GeneticsTier 1Medical Sciences concept

Cystic fibrosis genetics (CFTR mutations, genotype-phenotype)

Core concept

CFTR, chromosome 7q31.2 - an ABC transporter family cAMP/PKA-gated chloride and bicarbonate channel on the apical epithelial membrane
Autosomal recessive; ~1 in 25 Caucasians carries a variant, ~1 in 2,500 births
Function is more than chloride
- Secretes Cl- and HCO3-
- Tonically inhibits ENaC -> loss of CFTR increases Na+ (and water) reabsorption
- -> airway surface liquid depletion, dehydrated viscid mucus, impaired mucociliary clearance
- dec HCO3- -> acidic ASL -> impaired antimicrobial peptide function and abnormal mucin unfolding
The sweat duct is the exception: CFTR there reabsorbs Cl- from sweat, so loss gives salty sweat - the basis of the sweat test
>2,000 variants; F508del is by far the commonest (~70% of alleles, ~85% of patients carry at least one copy)
- Deletion of phenylalanine at position 508 -> misfolding, ER retention, proteasomal degradation plus a gating and stability defect

Mutation classes - the class dictates the drug

Class	Defect	Example	Residual function	Matched therapy
I	No protein - nonsense, frameshift, splice-null	G542X, W1282X, 621+1G>T	None	Read-through agents - still experimental; not modulator-responsive
II	Processing/trafficking - misfolded, ER-retained	F508del, N1303K	None (severe)	Corrector + potentiator
III	Gating - channel at surface but won't open	G551D	None (severe)	Potentiator (ivacaftor - the original indication)
IV	Conductance - reduced pore flux	R117H, R334W	Some	Potentiator
V	Reduced quantity - splicing/promoter	3849+10kbC>T, A455E	Some	Potentiator / splice modulation
VI	Reduced membrane stability	c.120del23, rescued F508del	Some	Stabiliser / potentiator

Classes I-III = "minimal function" = severe; IV-VI retain residual function = milder, pancreatic-sufficient, later diagnosis
Rescued F508del reaches the membrane but then behaves like a class III/VI protein - which is why a corrector alone is insufficient and a potentiator is added

Genotype-phenotype

Pancreatic status tracks genotype tightly - two severe alleles -> pancreatic insufficiency in >95%
Lung disease correlates poorly with genotype - modifier genes (TGF-beta1, MBL2, SLC26A9), environment and infections dominate
CFTR-related disorders - one severe + one mild/variable allele
- Congenital bilateral absence of the vas deferens (CBAVD) - >95% of CF men are infertile; CBAVD alone is often R117H with the 5T poly-T variant in cis
- Idiopathic pancreatitis, chronic rhinosinusitis, bronchiectasis, ABPA
The 5T/7T/9T poly-T tract in intron 8 modifies exon 9 splicing - 5T is the least efficient; must be phased with R117H to interpret

Diagnosis

Sweat chloride - >=60 mmol/L diagnostic, 30-59 intermediate, <30 normal
Newborn screening: immunoreactive trypsinogen -> CFTR panel -> sweat test
Extended panels miss rare alleles; a negative panel in a high-suspicion case needs full CFTR sequencing plus deletion/duplication analysis
Nasal potential difference and intestinal current measurement for equivocal cases

Why genotype matters at the bedside

CFTR modulator eligibility is now defined by whether the variant produces responsive protein, not by class alone
- Elexacaftor/tezacaftor/ivacaftor and vanzacaftor/tezacaftor/deutivacaftor (once-daily) now cover ~95% of people with CF on functional-response criteria
- Ivacaftor alone for gating (class III) variants such as G551D
- Class I nonsense variants remain the main unaddressed group - the argument for read-through, mRNA and gene-editing approaches
Carrier and cascade testing; reproductive counselling with preimplantation genetic testing
Complications to anticipate: CF-related diabetes (insulin, not oral agents), distal intestinal obstruction syndrome, biliary cirrhosis, osteoporosis, male infertility, Pseudomonas and Burkholderia cepacia colonisation

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