Marfan syndrome

Marfan syndrome is a connective_tissue genetic disease caused by autosomal dominant variants in FBN1, acting through dominant-negative and haploinsufficiency mechanisms. Within this volume's rankable burden cohort it sits at residual rank 22 of 23, where established therapy is substantially disease-modifying. That order is a provisional [H]-grade prioritisation device, not a registry-locked ranking.

Marfan syndrome is inherited as autosomal dominant and acts by dominant-negative / haploinsufficiency (fibrillin-1) ([L]). Its pre-treatment burden proxy is 0.5750 and, after the established therapy's efficacy offset e = 0.5500 is applied, its residual burden score is 0.2587 ([L]), placing it at residual rank 22 of 23.

Gene, inheritance, and molecular mechanism

Marfan syndrome is inherited as Autosomal dominant inheritance [L] and is classified mechanistically as dominant-negative / haploinsufficiency (fibrillin-1) [L]. FBN1 encodes fibrillin-1, the scaffold protein of connective-tissue microfibrils. Defective fibrillin-1 weakens the extracellular matrix and dysregulates TGF-beta signalling, acting through dominant-negative and haploinsufficiency modes.

Inheritance source: medgen:esummary:ModeOfInheritance:2026-06-17. Mechanism source: curated_rule:fbn1_dn; established molecular genetics; OMIM(row) molecular section; OMIM:154700. These are observed, cited inputs; the inheritance and mechanism classification is the reproducible analysis layer (C-D1).

In-scope clinical involvement

In-scope features are skeletal (tall marfanoid habitus, long limbs, scoliosis), ocular (ectopia lentis), and dural (dural ectasia); clinical variability is high.

Organ systems [L] from HPO phenotype.hpoa v2026-06-06 (OMIM 134797,154700); P-aspect terms rolled up to HP:0000118 organ-system categories via hp.obo.

Reproducible burden position

Of the five axes, 4 are scored (the rankability cut is ≥ 3 of 5); the pre-treatment composite is the renormalised mean over the scored axes, raw_burden = 0.5750. The registry-grade [L] axes here are onset, progression, severity, and mortality (onset from the Orphanet AverageAgeOfOnset register / HPO).

All 4 scored axes for this disease are registry-grade [L]/[V]: its burden value is registry-locked (order_locked) and no longer rests on definition-only inference. The cohort order overall is still a provisional [H] prioritisation device, not a registry-locked ranking — this disease’s absolute rank depends on neighbours whose axes remain [H].

The natural-history registry passes have been run against Orphanet/Orphadata (CC BY 4.0, R6) and the openly published GBD 2013 disability-weights table (Salomon et al., CC BY, R7). R6 lifts onset to registry-grade [L] across most of the cohort (earliest AverageAgeOfOnset category, entity-anchored per ORPHAcode, Exact OMIM↔ORPHA only); R7 lifts disability to [L] where one dominant untreated sequela maps to a named GBD health state (published disability weight binned by declared cut-points), and independently corroborates a mortality axis from PMC survival literature where a quantitative disease-typical figure exists. Severity now lifts to registry [L] for the one disease whose dominant sequela carries a cited HPO Severity-modifier annotation (the HP:0012824 subtree, R8); for the rest the open HPO severity annotations are feature-level (using one feature as the disease tier would be a category error), so severity stays [H]/[O] with the obstacle named. Progression lifts to registry [L] where a cited PMC open-access source states a disease-level magnitude for the dominant untreated sequela and the frozen R3 tier function derives the tier from that verbatim sentence (R9, curated dominant-sequela join, non-spectrum); for the rest progression stays [H]/[O]. The OMIM clinical synopsis (the disease-level alternative) is API-key-gated and the key is unobtainable for an individual researcher — that path is removed, not guessed.

Marfan syndrome perturbs connective-tissue patterning, relevant to the morphogenetic baseline the carried engine simulates.

Established treatment and residual burden

The established disease-directed approach is comprehensive cardiovascular management (beta-blockade or ARB with prophylactic aortic-root surgery). Mechanistically: reduces aortic-wall stress; surgical root replacement removes dissection risk [L].

Its effect on natural history is classified disease-modifying (substantial), mapping to an efficacy offset e = 0.5500 and a residual factor R_treat = 0.4500. Applied to the pre-treatment proxy this gives the residual burden score 0.2587, moving the disease from raw rank 21 to residual rank 22 (shift -1).

Evidence tier: accession-dated to the GeneReviews NBK1335 Management section [L] (initial posting April 18, 2001; last revision February 17, 2022; retrieved 2026-06-18; corroborating term(s): “comprehensive, cardiovascular, surgery”). The natural-history axis grades remain a mix of [L] (GeneReviews-corroborated) and [H] (definition-only), so the burden order is still provisional.