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Variante pathogène/probable pathogénique confirmée dans DDX41 — la plus courante p...

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IDRF-DDX41-CONFIRMED-CARRIER
TypeSignal d’alerte
Étatreviewed 2026-05-20 | pending_clinical_signoff
MaladiesDIS-AML DIS-MDS-HR
SourcesSRC-ELN-AML-2022 SRC-ESMO-MDS-2021 SRC-NCCN-AML-2025

Origine du drapeau rouge

DéfinitionConfirmed germline pathogenic / likely-pathogenic variant in DDX41 — most commonly the p.D140fs (p.Asp140fs) Northern European / Ashkenazi founder allele, but a growing list of recurrent loss-of-function alleles is now recognized worldwide. Patient has had germline panel testing returned positive, ideally confirmed on buccal / fibroblast germline tissue. The penetrance pattern is distinctive: late-onset MDS / AML, typically presenting in the sixth-to-eighth decade (median age at AML diagnosis ~66 years), with cumulative MDS / AML incidence ~50-70% by age 80 in confirmed-carrier pedigrees. A hallmark biologic feature is the somatic DDX41 "second hit" (usually p.R525H, the recurrent hot-spot helicase-domain missense) acquired in trans within the tumor clone — this molecular pattern is diagnostic of germline-DDX41-driven MDS / AML and distinguishes it from sporadic disease. Clinical import...
Direction cliniqueenquêter
Catégorieautres

Logique de déclenchement

{
  "any_of": [
    {
      "finding": "germline_ddx41_pathogenic_variant_confirmed",
      "value": true
    },
    {
      "finding": "germline_ddx41_d140fs_confirmed",
      "value": true
    }
  ],
  "type": "lab_value"
}

Notes

Wave P confirmed-carrier surveillance pathway — germline DDX41. Fires on documented germline DDX41 pathogenic variant positivity (any allele recognized as germline DDX41 LoF, with p.D140fs the Ashkenazi founder and other recurrent alleles in non-Ashkenazi populations). Engine routes to PreventionPlan recommending: (a) IND-DDX41-CARRIER-SURVEILLANCE (standard) — CBC q6 months from age 50 (or from carrier confirmation if later); BMA + cytogenetics + myeloid NGS panel at any unexplained cytopenia, persistent macrocytosis, or new dysplastic feature on smear; cascade testing to all first-degree relatives with documented buccal / fibroblast germline confirmation (NOT blood-only; somatic DDX41 R525H second-hit clones in carriers can contaminate blood-based germline assay). (b) IND-DDX41-CARRIER-INTENSIFIED (aggressive) — standard protocol PLUS q3-4 month CBC + smear from age 50; BMA + NGS every 2-3 years from age 50 even without provoked indication; preemptive HLA typing on candidate sibling donors with germline DDX41 screening (sibling carriers must NOT be used as donors — donor-derived disease documented in DDX41 syndrome); early engagement with hereditary-myeloid-program transplant te...

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Indication