COL4A1 – HANAC Syndrome

COL4A1 encodes the α1 chain of type IV collagen, a critical basement membrane component. Autosomal-dominant mutations in COL4A1 were first linked to a systemic syndrome of hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC), characterised by hematuria, arterial retinal tortuosity, muscle cramps, intracranial aneurysms, and kidney cysts (PMID:18160688).

Clinical Validity (Strong)

Multiple independent families (three in NEJM 2007, three in Am. J. Med. Genet. 2010, one in Brain & Dev. 2023, and one in Am. J. Kidney Dis. 2018) harbour heterozygous glycine substitutions in the CB3[IV] domain of COL4A1, segregating with HANAC features. In total, ~15 probands and ≥12 affected relatives have been reported across five pedigrees, with consistent phenotype overlap and no credible conflicting reports, supporting a Strong ClinGen classification for the COL4A1–HANAC association.

Genetic Evidence (Strong)

Inheritance is autosomal dominant. Segregation in four families demonstrates co-segregation of COL4A1 variants with disease in ≥12 relatives. Case series include 3 glycine missense mutations in exons 24–25 (c.1555G>A (p.Gly519Arg), c.1583G>A (p.Gly528Glu), c.1493G>T (p.Gly498Val)) ([PMID:18160688]), 3 glycine substitutions in CB3[IV] (c.1528G>A (p.Gly510Arg), c.1492G>C (p.Gly498Arg), p.Gly525Leu) ([PMID:20818663]), a novel p.Gly513Asp in four‐generation muscle‐cramp pedigree ([PMID:36922284]), and a p.Gln247Ter truncation in a 7-generation cystic kidney cohort ([PMID:29395486]). The spectrum is dominated by glycine substitutions disrupting triple-helix stability.

Functional Evidence (Moderate)

Experimental studies demonstrate that CB3[IV] glycine substitutions impair collagen IV secretion, cause intracellular retention, activate the unfolded protein response, and disrupt basement membrane integrity in cellular assays. Murine Col4a1 p.Gly498Val models recapitulate HANAC vascular and muscular features, including endothelial ER stress, capillary basement membrane defects, muscle cramps, and elevated creatine kinase, confirming a dominant-negative mechanism ([PMID:28056338]). Drosophila col4a1 mutants similarly show muscle basement membrane disruption and myopathy, reinforcing pathogenic concordance.

Integration and Clinical Utility

Collectively, the genetic and experimental concordance across multiple pedigrees establishes COL4A1 glycine substitutions as a definitive cause of HANAC syndrome. Diagnostic sequencing of COL4A1 should be considered in patients with idiopathic hematuria, retinal tortuosity, muscle cramps, or familial aneurysms. Precise molecular diagnosis informs prognosis, guides surveillance for intracranial aneurysms, and underpins inclusion in emerging collagen-targeted therapies.

Key Take-home: Autosomal-dominant COL4A1 glycine variants in the CB3[IV] domain cause HANAC syndrome via dominant-negative basement membrane defects, warranting targeted genetic testing for optimal patient management.

References

• The New England Journal of Medicine • 2007 • COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps PMID:18160688
• American Journal of Medical Genetics Part A • 2010 • Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain PMID:20818663
• Brain & Development • 2023 • Clinical characteristics of muscle cramps in hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome associated with a novel COL4A1 pathogenic variant: A family case study PMID:36922284
• American Journal of Kidney Diseases • 2018 • The Value of Genetic Testing in Polycystic Kidney Diseases Illustrated by a Family With PKD2 and COL4A1 Mutations PMID:29395486

Evidence Based Scoring (AI generated)