HFE – Cystic Fibrosis Modifier Effects

ClinGen Clinical Validity: Limited

Cystic fibrosis (CF) is an autosomal recessive disorder caused by pathogenic variants in CFTR. Modifier genes such as HFE have been investigated for their impact on lung disease severity and related complications in CF. HFE encodes a protein involved in iron homeostasis, and common missense variants c.187C>G (p.His63Asp) and c.845G>A (p.Cys282Tyr) have been evaluated as modifiers of CF clinical course.

In a discordant sibpair analysis, three brothers with identical CFTR genotypes demonstrated variable lung disease severity; the least affected sibling was homozygous for HFE c.187C>G (p.His63Asp) (n=3 siblings (PMID:32014855)). In a cohort of 104 children with CF, 23% carried H63D and 11% carried C282Y; presence of C282Y was associated with increased pulmonary exacerbations by age 6 (n=104 (PMID:40071665)). An Irish study of 108 CF patients assessed C282Y and H63D carrier rates in relation to meconium ileus and liver disease but found no significant enrichment (n=108 (PMID:12885340)).

No direct functional studies have evaluated HFE variants in CF model systems, and mechanistic inference relies on HFE’s role in iron handling and host–pathogen interactions in chronic airway infection. Additional large-scale studies are required to clarify the modifier effect size and clinical utility of HFE genotyping in CF.

Key take-home: HFE c.187C>G (p.His63Asp) and c.845G>A (p.Cys282Tyr) show limited evidence as CF modifiers; routine HFE testing is not yet warranted for CF management.

References

• Cold Spring Harbor Molecular Case Studies • 2020 • Applying whole-genome sequencing in relation to phenotype and outcomes in siblings with cystic fibrosis. PMID:32014855
• Pediatric Pulmonology • 2025 • The Frequency and Potential Implications of HFE Genetic Variants in Children With Cystic Fibrosis. PMID:40071665
• Genetic Testing • 2003 • HFE alleles in an Irish cystic fibrosis population. PMID:12885340

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