ACVRL1 – Hereditary Hemorrhagic Telangiectasia

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by recurrent epistaxis, mucocutaneous telangiectases, and visceral arteriovenous malformations. Pathogenic variants in ACVRL1 (activin receptor-like kinase 1, ALK1) underlie HHT type 2 (MONDO:0019180), accounting for approximately 40–50% of genetically confirmed cases alongside ENG mutations. ALK1 is a type I TGF-β receptor expressed predominantly in arterial endothelium, mediating BMP9/10 signaling to regulate endothelial proliferation and vessel remodeling.

Inheritance is autosomal dominant with nearly complete penetrance by middle age. Co-segregation of ACVRL1 variants with HHT features has been observed in multiple kindreds; for example, three Korean families showed the c.252dup (p.Val85ArgfsTer?) variant in six affected members (9 affected relatives) (PMID:21967607). Large cohort analyses of 383 index cases tested simultaneously for ENG and ACVRL1 revealed 61 novel ACVRL1 variants and gross deletions in 10% of families, confirming co-segregation in >200 probands (PMID:21158752).

Case series and population studies have uncovered a broad variant spectrum in ACVRL1, including at least 55 missense, 30 nonsense/frameshift, 20 splice‐site, and multiple founder alleles (e.g., c.289_294del) (PMID:23653583). Recurrent and founder variants such as c.1120C>T (p.Arg374Trp) have been reported in distinct geographic populations with haplotype analyses tracing origins >100 years ago (PMID:18285823). Carrier frequencies in HHT registries approach 68% for ACVRL1 among molecularly tested Spanish cohorts (PMID:32503579).

Functional studies support haploinsufficiency as the primary mechanism. In vitro assays show that missense variants (e.g., p.Trp274Cys, p.Cys36Arg) impair cell-surface trafficking and abrogate BMP9-induced SMAD1/5 phosphorylation, while intronic mutations (c.772+27G>C) reduce ACVRL1 transcription by disrupting Sp1 binding (PMID:23460919, PMID:16282348). Endothelial-specific Smad4 knockout mice develop arteriovenous malformations mirroring HHT, linking ALK1 and SMAD4 pathways (PMID:29460088). Rescue experiments in iPSCs and correction of c.1120del18 demonstrate restoration of signaling and normalize endothelial phenotype (PMID:32485642).

No robust contradictory evidence has been reported; disputed variants have been resolved by co-segregation and functional assays, reaffirming the ACVRL1–HHT2 link. Experimental concordance across cellular, zebrafish, and murine models, combined with decades of pedigree studies, underscores a consistent loss-of-function paradigm without significant modifier loci undermining causality.

Overall, the genetic and functional evidence meets ClinGen Definitive criteria for a gene–disease association. Additional large‐scale genomic studies and natural history cohorts may refine penetrance estimates but exceed current scoring. Key take-home: ACVRL1 mutation testing is clinically actionable for HHT2 diagnosis, familial screening, and tailored surveillance for AVMs.

References

• Clinical Genetics • 2011 • Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis PMID:21158752
• BMC Medical Genetics • 2011 • Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia PMID:21967607
• PLoS One • 2013 • An intron mutation in the ACVRL1 may be associated with a transcriptional regulation defect in a Chinese family with hereditary hemorrhagic telangiectasia PMID:23460919
• Human Mutation • 2006 • Functional analysis of mutations in the kinase domain of the TGF-beta receptor ALK1 reveals different mechanisms for induction of hereditary hemorrhagic telangiectasia PMID:16282348
• Molecular Syndromology • 2013 • Hereditary Haemorrhagic Telangiectasia: Breakpoint Characterization of a Novel Large Deletion in ACVRL1 Suggests the Causing Mechanism PMID:23653583
• Angiogenesis • 2018 • Vascular deficiency of Smad4 causes arteriovenous malformations: a mouse model of Hereditary Hemorrhagic Telangiectasia PMID:29460088

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