Bone Marrow Failure IEIs (IUIS Table 9)

name: Bone Marrow Failure IEIs
display_name: Bone Marrow Failure IEIs (IUIS Table 9)
creation_date: "2026-08-20T00:00:00Z"
description: >-
  IUIS Table 9 — bone marrow failure. These inborn errors of immunity reach the
  immune system from below, through failure of the haematopoietic stem and
  progenitor compartment itself rather than through a lesion in a mature immune
  cell or pathway. The underlying defects are typically in genome maintenance,
  DNA replication or telomere biology, so the immunodeficiency arrives packaged
  with cytopenias, growth failure, chromosomal instability and a substantial
  risk of myelodysplasia and malignancy.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped on the IUIS Table 9 pattern: immunodeficiency as a consequence of
  haematopoietic failure. The table exists because these disorders are not
  immune-pathway diseases at all — the same genome-maintenance lesion that
  depletes lymphocytes also depletes the other lineages and drives
  cancer predisposition, which changes both the surveillance a patient needs and
  the calculus around haematopoietic stem cell transplantation. Members are kept
  as separate Disease entries because the specific genome-maintenance defect
  differs. No MONDO mapping: MONDO:0000159 (bone marrow failure syndrome) is a
  phenotype-defined class that does not subsume the listed member — verified
  2026-08-20 with `runoak -i sqlite:obo:mondo descendants -p i MONDO:0000159`,
  which does not return MONDO:0013118 — so mapping to it would assert a
  subsumption the ontology does not carry.
membership_criteria:
- description: >-
    A disorder belongs to IUIS Table 9 if it is an inborn error of immunity in
    which the immune defect arises from failure of the haematopoietic stem and
    progenitor compartment, typically through a genome-maintenance,
    DNA-replication or telomere-biology lesion.
  criteria_semantics: NECESSARY
  logic:
    criterion_predicate: HAS_CLASSIFICATION
    classification: "iuis_category:bone marrow failure"
    description: >-
      Assigned to IUIS Table 9 (bone marrow failure) via
      classifications.iuis_category on the member Disease entry. Stated in the
      keyed `<slot>:<value>` form so the audit reads the structured
      classifications block.
members:
- member: Fanconi_Anemia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic defects in the FA/BRCA interstrand-crosslink repair pathway, so the
      replication fork cannot resolve a crosslink and the cell accumulates
      chromosomal breaks and radial figures. Fanconi anemia is the largest single
      block in IUIS Table 9: twenty-two rows, one per complementation group, Types
      A through W, each with its own gene and OMIM number. FANCA is bound here as
      the commonest of those loci, not as the disease's only gene. What separates
      it from the other members of this grouping is that the initiating lesion is
      crosslink repair rather than telomere maintenance, transcription-coupled
      repair or a haematopoietic transcription factor, and that the marrow failure
      arrives packaged with the congenital anomaly pattern the table's
      associated-features cell lists.
    gene:
      preferred_term: FANCA
      term:
        id: hgnc:3582
        label: FANCA
- member: Dyskeratosis Congenita
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Impaired telomere maintenance, so telomeres shorten below the length that
      sustains self-renewal and the stem and progenitor compartment exhausts. IUIS
      Table 9 enters the disease as fourteen gene rows sharing one subcategory
      cell, DKCX1 through DKCB7, spanning the telomerase RNP (DKC1, TERC, TERT,
      NOP10, NHP2, WRAP53), the shelterin complex (TINF2, ACD), the helicase RTEL1
      and the deadenylase PARN. DKC1 is bound here as the X-linked founding locus.
      The separator from Fanconi anemia is that nothing is wrong with the repair of
      a lesion; the defect is in the maintenance of a structure, which is why the
      phenotype is a replicative-exhaustion one and includes pulmonary and hepatic
      fibrosis rather than chromosomal breakage.
    gene:
      preferred_term: DKC1
      term:
        id: hgnc:2890
        label: DKC1
- member: Revesz Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous TINF2 variants in a nine-residue window of exon 6 produce the
      severe infantile end of the telomere biology spectrum. It is listed in IUIS
      Table 9 as the DKCA5 row within the dyskeratosis congenita block, identified
      by OMIM 268130. It is kept as a separate member rather than folded into
      Dyskeratosis Congenita because the tissues that fail differ: bilateral
      exudative retinopathy and intracranial calcification with cerebellar
      hypoplasia sit alongside the marrow failure, and neither limb exists in the
      Dyskeratosis Congenita pathograph. Upstream the mechanism is the same
      shelterin lesion, so this member and Dyskeratosis Congenita are a severity
      and tissue-distribution split, not a mechanistic one.
    gene:
      preferred_term: TINF2
      term:
        id: hgnc:11824
        label: TINF2
- member: Autosomal Dominant Aplasia and Myelodysplasia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous germline SRP72 variants, entered in IUIS Table 9 as BMFS1. The
      lesion is in the signal recognition particle, so the failing process is
      co-translational targeting of nascent secretory and membrane proteins rather
      than any form of genome maintenance. That makes it the mechanistic outlier
      among this grouping's members, and the table's associated-features cell
      carries the matching clinical oddity, congenital nerve deafness beside the
      marrow failure. The lymphocyte columns are recorded as NA, so the IEI status
      rests on stem and progenitor failure alone.
    gene:
      preferred_term: SRP72
      term:
        id: hgnc:11303
        label: SRP72
- member: Pancytopenia-Developmental Delay Syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic ERCC6L2 variants, entered in IUIS Table 9 as BMFS2. ERCC6L2 works
      with DNA-PK to keep RNA polymerase II transcription from colliding with
      damage, so the defect is transcription-coupled repair rather than the
      interstrand-crosslink repair of Fanconi anemia or the telomere maintenance of
      the dyskeratosis congenita members. The table's associated-features cell
      pairs the marrow failure with learning difficulties and microcephaly, and as
      with BMFS1 the lymphocyte columns are NA.
    gene:
      preferred_term: ERCC6L2
      term:
        id: hgnc:26922
        label: ERCC6L2
- member: Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heterozygous MECOM variants, entered in IUIS Table 9 as MECOM deficiency and
      recorded in the table's own footnote as the single new inborn error of
      immunity added to Table 9 in the 2022 update. MECOM is a haematopoietic
      transcription factor, so unlike every other member here the lesion is in the
      transcriptional programme that maintains the stem cell rather than in a
      genome-maintenance or telomere pathway. It is also the only member whose
      immune arm is a named B-cell deficiency in the table's own B-cell column, and
      the only one carrying a skeletal malformation, radioulnar synostosis, that is
      a fusion rather than a reduction defect.
    gene:
      preferred_term: MECOM
      term:
        id: hgnc:3498
        label: MECOM
- member: Nijmegen Breakage Syndrome-like Disorder
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Biallelic hypomorphic RAD50 variants destabilise the MRE11-RAD50-NBN
      double-strand-break sensor, abolishing damage-induced MRN focus formation
      and impairing ATM activation. The result is checkpoint failure,
      radioresistant DNA synthesis and chromosomal instability, clinically
      phenocopying Nijmegen breakage syndrome. RAD50 is one of the three
      entities newly added to Table 9 in the IUIS 2024 update, and its
      placement there rather than in the syndromic combined-immunodeficiency
      table (where NBS itself sits) is the distinction this grouping turns on.
    gene:
      preferred_term: RAD50
      term:
        id: hgnc:9816
        label: RAD50
notes: >-
  Created 2026-08-20 to give the IUIS Table 9 disorders a place in the Inborn
  Errors of Immunity tree; the sole founding member already carried
  `classifications.iuis_category: bone marrow failure` but was unreachable from
  the umbrella grouping. Intentionally unmapped to MONDO — see
  grouping_rationale.

  Expanded 2026-09-13 from one member to seven, by reading IUIS 2022 Table 9
  (Tangye et al., PMID:35748970, lines 4104 to 4287 of the cached reference) row
  by row and matching each row against `kb/disorders/`. Added: Fanconi_Anemia
  (the Type A to Type W block, 22 rows), Dyskeratosis Congenita (the DKCX1 to
  DKCB7 block, 14 gene rows), Revesz Syndrome (the DKCA5 row, identified through
  OMIM 268130), Autosomal Dominant Aplasia and Myelodysplasia (BMFS1, SRP72),
  Pancytopenia-Developmental Delay Syndrome (BMFS2, ERCC6L2), and Radioulnar
  Synostosis with Amegakaryocytic Thrombocytopenia (MECOM deficiency). The MECOM
  entry had carried the classification since before this grouping existed and was
  simply never listed here, which is the failure mode `just check-groupings`
  cannot catch: it evaluates the members a grouping already names and never goes
  looking for ones it omits. The membership was therefore diffed by hand against
  `rg -l "classification_value: bone marrow failure" kb/disorders/`, and that diff
  is now empty.

  Two corrections to what this file previously said. It named Shwachman-Diamond
  syndrome as a classical Table 9 entity; it is not, it is in Table 5 (congenital
  defects of phagocyte number or function). It also named severe congenital
  neutropenia with marrow failure, likewise a Table 5 entity. Neither should be
  added here. Diamond-Blackfan anaemia, which the old iuis_category enum
  description also listed under Table 9, does not appear anywhere in the IUIS 2022
  classification. That enum text was fixed in dismech#10107.

  Table 9 rows still without a dismech entry, and so not yet members: MIRAGE
  syndrome (SAMD9), ataxia pancytopenia syndrome (SAMD9L), Coats plus syndrome
  (CTC1, STN1 — both genes are curated as subtypes inside Dyskeratosis Congenita,
  but the Coats plus entity has no entry of its own), and BMFS5 (TP53). Note that
  Nijmegen Breakage Syndrome-like Disorder, the founding member, is a Table 9 row
  in the IUIS 2024 update rather than in 2022; it is retained on that basis, which
  its own differentiating_mechanisms block states.