COX16-Related COX Deficiency

Mendelian MONDO:0859160 Pathograph 9 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX16-related COX deficiency (mitochondrial complex IV deficiency nuclear type 22, MC4DN22) is an ultra-rare autosomal recessive nuclear form of isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic loss-of-function variants in COX16. COX16 encodes a small mitochondrial transmembrane protein, facing the intermembrane space and highly expressed in skeletal and cardiac muscle, that acts as a Complex IV assembly factor in the copper-delivery route of the COX2 module: it interacts with newly synthesized COX2 and its copper-center-forming metallochaperones (SCO1, SCO2, COA6) and is implicated in CuA-site formation. Loss of COX16 prevents assembly of the COX2 subassembly module and causes complete loss of the holo-enzyme, producing an isolated Complex IV deficiency. The first reported patients (two unrelated cases homozygous for the nonsense variant c.244C>T, p.Arg82*) presented with hypertrophic cardiomyopathy, encephalopathy, severe fatal neonatal lactic acidosis, and liver dysfunction. The entry conforms to the conserved Complex IV assembly/biogenesis-deficiency mechanism, with the lesion localized to an assembly factor in the COX2 copper-delivery pathway rather than a structural subunit.

Ask OpenScientist

Ask a research question about COX16-Related COX Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

3
Pathophys.
4
Phenotypes
9
Pathograph
1
Genes
1
Medical Actions
⚙

Pathophysiology

3
COX16 Loss and Impaired COX2 Copper Delivery
Biallelic loss-of-function of COX16 removes a Complex IV assembly factor that interacts with newly synthesized COX2 and its copper-center-forming metallochaperones (SCO1, SCO2, COA6) and participates in copper delivery to COX2 / CuA-site formation. Loss of COX16 blocks formation of the COX2 subassembly module and produces complete loss of the holo-complex IV, i.e. failed Complex IV biogenesis with isolated Complex IV deficiency.
mitochondrial respiratory chain complex IV assembly GO:0033617 ↓ DECREASED copper ion delivery to COX2 GO:0006825 ↓ DECREASED
Downstream
Impaired Terminal Electron Transfer and ATP Synthesis An unassembled, COX16-deficient Complex IV cannot transfer electrons to oxygen, impairing oxidative ATP synthesis.
Show evidence (8 references)
PMID:33169484 SUPPORT Human Clinical
"The absence of COX16 protein expression leads to a complete loss of the holo-complex IV, as detected by Western blot in patient fibroblasts"
Loss of COX16 abolishes the assembled holo-enzyme in patient fibroblasts, i.e. failed Complex IV biogenesis.
PMID:33169484 SUPPORT In Vitro
"Lentiviral transduction of patient fibroblasts with wild-type COX16 complementary DNA rescued complex IV biosynthesis"
Re-expression of wild-type COX16 restores Complex IV biosynthesis, confirming COX16 loss as the direct molecular lesion.
PMID:33169484 SUPPORT Other
"We hypothesize that COX16 could play a role in the copper delivery route of the COX2 module as part of the complex IV assembly"
Localizes the COX16 lesion to the copper-delivery route of the COX2 assembly module.
+ 5 more references
Impaired Terminal Electron Transfer and ATP Synthesis
Deficient Complex IV blocks electron transfer from cytochrome c to oxygen and the coupled proton pumping, collapsing oxidative ATP synthesis. High-energy tissues — heart and brain — are preferentially injured, producing hypertrophic cardiomyopathy and encephalopathy.
cardiac muscle cell CL:0000746 neuron CL:0000540
mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED
Downstream
Lactic Acidosis and Metabolic Decompensation Impaired oxidative ATP synthesis forces anaerobic glycolysis, producing lactic acidosis.
Hypertrophic Cardiomyopathy Chronic bioenergetic failure in cardiomyocytes drives hypertrophic remodeling.
Encephalopathy Energy deficit in high-demand neural tissue produces encephalopathy.
Show evidence (1 reference)
PMID:33169484 SUPPORT Human Clinical
"hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency"
Reduced Complex IV in these patients is the biochemical basis for impaired terminal electron transfer and the high-energy-tissue (cardiac, neural) phenotypes.
Lactic Acidosis and Metabolic Decompensation
The block in oxidative phosphorylation shifts pyruvate toward lactate, producing severe, fatal neonatal lactic acidosis with systemic metabolic decompensation and secondary liver dysfunction.
Downstream
Lactic Acidosis Accumulated lactate produces the measured lactic acidosis.
Decreased Liver Function Energy failure and metabolic decompensation impair hepatocyte function, producing liver dysfunction.
Show evidence (1 reference)
PMID:33169484 SUPPORT Human Clinical
"severe fatal lactic acidosis"
Severe fatal lactic acidosis is a defining metabolic feature of the index patients.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for COX16-Related COX Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Cardiovascular 1
Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy HP:0001639
Show evidence (1 reference)
PMID:33169484 SUPPORT Human Clinical
"two unrelated patients with the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency"
The two index patients carrying the homozygous COX16 variant presented with hypertrophic cardiomyopathy.
Digestive 1
Decreased Liver Function Decreased liver function HP:0001410
Show evidence (1 reference)
PMID:33169484 SUPPORT Human Clinical
"encephalopathy, cardiomyopathy, and liver dysfunction"
Liver dysfunction is reported among the features of COX16 deficiency.
Metabolism 1
Lactic Acidosis Lactic acidosis HP:0003128
Severity: SEVERE
Show evidence (1 reference)
PMID:33169484 SUPPORT Human Clinical
"severe fatal lactic acidosis"
Severe fatal lactic acidosis is a presenting feature of the index patients.
Nervous System 1
Encephalopathy Encephalopathy HP:0001298
Show evidence (1 reference)
PMID:33169484 SUPPORT Human Clinical
"hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis"
Encephalopathy is reported as a presenting feature of the index patients.
🧬

Genetic Associations

1
COX16 pathogenic variants causing MC4DN22
Gene: COX16 hgnc:20213
Autosomal recessive
Show evidence (1 reference)
PMID:33169484 SUPPORT Human Clinical
"the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16"
Defines the causal COX16 nonsense variant.
💊

Medical Actions

1
Supportive and Metabolic Care
Action: supportive care MAXO:0000950
No curative therapy exists; management is supportive, directed at the metabolic decompensation and lactic acidosis, cardiac and neurologic surveillance, and multidisciplinary care. The reported neonatal presentation was fatal.
{ }

Source YAML

click to show 
name: COX16-Related COX Deficiency
category: Mendelian
creation_date: "2026-06-23T00:00:00Z"
synonyms:
- COX16 deficiency
- Mitochondrial complex IV deficiency, nuclear type 22
- MC4DN22
- COX16-related cytochrome c oxidase deficiency
description: >
  COX16-related COX deficiency (mitochondrial complex IV deficiency nuclear
  type 22, MC4DN22) is an ultra-rare autosomal recessive nuclear form of
  isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic
  loss-of-function variants in COX16. COX16 encodes a small mitochondrial
  transmembrane protein, facing the intermembrane space and highly expressed in
  skeletal and cardiac muscle, that acts as a Complex IV assembly factor in the
  copper-delivery route of the COX2 module: it interacts with newly synthesized
  COX2 and its copper-center-forming metallochaperones (SCO1, SCO2, COA6) and is
  implicated in CuA-site formation. Loss of COX16 prevents assembly of the COX2
  subassembly module and causes complete loss of the holo-enzyme, producing an
  isolated Complex IV deficiency. The first reported patients (two unrelated
  cases homozygous for the nonsense variant c.244C>T, p.Arg82*) presented with
  hypertrophic cardiomyopathy, encephalopathy, severe fatal neonatal lactic
  acidosis, and liver dysfunction. The entry conforms to the conserved Complex
  IV assembly/biogenesis-deficiency mechanism, with the lesion localized to an
  assembly factor in the COX2 copper-delivery pathway rather than a structural
  subunit.
disease_term:
  preferred_term: COX16-related COX deficiency (MC4DN22)
  term:
    id: MONDO:0859160
    label: mitochondrial complex IV deficiency, nuclear type 22
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
pathophysiology:
- name: COX16 Loss and Impaired COX2 Copper Delivery
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  description: >
    Biallelic loss-of-function of COX16 removes a Complex IV assembly factor
    that interacts with newly synthesized COX2 and its copper-center-forming
    metallochaperones (SCO1, SCO2, COA6) and participates in copper delivery to
    COX2 / CuA-site formation. Loss of COX16 blocks formation of the COX2
    subassembly module and produces complete loss of the holo-complex IV, i.e.
    failed Complex IV biogenesis with isolated Complex IV deficiency.
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  - preferred_term: copper ion delivery to COX2
    term:
      id: GO:0006825
      label: copper ion transport
    modifier: DECREASED
  evidence:
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The absence of COX16 protein expression leads to a complete loss of the holo-complex IV, as detected by Western blot in patient fibroblasts
    explanation: Loss of COX16 abolishes the assembled holo-enzyme in patient fibroblasts, i.e. failed Complex IV biogenesis.
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Lentiviral transduction of patient fibroblasts with wild-type COX16 complementary DNA rescued complex IV biosynthesis
    explanation: Re-expression of wild-type COX16 restores Complex IV biosynthesis, confirming COX16 loss as the direct molecular lesion.
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: We hypothesize that COX16 could play a role in the copper delivery route of the COX2 module as part of the complex IV assembly
    explanation: Localizes the COX16 lesion to the copper-delivery route of the COX2 assembly module.
  - reference: PMID:29381136
    reference_title: "COX16 promotes COX2 metallation and assembly during respiratory complex IV biogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: COX16, a protein required for cytochrome c oxidase assembly, interacts specifically with newly synthesized COX2 and its copper center-forming metallochaperones SCO1, SCO2, and COA6
    explanation: Defines the molecular role of COX16 in COX2 metallation/assembly that is lost in disease.
  - reference: PMID:29381136
    reference_title: "COX16 promotes COX2 metallation and assembly during respiratory complex IV biogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These findings implicate COX16 in CuA-site formation
    explanation: COX16 is implicated in forming the copper CuA center of COX2, the step impaired by COX16 loss.
  - reference: PMID:29355485
    reference_title: "COX16 is required for assembly of cytochrome c oxidase in human cells and is involved in copper delivery to COX2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: its ablation in HEK293 cells impairs COX assembly
    explanation: Genetic ablation of COX16 in human cells impairs Complex IV assembly, supporting the assembly-factor role.
  - reference: PMID:29355485
    reference_title: "COX16 is required for assembly of cytochrome c oxidase in human cells and is involved in copper delivery to COX2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Its knockdown in C. elegans produces COX deficiency
    explanation: COX16 knockdown in an animal model recapitulates COX deficiency, supporting conserved essentiality.
  - reference: PMID:29355485
    reference_title: "COX16 is required for assembly of cytochrome c oxidase in human cells and is involved in copper delivery to COX2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: copper supplementation increases COX activity and restores normal steady state levels of COX subunits in COX16 knockout cells, indicating that, even in the absence of a canonical copper binding motif, COX16 could be involved in copper delivery to COX2
    explanation: Copper rescue of COX16-null cells supports COX16's function in copper delivery to COX2.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
    description: An unassembled, COX16-deficient Complex IV cannot transfer electrons to oxygen, impairing oxidative ATP synthesis.
    evidence:
    - reference: PMID:33169484
      reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: isolated complex IV deficiency. The absence of COX16 protein expression leads to a complete loss of the holo-complex IV
      explanation: Failed COX16-dependent assembly produces complete loss of the holo-complex IV and an isolated Complex IV deficiency, the basis for impaired terminal electron transfer.
- name: Impaired Terminal Electron Transfer and ATP Synthesis
  conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
  description: >
    Deficient Complex IV blocks electron transfer from cytochrome c to oxygen and
    the coupled proton pumping, collapsing oxidative ATP synthesis. High-energy
    tissues — heart and brain — are preferentially injured, producing
    hypertrophic cardiomyopathy and encephalopathy.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: mitochondrial electron transport, cytochrome c to oxygen
    term:
      id: GO:0006123
      label: mitochondrial electron transport, cytochrome c to oxygen
    modifier: DECREASED
  - preferred_term: ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  evidence:
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency
    explanation: Reduced Complex IV in these patients is the biochemical basis for impaired terminal electron transfer and the high-energy-tissue (cardiac, neural) phenotypes.
  downstream:
  - target: Lactic Acidosis and Metabolic Decompensation
    causal_link_type: DIRECT
    description: Impaired oxidative ATP synthesis forces anaerobic glycolysis, producing lactic acidosis.
  - target: Hypertrophic Cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic bioenergetic failure in cardiomyocytes drives hypertrophic remodeling.
  - target: Encephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy deficit in high-demand neural tissue produces encephalopathy.
- name: Lactic Acidosis and Metabolic Decompensation
  conforms_to: "complex_iv_assembly_deficiency#Lactic Acidosis and Metabolic Decompensation"
  description: >
    The block in oxidative phosphorylation shifts pyruvate toward lactate,
    producing severe, fatal neonatal lactic acidosis with systemic metabolic
    decompensation and secondary liver dysfunction.
  evidence:
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe fatal lactic acidosis
    explanation: Severe fatal lactic acidosis is a defining metabolic feature of the index patients.
  downstream:
  - target: Lactic Acidosis
    causal_link_type: DIRECT
    description: Accumulated lactate produces the measured lactic acidosis.
  - target: Decreased Liver Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy failure and metabolic decompensation impair hepatocyte function, producing liver dysfunction.
phenotypes:
- name: Hypertrophic Cardiomyopathy
  description: Hypertrophic cardiomyopathy reported in the index COX16 patients.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: two unrelated patients with the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency
    explanation: The two index patients carrying the homozygous COX16 variant presented with hypertrophic cardiomyopathy.
- name: Encephalopathy
  description: Encephalopathy as part of the COX16-related mitochondrial presentation.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis
    explanation: Encephalopathy is reported as a presenting feature of the index patients.
- name: Lactic Acidosis
  description: Severe, fatal neonatal lactic acidosis.
  phenotype_term:
    preferred_term: Severe lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
    severity: SEVERE
  evidence:
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe fatal lactic acidosis
    explanation: Severe fatal lactic acidosis is a presenting feature of the index patients.
- name: Decreased Liver Function
  description: Liver dysfunction accompanying the severe neonatal metabolic crisis.
  phenotype_term:
    preferred_term: Liver dysfunction
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: encephalopathy, cardiomyopathy, and liver dysfunction
    explanation: Liver dysfunction is reported among the features of COX16 deficiency.
genetic:
- name: COX16 pathogenic variants causing MC4DN22
  gene_term:
    preferred_term: COX16
    term:
      id: hgnc:20213
      label: COX16
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:33169484
      reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: two unrelated patients with the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16
      explanation: A homozygous nonsense variant in two unrelated patients is consistent with autosomal recessive inheritance.
  variants:
  - name: COX16 c.244C>T (p.Arg82*)
    description: >
      Homozygous nonsense variant abolishing COX16 protein expression and
      holo-complex IV assembly. Identified in two unrelated patients and the
      only pathogenic COX16 variant reported to date for MC4DN22.
    gene:
      preferred_term: COX16
      term:
        id: hgnc:20213
        label: COX16
    evidence:
    - reference: PMID:33169484
      reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16
      explanation: Defines the causal COX16 nonsense variant.
  features: >
    Both reported patients are homozygous for the nonsense variant c.244C>T
    (p.Arg82*) in COX16, which abolishes COX16 protein expression and the
    assembled holo-complex IV.
  evidence:
  - reference: PMID:33169484
    reference_title: "A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16
    explanation: Defines the causal COX16 nonsense variant.
treatments:
- name: Supportive and Metabolic Care
  description: >
    No curative therapy exists; management is supportive, directed at the
    metabolic decompensation and lactic acidosis, cardiac and neurologic
    surveillance, and multidisciplinary care. The reported neonatal presentation
    was fatal.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
notes: >
  COX16-related disease is reported to date in two unrelated patients homozygous
  for c.244C>T (p.Arg82*) (Wintjes et al., 2021, Hum Mutat; PMID:33169484). COX16
  is an assembly factor in the copper-delivery route of the COX2 module rather
  than a structural subunit; its biochemical signature is an isolated Complex IV
  deficiency with complete loss of the holo-enzyme, rescued by wild-type COX16
  re-expression. The molecular role of COX16 in COX2 metallation and CuA-site
  formation is established by Aich et al. (2018, eLife; PMID:29381136) and Cerqua
  et al. (2018, BBA Bioenergetics; PMID:29355485). MONDO:0859160 (MC4DN22) maps
  to OMIM:619355; the COX16 gene is OMIM:618064 / hgnc:20213. Added as a member
  of the Mitochondrial_Complex_IV_Deficiency grouping (issue #4239): this entry
  conforms to the complex_iv_assembly_deficiency#Complex IV Biogenesis Failure
  node, satisfying the grouping's NECESSARY_AND_SUFFICIENT module-conformance
  criterion (the grouping's own evaluator flags it as a candidate member), and
  MONDO:0859160 is an is-a descendant of the grouping's MONDO:0033885
  nuclear-type anchor.