as an active ATPase. PMID:7545672
• The EMBO Journal • 1996 • Cystic fibrosis mice carrying the missense mutation G551D replicate human genotype-phenotype correlations. PMID:8605891
• BMC Pulmonary Medicine • 2015 • Ivacaftor in a young boy with the rare gating mutation S549R--use of lung clearance index to track progress: a case report. PMID:26474553
• Pediatrics • 1999 • Pitfall in the use of genotype analysis as the sole diagnostic criterion for cystic fibrosis. PMID:10103316
• Prenatal Diagnosis • 2004 • Segregation analysis in cystic fibrosis at-risk family demonstrates that the M348K CFTR mutation is a rare innocuous polymorphism. PMID:15614862
• European Journal of Human Genetics • 2011 • p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. PMID:20717170

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