# Pathograph node classes -- worked representatives # # A hand-built tree of candidate node classes. Leaves are REAL pathophysiology # nodes from kb/disorders/, written as: [Disease_Entry] # # Representatives only, not a census. The point is to find out whether the # categories survive contact with actual curated nodes. # # No schema, no enum, no slot. Nothing in kb/ or the schema depends on this file. # Companion: pathograph_node_class_go_seed.tsv (GO BP term -> class, 640 terms) # See docs/superpowers/specs/2026-08-16-pathograph-node-classification-brainstorm.md # # ---- GRAMMAR (parser: src/dismech/node_classes.py) ------------------------- # # just node-classes check the grammar (instant) # just node-classes --verify-kb also resolve every leaf in kb/ # just node-classes --format yaml emit YAML (also: json, text, summary) # # Indentation is exactly two spaces per level; tabs are rejected. Blank lines and # lines whose first non-space character is `#` are ignored, so these notes are # invisible to the parser. Every other line is one of three things, tested in # this order: # # Node name [Disease_Entry] an EXAMPLE -- two or more spaces before `[`, # so a class name may contain single spaces # :key free text value an ATTRIBUTE of the nearest enclosing node # (class or example); repeats accumulate # CLASS NAME -- optional gloss a CLASS; gloss follows two+ spaces and `--` # # Sibling class names must be unique, depth may increase by at most one level per # line, and an example may carry attributes but not class children. Class ids are # derived as upper-snake (`MOLECULAR ACTIVITY EFFECT` -> MOLECULAR_ACTIVITY_EFFECT). # `--format text` round-trips, which is the migration path to YAML when the # design settles. GENOMIC EFFECT -- the lesion at the level of DNA/chromatin genome instability -- an elevated RATE of new lesions rather than a lesion itself. From MeSH Genomic Instability (D042822); 41 nodes had no home. Genomic Instability [Fanconi_Anemia] Genomic Instability [Li-Fraumeni_Syndrome] Chromosomal Instability [Esophageal_Adenocarcinoma] Mismatch Repair Deficiency and Microsatellite Instability [Gastric_Adenocarcinoma] Telomere Dysfunction and Genomic Instability [Hepatocellular_Carcinoma] Oxidative Stress and Chromosomal Instability [COX4I1-Related_COX_Deficiency] Genome Instability and Abnormal DNA Damage Response [DTYMK-Related_Neurodegeneration] Mitochondrial DNA Instability and Multiple mtDNA Deletions [Behr_Syndrome] Replication Fork Destabilization Under Replication Stress [Chung-Jansen_Syndrome] TP53/RB1 Loss and Chromosomal Instability [Transitional_Cell_Carcinoma] Genomic Instability and Chromosomal Rearrangements [Rothmund-Thomson_Syndrome] Increased Loss of Heterozygosity [Bloom_Syndrome] Impaired homologous recombination [MCM9-related_gametogenic_failure] Impaired DNA end resection and homologous recombination repair [Nijmegen_Breakage_Syndrome-like_Disorder] Homologous Recombination Deficiency [Fallopian_Tube_Cancer] Chromosomal Instability and Aneuploidy [Choroid_Plexus_Neoplasm] Microsatellite Instability [MSI_High_Endometrial_Cancer] Cell-cycle checkpoint failure and radioresistant DNA synthesis [Nijmegen_Breakage_Syndrome-like_Disorder] Reduced Functional mtDNA-Maintenance Capacity [Autosomal_Dominant_Progressive_External_Ophthalmoplegia] Telomere-Telomerase Imbalance and Chromosome Fragility [Familial_Nonmedullary_Thyroid_Carcinoma] Female oocyte aneuploidy and recurrent pregnancy loss (contested) [SYCP3-related_spermatogenic_failure] Impaired DNA repair and oxidative stress hypersensitivity [Triple_A_Syndrome] pathogenic sequence variant -- the coding lesion itself, where the entry draws it as a node Pathogenic APP, PSEN1, or PSEN2 Germline Variant [Early-Onset_Autosomal_Dominant_Alzheimer_Disease] DNMT1 Exon 21 RFTS Domain Missense Variant [ADCA-DN] Heterozygous FOXP1 Loss-of-Function Variation [FOXP1_Syndrome] Biallelic Damaging DTYMK Variants [DTYMK-Related_Neurodegeneration] GNAO1 Pathogenic Variant (Gao) [GNAO1-Related_Developmental_and_Epileptic_Encephalopathy] KCNQ2 Pathogenic Variant [KCNQ2_Developmental_and_Epileptic_Encephalopathy] Complex I Subunit Missense Mutation [Leber_Hereditary_Optic_Neuropathy] Biallelic OTUD6B Loss-of-Function Variants [OTUD6B-Related_Neurodevelopmental_Disorder] NUP62 p.Q391P Germline Variant [NUP62-Related_Infantile_Bilateral_Striatal_Necrosis] Biallelic COL7A1 Pathogenic Variants (RDEB) [Dystrophic_Epidermolysis_Bullosa] HSD17B10 Pathogenic Variants [HSD10_Mitochondrial_Disease] PTEN Tumor Suppressor Loss [Glioblastoma_IDH_Wildtype] Damaging SARS1 Alleles in the Catalytic Core [SARS1-Related_Neurodevelopmental_Disorder] Genetic Lesion in an Ion Channel or Synaptic Gene [Genetic_Developmental_and_Epileptic_Encephalopathy] Menin Tumor Suppressor Loss [Thymic_Neuroendocrine_Carcinoma] NR5A1 Arg92 regulatory switch [46_XX_Testicular_DSD] Biallelic NF1 Inactivation in Schwann Cell Lineage [Neurofibroma] NF1 Tumor Suppressor Loss [Neurofibromatosis_Type_1] TP53 Loss and p53-Mediated DNA Damage Response Failure [Anaplastic_Thyroid_Carcinoma] Tumor Suppressor Inactivation in Malignant Progression [Pancreatic_Mucinous_Cystadenoma] GLMN Loss of Function with Somatic Second Hit [Glomus_Tumor] Biallelic NF2 Merlin Inactivation [Schwannoma] WT1 C-terminal regulatory alteration [46_XX_Testicular_DSD] NER Gene Biallelic Loss-of-Function [COFS_Syndrome] FNIP1 Loss of Function [Immunodeficiency_93_and_Hypertrophic_Cardiomyopathy] Biallelic PUS3 Loss-of-Function Variants [PUS3-Related_Neurodevelopmental_Disorder] Somatic second-hit AIP inactivation [AIP-related_pituitary_adenoma_predisposition] Driver Alterations in Thyroid Follicular Cells [Papillary_Thyroid_Carcinoma] Atrial Ion-Channel or Coupling Variant [Familial_Atrial_Fibrillation] RAS and PAX8-PPARG Driver Alterations [Thyroid_Follicular_Carcinoma] ATRX/TP53 Cooperative Loss [Diffuse_Astrocytoma] SCN1A Gene Mutation [Dravet_syndrome] FLNB Variant Clustering in Functional Protein Domains [Larsen_Syndrome] HPV-Independent Somatic Driver Accumulation [Vulvar_Carcinoma] FGFR2 linker-region activating mutations [Apert_Syndrome] HABP2 G534E Loss of Tumor-Suppressor Function [Familial_Nonmedullary_Thyroid_Carcinoma] SLC17A5 Gene Mutation [Salla_Disease] TP53 Loss [Pleuropulmonary_Blastoma] GRIN2A Null or Ligand-Binding/Amino-Terminal Domain Missense Variant [GRIN2A-Related_Epileptic_Encephalopathy_and_Intellectual_Disability] dosage Recurrent LCR22-mediated multigene deletion [22q11.2_Deletion_Syndrome] Maternal 15q11-q13 dosage increase [15q11q13_Microduplication_Syndrome] Partial contribution of HDAC4 haploinsufficiency [2q37_Microdeletion_Syndrome] Allele-Specific ADNP Haploinsufficiency [ADNP-Related_Syndrome] JAG1 haploinsufficiency [Alagille_syndrome] NOTCH1 Haploinsufficiency [Adams-Oliver_Syndrome] BRPF1 Haploinsufficiency [BRPF1-Related_Intellectual_Disability] ANKRD11 Haploinsufficiency [KBG_Syndrome] SHOX haploinsufficiency in growth plate chondrocytes [Leri-Weill_Dyschondrosteosis] MED13L haploinsufficiency [MED13L_Syndrome] GPR101 copy-number gain [GPR101-related_pituitary_adenoma_2] USP7 haploinsufficiency [Hao-Fountain_syndrome] SUZ12 Haploinsufficiency and Elevated MPNST Risk [NF1_Microdeletion_Syndrome] TP53 Mutation and Copy-Number High State [Endometrial_Carcinoma] 14q22-q23 contiguous gene deletion [Frias_Syndrome] Eye Field Transcription Factor Network Dosage Loss [Isolated_Anophthalmia-Microphthalmia_Syndrome] PAX6 haploinsufficiency and ocular maldevelopment [WAGR_Syndrome] Desmoplakin Haploinsufficiency — Desmosomal Disruption [DSP_Cardiomyopathy] Type I Collagen Haploinsufficiency [Osteogenesis_Imperfecta_Type_I] 17p13.3 Contiguous-Gene Deletion [Miller-Dieker_Lissencephaly_Syndrome] LIS1 Haploinsufficiency and Dynein/Microtubule Motor Dysfunction [Miller-Dieker_Lissencephaly_Syndrome] Contiguous-gene 2q32-q33 haploinsufficiency [Chromosome_2q32-q33_Deletion_Syndrome] Altered Alpha 4 (IGBP1) Protein Dosage [Corpus_Callosum_Agenesis-Intellectual_Disability-Coloboma-Micrognathia_Syndrome] OCA2 haploinsufficiency in deletion subtype [Angelman_Syndrome] MAP3K7 haploinsufficiency [Cardiospondylocarpofacial_Syndrome] WAC haploinsufficiency [DeSanto-Shinawi_Syndrome] SALL4 Haploinsufficiency and DNA-Binding Defect [Duane_Radial_Ray_Syndrome] X-chromosome Inactivation Escape / Gene Dosage Imbalance [Klinefelter_Syndrome] structural variant Somatic PML-RARA Fusion [APL_PML_RARA] ALK fusion oncoprotein formation [ALK_Rearranged_NSCLC] WWTR1-CAMTA1 Fusion Oncogene Formation [Epithelioid_Hemangioendothelioma] FGFR2 Fusion and Constitutive Activation [FGFR_Altered_Cholangiocarcinoma] NTRK Gene Fusion and Constitutive TRK Activation [NTRK_Fusion_Positive_Cancer] NF-kB-Activating Translocations [MALT_Lymphoma] C9orf72 Repeat Expansion Toxicity [Amyotrophic_Lateral_Sclerosis] ATN1 CAG Repeat Expansion [Dentatorubral-Pallidoluysian_Atrophy] Biallelic RFC1 Intronic Repeat Expansion [CANVAS] Variable breakpoint-dependent 2q37 deletion [2q37_Microdeletion_Syndrome] Enhancer Adoption From Upstream Deletion [Adult-Onset_Autosomal_Dominant_Demyelinating_Leukodystrophy] CRTC1-MAML2 Fusion Oncogene Formation [Mucoepidermoid_Carcinoma] MIR143-NOTCH Gene Fusion [Glomus_Tumor] Isochromosome 12p and Copy-Number-Driven Genome [Testicular_Seminoma] JPH3 trinucleotide repeat expansion [Huntington_Disease-like_2] Meiotic Non-Mosaic Ring With Terminal Deletion [Ring_Chromosome_20_Syndrome] In-Frame TTNsv Produces Internally Deleted Titin [TTN_Related_Myopathy_Dominant_Negative_TTNsv] Multiple Large-Scale mtDNA Deletions and Depletion [Autosomal_Recessive_Progressive_External_Ophthalmoplegia_1] Contiguous Loss of Neighbouring Genes [WAPL-Related_Developmental_Disorder] Recurrent 10q22.3q23.2 Deletion [WAPL-Related_Developmental_Disorder] cis-regulatory variant -- a lesion in noncoding regulatory DNA: enhancer, promoter, or the 3D contacts between them. The gene is intact and the coding sequence is untouched; what changed is where and how much it is transcribed. ~25 nodes, and they had been split between `pathogenic sequence variant` (which reads as coding) and `epigenetic` (which is a mark, not a lesion). ZRS or pZRS Regulatory Gain of Ectopic Expression [ZRS-Related_Limb_Malformation] ECR5 Enhancer Deletion Causing SOST Downregulation [Van_Buchem_Disease] TERT Promoter Activation [Glioblastoma_IDH_Wildtype] Non-coding regulatory variant pathogenesis [Microphthalmia_with_Coloboma] Three-Dimensional Chromatin Reorganization (Position Effect) [NF1_Microdeletion_Syndrome] SOX9 enhancer dosage gain [46_XX_Testicular_DSD] IGBP1 5'-Regulatory Variants [Corpus_Callosum_Agenesis-Intellectual_Disability-Coloboma-Micrognathia_Syndrome] Parent-Specific FOXF1 Enhancer Activity [Alveolar_Capillary_Dysplasia_with_Misalignment_of_Pulmonary_Veins] Super-Enhancer Translocation and MYB Positive Feedback Loop [Adenoid_Cystic_Carcinoma] epigenetic 11p15.5 Imprinting Dysregulation [Beckwith-Wiedemann_Syndrome] Maternal Chromosome 7 Uniparental Disomy [Silver_Russell_Syndrome] CDKN2A/p16 Epigenetic Silencing [Rhabdoid_Tumor] Somatic FDFT1 Promoter Hypermethylation [Porokeratosis] D4Z4 Epigenetic Derepression [Facioscapulohumeral_Muscular_Dystrophy] DNA Hypermethylation [IDH_Mutant_AML] Epigenetic Reprogramming and CIMP-High Phenotype [EBV_Associated_Gastric_Cancer] EHMT1 haploinsufficiency and epigenetic dysregulation [Kleefstra_Syndrome] X-Inactivation Mosaicism and Negative Selection of Mutant-Expressing Cells [CHILD_Syndrome] Mosaic BCOR Deficiency from X-Inactivation [Oculofaciocardiodental_Syndrome] Epigenetic dysregulation via alpha-KG-dependent dioxygenase inhibition [D-2-Hydroxyglutaric_Aciduria] Lactate-Mediated Signaling and Epigenetic Modification [Rheumatoid_Arthritis] Epigenetic Regulation of Subtype Identity [Testicular_Germ_Cell_Tumor] Failure of Locus-Specific H3K4me3 Fine-Tuning at CpG-Island Promoters [Claes-Jensen_Type_X-Linked_Intellectual_Disability] Epigenetic Reprogramming [Synovial_Sarcoma] Reduced H3K4 Methylation [SETD1B-Related_Neurodevelopmental_Disorder] Impaired LSD1 Engagement of Developmental Transcription Factors [KDM1A-Related_Neurodevelopmental_Disorder] BAF Subunit Switching in Neural Development [Blepharophimosis-Impaired_Intellectual_Development_Syndrome] Chromatin Architecture Disruption [CTCF-related_Neurodevelopmental_Disorder] DAXX/ATRX Chromatin Remodeling Deficiency [Gastroenteropancreatic_Neuroendocrine_Neoplasm] SRCAP truncation-driven chromatin dysregulation [Floating-Harbor_syndrome] Disrupted Nucleosome Assembly and Chaperone Interaction [Bryant-Li-Bhoj_Neurodevelopmental_Syndrome_2] Altered Chromatin Accessibility and Transcriptional Dysregulation [Bryant-Li-Bhoj_Neurodevelopmental_Syndrome_2] H3 K27M Oncohistone Dominant-Negative PRC2 Inhibition [Diffuse_Astrocytoma] Dysregulation of histone acetylation and transcriptional coactivation [Genitopatellar_Syndrome] CHD4/NuRD chromatin remodeling dysfunction [Sifrim-Hitz-Weiss_Syndrome] Dysregulated Immediate Early Gene and REST-Dependent Neuronal Transcription [Blepharophimosis_Intellectual_Disability_Syndrome_MKB_Type] Epigenetic regulator loss [Sezary_Syndrome] Cis-Regulatory PRDM13 Dysregulation [North_Carolina_Macular_Dystrophy] transcript-level Derepression of GLI3-Dependent Sonic Hedgehog Target Transcription [FG_Syndrome_1] RBM15::MRTFA Fusion Deregulates RBPJ Transcription [Acute_Megakaryoblastic_Leukemia] Genome-Wide Transcriptional Dysregulation [Bainbridge-Ropers_Syndrome] Developmental transcriptional dysregulation [Cornelia_de_Lange_Syndrome] Loss of FOXP1 Transcriptional Repression [FOXP1_Syndrome] Transcriptional Dysregulation [Huntington_Disease] Constitutive Nuclear TAZ-TEAD Transcriptional Activation [Epithelioid_Hemangioendothelioma] U12-type intron retention and transcriptome dysregulation [RNU12-related_Minor_Spliceopathy] Widespread mRNA Mis-Splicing [THOC6-Related_Developmental_Delay-Microcephaly-Facial_Dysmorphism_Syndrome] Reduced Transcriptional Activation of COL1A1 and Type I Collagen Synthesis [Osteogenesis_Imperfecta_Type_XVI] ZEB1 EMT-Axis Transcription Factor Dysregulation [Posterior_Polymorphous_Corneal_Dystrophy] Aberrant RNA Polymerase II Elongation and Transcriptional Infidelity [SETD5_Haploinsufficiency_Syndrome] PTCL-NOS transcriptional polarization [Peripheral_T_Cell_Lymphoma] Neurodevelopmental Transcriptional Dysregulation [Mediator_Complex_Neurodevelopmental_Disorder] Pro-cathelicidin transcription [Rosacea] INSR Splicing Shift and Insulin Resistance [Myotonic_Dystrophy_Type_1] Neurodevelopmental transcriptional dysregulation [MED13_Syndrome] Dysregulation of the Pluripotency Transcriptional Network [Otofacial_Neurodevelopmental_Syndrome] Reduced TXNL4A Expression from Biallelic Promoter and Loss-of-Function Variants [Burn-McKeown_Syndrome] BIN1 Mis-splicing and T-tubule Disruption [Myotonic_Dystrophy_Type_1] Dysregulated Neuronal Gene Expression [Autism_Susceptibility_to_X-Linked_3] Disrupted neurodevelopmental transcriptional programs [SETBP1_Disorder] Aberrant EGR1-Target Transactivation [Solitary_Fibrous_Tumor] RAN translation and FMRpolyG production [Fragile_X-Associated_Primary_Ovarian_Insufficiency] SECISBP2-dependent Sec incorporation defect [SECISBP2_Deficiency] FMR1 premutation CGG expansion and elevated FMR1 mRNA [Fragile_X-Associated_Primary_Ovarian_Insufficiency] ENVIRONMENTAL EFFECT -- the insult from outside infectious agent Persistent HIV Infection and Replication [Acquired_Immunodeficiency_Syndrome] Non-polio Enterovirus Respiratory Infection [Acute_Flaccid_Myelitis] EBV Latent Infection of Gastric Epithelium [EBV_Associated_Gastric_Cancer] HHV-8 Latent Infection of Endothelial Cells [Kaposi_Sarcoma] Trophozoite colonization of the proximal small-intestinal epithelial surface [Giardiasis] Respiratory entry and SLAM-mediated immune cell infection [Measles] Bartonella erythrocyte infection and hemolysis [Oroya_Fever] Viremia and systemic dissemination [Hand_Foot_and_Mouth_Disease] Polymicrobial infection with tissue necrosis [Noma] Recurrent Invasive Neisserial Infection [Late_Complement_Component_Deficiency] Infant intestinal colonization and in-situ toxin production [Botulism] Persistent Mucocutaneous Candida albicans Infection [Chronic_Mucocutaneous_Candidiasis] Trophozoite colonization of colonic mucosa [Dientamoebiasis] Viral T Antigen Oncogenesis [Merkel_Cell_Carcinoma] MERS-CoV Spike-Mediated Entry via DPP4 [Middle_East_Respiratory_Syndrome] Persistent High-Risk HPV Infection [Cervical_Squamous_Cell_Carcinoma] chemical / drug / toxin Supratherapeutic Acetaminophen Exposure [Acetaminophen_Hepatotoxicity] Ethanol Exposure and Acetaldehyde-Generating Oxidative Metabolism [Alcohol_Use_Disorder] Cyanogenic Glucoside (Linamarin) and Cyanide Exposure from Bitter Cassava [Konzo] Developmental fluoride overexposure during amelogenesis [Dental_Fluorosis] Exposure to Avian Proteins [Bird_Fanciers_Lung] Cigarette Smoke Exposure [Ectopic_Pregnancy] UV Exposure [Melanoma_in_Congenital_Melanocytic_Nevus] Prolonged broad-spectrum antibiotic exposure in acne or rosacea [Folliculitis] Fatal Opioid Overdose [Opioid_Use_Disorder] physical exposure Acoustic Overexposure and Cochlear Energy Delivery [Noise_Induced_Hearing_Loss] Aerosol exposure and Old World hantavirus inoculation [Hantavirus_Hemorrhagic_Fever_with_Renal_Syndrome] Thunderstorm Concentration and Osmotic Rupture of Pollen Grains [Thunderstorm_Asthma] hormonal / physiological exposure Pubertal Testosterone Exposure [46_XY_DSD_Due_to_5_Alpha_Reductase_2_Deficiency] Estrogen-mediated acceleration of premature epiphyseal fusion [Leri-Weill_Dyschondrosteosis] physiological stressor -- the intermittent trigger that unmasks a latent lesion Catabolic Stress-Unmasked Ketone-Body Energy Deficit [3-Hydroxy-3-Methylglutaryl-CoA_Synthase_Deficiency] Fever-induced accentuation of sodium-channel loss of function [Brugada_Syndrome] Febrile Illness Unmasking of Pump Reserve Failure [CAPOS_Syndrome] Fasting- and Stress-Induced Bilirubin Elevation [Gilberts_Syndrome] Preceding Febrile Infection Trigger [Febrile_Infection-Related_Epilepsy_Syndrome] Fever-Sensitive Clustering Seizures [PCDH19_Clustering_Epilepsy] Catabolic Stress Exposure [TANGO2_Deficiency_Disorder] Starvation-Adaptation Endocrine Response [Anorexia_Nervosa] Volume Depletion and Dehydration [Arthrogryposis-Renal_Dysfunction-Cholestasis_Syndrome] Intermittent Hypoxia [Obstructive_Sleep_Apnea] Traumatic Stress Exposure [Post-Traumatic_Stress_Disorder] microbiome state -- the resident community as an exposure, not a single pathogen Gut Microbiome Dysbiosis [Parkinsons_Disease] Increased Microbial Community Instability [Ulcerative_Colitis] Microbiome Dysbiosis [Celiac_Disease] Oral Microbiome Dysbiosis [Dental_Caries] Gut Dysbiosis and Gut-Joint Axis [Ankylosing_Spondylitis] Microbiome Dysbiosis and Biofilm Formation [Hidradenitis_Suppurativa] Antibiotic-induced dysbiosis of ear canal microbiota [Otomycosis] Gut Microbiome Dysbiosis [Long_COVID] Malassezia-associated free fatty acid release [Seborrheic_Dermatitis] Loss of Colonization Resistance [Clostridioides_difficile_Infection] Gut-Liver Axis Dysregulation [Primary_Sclerosing_Cholangitis] Sebaceous gland activity and sebum-rich cutaneous milieu [Seborrheic_Dermatitis] MOLECULAR ACTIVITY EFFECT -- what the gene product can no longer do; GO molecular_function territory. Not the allele (GENOMIC or `genetic:`), not the resulting pool (SUBSTANCE). catalytic activity HMGCS2 Catalytic Loss [3-Hydroxy-3-Methylglutaryl-CoA_Synthase_Deficiency] ACADM molecular function deficiency [MCAD_Deficiency] ACADSB molecular function deficiency [2-Methylbutyryl-CoA_Dehydrogenase_Deficiency] OPLAH molecular function deficiency [5-Oxoprolinase_Deficiency] ACAT1 molecular function deficiency [Beta-Ketothiolase_Deficiency] NAGS molecular function deficiency [N-Acetylglutamate_Synthase_Deficiency] HLCS molecular function deficiency [Holocarboxylase_Synthetase_Deficiency] D2HGDH molecular function deficiency (type I) [D-2-Hydroxyglutaric_Aciduria] Aspartoacylase enzyme deficiency [Canavan_Disease] CYP21A2 21-Hydroxylase Deficiency [Congenital_Adrenal_Hyperplasia] ECHS1 (short-chain enoyl-CoA hydratase) enzyme deficiency [ECHS1_Deficiency] ALG1 beta-1,4-mannosyltransferase deficiency [ALG1-Congenital_Disorder_of_Glycosylation] EXTL3 Glycosyltransferase Deficiency [Immunoskeletal_Dysplasia_with_Neurodevelopmental_Abnormalities] HPRT1 Enzyme Deficiency and Purine Overproduction [Lesch-Nyhan_Syndrome] G6PC3 endoplasmic-reticulum phosphatase deficiency [G6PC3_Deficiency] TSC2 GAP Domain Catalytic Loss [Tuberous_Sclerosis_Complex] SRD5A2 Loss of Function [46_XY_DSD_Due_to_5_Alpha_Reductase_2_Deficiency] ACADVL molecular function deficiency [VLCAD_Deficiency] OCRL phosphatidylinositol dephosphorylation defect [Lowe_Syndrome] Protease-Antiprotease Imbalance [Bronchiectasis] UMP Synthetase Enzymatic Block [Hereditary_Orotic_Aciduria] GNPTAB phosphotransferase deficiency [Mucolipidosis_Type_III_Alpha_Beta] Impaired Twinkle Helicase Function and mtDNA Replication [Mitochondrial_DNA_Depletion_Syndrome_7] Impaired Cytoplasmic Pre-60S Ribosomal Maturation [AFG2A-Related_Encephalopathy] Constitutive Gs-alpha adenylate cyclase activation [GNAS-related_pituitary_adenoma_3] CYB5R3 cytochrome b5 reductase deficiency [Hereditary_Methemoglobinemia] PFKM Molecular Function Deficiency [Glycogen_Storage_Disease_Type_VII] GlcAT-I Loss of Function [Larsen-like_Syndrome_B3GAT3_Type] Erythrocyte Pyruvate Kinase Loss of Function [Pyruvate_Kinase_Deficiency] Acid Ceramidase Deficiency [Spinal_Muscular_Atrophy_Progressive_Myoclonic_Epilepsy] TALDO1 transaldolase activity deficiency [Transaldolase_Deficiency] High-molecular-weight kininogen cleavage and bradykinin liberation [Hereditary_Angioedema] Impaired TNAP-Dependent Vitamin B6 Activation [Multiple_Congenital_Anomalies-Hypotonia-Seizures_Syndrome] RP2 Loss of ARL3 GAP Activity [RP2-Related_Retinopathy] Arylsulfatase A Deficiency [Metachromatic_Leukodystrophy] MAN2B1 lysosomal alpha-mannosidase deficiency [Alpha_Mannosidosis] MMUT/AdoCbl pathway molecular function deficiency [Methylmalonic_Acidemia] IDUA enzyme deficiency [Hurler_syndrome] Fumarylacetoacetate hydrolase deficiency [Tyrosinemia_Type_I] PHEX Loss of Function in Mineralizing Cells [X-Linked_Hypophosphatemia] Type A GALNS deficiency [Morquio_syndrome] PNPLA2/ATGL Deficiency [Neutral_Lipid_Storage_Myopathy] Ceruloplasmin ferroxidase deficiency [aceruloplasminemia] ALG3 Alpha-1,3-Mannosyltransferase Deficiency [ALG3-Congenital_Disorder_of_Glycosylation] RAF1/BRAF Kinase Gain-of-Function [Noonan_Syndrome_with_Multiple_Lentigines] Hypomorphic MBTPS2 Impairs Site-2 Protease (S2P) Regulated Intramembrane Proteolysis [Osteogenesis_Imperfecta_Type_XIX] channel conductance SCN5A Sodium-Channel Loss of Function [Atrial_Standstill] Cone CNG Channel Dysfunction [Achromatopsia] Dominant-Negative Kir2.1 Tetramer Dysfunction [Andersen-Tawil_Syndrome] CLCN7 Dominant Negative Chloride Channel Dysfunction [Autosomal_Dominant_Osteopetrosis_Type_II] P/Q-type Calcium Channel Dysfunction [CACNA1A_Related_Disorder] Kir4.1 Potassium Channel Loss of Function [EAST_Syndrome] BEST1 Calcium-Activated Chloride Channel Dysfunction [BEST1-Related_Dominant_Retinopathy] Voltage-gated sodium channel dysfunction [Generalized_Epilepsy_with_Febrile_Seizures_Plus] Postsynaptic Glycine Receptor Chloride Channel Dysfunction [Hereditary_Hyperekplexia] CLCN1 chloride channel dysfunction [Thomsen_and_Becker_disease] Gain-of-Function Kv1.2 Conductance and Neuronal Silencing [KCNA2-Related_Developmental_and_Epileptic_Encephalopathy] Increased potassium-channel conductance [Zimmermann_Laband_Syndrome] KCNJ5 selectivity filter loss and sodium conductance [Familial_Hyperaldosteronism] Loss of Sarcolemmal KATP Conductance in Skeletal Muscle [ABCC9-Related_Intellectual_Disability_and_Myopathy_Syndrome] Dominant-Negative Loss of Delayed-Rectifier K+ Current [KCNB1-Related_Developmental_and_Epileptic_Encephalopathy] TMEM38B Loss Eliminates the ER Cation Channel TRIC-B and Disrupts ER Calcium Flux [Osteogenesis_Imperfecta_Type_XIV] Loss of M-Current Control of Neuronal Excitability [Benign_Neonatal_Seizures] Decreased Nav1.2 Sodium Current (Loss of Function) [SCN2A-Related_Developmental_and_Epileptic_Encephalopathy] CFTR Dysfunction [Cystic_Fibrosis] SCN9A-mediated Nav1.7 hyperexcitability subset [erythromelalgia] RyR2 Interdomain Unzipping [RYR2_CPVT] CASQ2 Loss-of-Function [RYR2_CPVT] TRPV4 Channel Hyperactivity in Growth Plate Chondrocytes [Metatropic_Dysplasia] TRPV4 Channel Gain-of-Function [Scapuloperoneal_Spinal_Muscular_Atrophy] transport activity Loss of GLUT2 Transporter Function [Fanconi-Bickel_Syndrome] Reduced GLUT1 Transporter Function at the Blood-Brain Barrier [GLUT1_Deficiency_Syndrome] SLC22A5/OCTN2 transporter dysfunction [Primary_Carnitine_Deficiency] NaCT Citrate Transporter Deficiency [SLC13A5_Citrate_Transporter_Disorder] Dopamine Transporter Loss of Function [Infantile_Parkinsonism-Dystonia] hENT3 (SLC29A3) Nucleoside Transporter Deficiency [H_Syndrome] SLC19A3 thiamine transporter deficiency [Biotin_Thiamine_Responsive_Basal_Ganglia_Disease] Impaired Folate Transport Across the Blood-CSF Barrier and Low CSF 5-MTHF [FOLR1-Related_Cerebral_Folate_Transport_Deficiency] Impaired KCC3-mediated ion transport and ionic homeostasis [Agenesis_of_the_Corpus_Callosum_with_Peripheral_Neuropathy] Impaired Golgi UDP-GlcNAc Transport [Autism_Spectrum_Disorder-Epilepsy-Arthrogryposis_Syndrome] Impaired GABA Transporter (GAT-1) Function [Epilepsy_with_Myoclonic_Atonic_Seizures] Sodium-potassium ATPase inhibition [Thallium_Poisoning] SLC6A8 creatine transport defect [Creatine_Transporter_Deficiency] MDR3-Mediated Biliary Phospholipid Secretion Failure [Progressive_Familial_Intrahepatic_Cholestasis] SLC5A2 Loss-of-Function [Familial_Renal_Glucosuria] Reduced Intestinal Oxalate Secretion [SLC26A6-Related_Hyperoxaluria_and_Nephrolithiasis] SLC16A2 Loss of Function [Allan-Herndon-Dudley_Syndrome] receptor / adaptor activity STAT3 dominant-negative dysfunction [Autosomal_Dominant_Hyper-IgE_Syndrome] FGFR3 p.Gly380Arg gain-of-function with impaired receptor down-regulation [Achondroplasia] ARHGAP31 Gain of Function [Adams-Oliver_Syndrome] GRIN2A/NMDA Receptor Dysfunction [Landau-Kleffner_Syndrome] Nicotinic acetylcholine receptor dysfunction [Familial_Sleep_Related_Hypermotor_Epilepsy] Androgen Receptor Dysfunction [Androgen_Insensitivity_Syndrome] RARB Receptor Dysfunction [RARB-related_syndromic_microphthalmia] Dominant-Negative Dynamin-1 Dysfunction [DNM1_Encephalopathy] Impaired pVHL Binding to Hydroxylated HIF-alpha [Chuvash_Polycythemia] Impaired IRE-Binding Activity of Residual IRP2 [IREB2-Related_Neurodegeneration] Impaired DNA binding by BAF [Nestor-Guillermo_progeria_syndrome] Impaired Syntaxin-1 Chaperoning and SNARE-Mediated Vesicle Fusion [STXBP1_Encephalopathy] PRRT2 Loss-of-Function and Impaired Synaptic Vesicle Release [Benign_Familial_Infantile_Epilepsy] Constitutive Rhodopsin Activation in Darkness [RHO-Related_Retinopathy] Failure of GABA-A Receptor Subunit Plasticity [Postpartum_Depression] DNAJC12 Co-chaperone Dysfunction [Disorder_of_Catecholamine_Synthesis] NMDA Receptor Overactivation and Calcium Influx [Isolated_Sulfite_Oxidase_Deficiency] Beta2-adrenergic receptor switch from Gs to Gi coupling [Takotsubo_Cardiomyopathy] Biallelic GM-CSF receptor subunit dysfunction [Hereditary_Pulmonary_Alveolar_Proteinosis] MERTK Loss of Function in RPE [MERTK-Related_Retinopathy] Loss of Platelet-Surface Coagulation Factor Binding [Bernard-Soulier_Syndrome] AP1S1 loss of function [MEDNIK_syndrome] structural-protein activity -- a structural protein failing to assemble, not an enzyme failing to catalyse Dominant-Negative Collagen Disruption [Osteogenesis_Imperfecta_Type_II] COL11A2 Dominant-Negative Disruption of Type XI Collagen [COL11A2_Skeletal_Spectrum] Dominant-Negative Disruption of Filament Assembly [Epidermolysis_Bullosa_Simplex] p.Arg138Trp-supported P5CS dominant-negative complex disruption [ALDH18A1_Cutis_Laxa] Truncated Filamin A Protein [Terminal_Osseous_Dysplasia] Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State [Hypertrophic_Cardiomyopathy_4] Enhanced AMPK-gamma2/Myosin Interaction [PRKAG2_Cardiac_Syndrome] SPARC Loss-of-Function Disrupts Osteonectin Collagen Binding in the Bone ECM [Osteogenesis_Imperfecta_Type_XVII] Dominant-Negative Collagen Defect [Osteogenesis_Imperfecta_Type_III] Predicted impaired CDH23-mediated cell adhesion [CDH23-associated_pituitary_adenoma_5] Impaired FLNB Dimerization and Protein Stability [Spondylocarpotarsal_Synostosis_Syndrome] Integrin Alpha-6-Beta-4 Deficiency [Junctional_Epidermolysis_Bullosa] Cadherin-11 Loss of Function [Elsahy-Waters_Syndrome] MOLECULAR SUBSTANCE EFFECT -- which molecules are now present in the wrong amount or the wrong form; one causal step below activity. metabolite accumulation Reactive valine-derived intermediate accumulation [3-Hydroxyisobutyryl-CoA_Hydrolase_Deficiency] Succinylpurine accumulation and neurotoxicity [Adenylosuccinate_Lyase_Deficiency] Diagnostic organic-acid accumulation [3-Hydroxy-3-Methylglutaric_Aciduria] 5-oxo-L-proline accumulation and urinary excretion [5-Oxoprolinase_Deficiency] L-2-hydroxyglutarate accumulation [L-2-Hydroxyglutaric_Aciduria] 2-HG Accumulation [IDH_Mutant_AML] Substrate Accumulation (VLCFA, Pristanic Acid, Bile-Acid Intermediates) [D-Bifunctional_Protein_Deficiency] Sialyloligosaccharide Lysosomal Accumulation [Juvenile_Sialidosis_Type_2] Lysosomal Tn-antigen Glycopeptide Accumulation [Kanzaki_Disease] Systemic Iron Overload [Hemochromatosis] 1,5-AG6P accumulation and hexokinase inhibition [G6PC3_Deficiency] Granular Osmiophilic Material (GOM) Accumulation [CADASIL_Type_1] Intestinal Lipid Storage [Wolman_Disease] Lysosomal Storage (NCL and Sialidosis) [Progressive_Myoclonus_Epilepsy] Systemic and CNS glycine accumulation [Nonketotic_Hyperglycinemia] Cytosolic Glyoxylate-to-Oxalate Overproduction [Primary_Hyperoxaluria_Type_3] Fucose-rich glycoconjugate lysosomal storage [Fucosidosis] Adrenal Lipid Storage [Wolman_Disease] Hyperornithinemia [ornithine_aminotransferase_deficiency] Neuromuscular polyglucosan storage [Glycogen_Storage_Disease_Type_IV] Sialylated metabolite lysosomal storage [Sialidosis_Type_1] Homogentisic acid accumulation [Alkaptonuria] Proposed Cerebral Excitatory Amino-Acid Imbalance [Asparagine_Synthetase_Deficiency] Lysosomal Cholesteryl Ester and Triglyceride Accumulation [Cholesteryl_Ester_Storage_Disease] Lysosomal heparan sulfate accumulation [Sanfilippo_syndrome] Neuronal Ki-67 substrate accumulation [Ferguson-Bonni_Neurodevelopmental_Syndrome] Lysosomal autofluorescent storage material accumulation [Northern_Epilepsy] Truncated lipid-linked oligosaccharide accumulation [MPDU1-congenital_disorder_of_glycosylation] Glucosylsphingosine accumulation [Kufor-Rakeb_syndrome] Lysosomal hyaluronan accumulation [Mucopolysaccharidosis_type_IX] Elevated baseline intracellular calcium [YWHAG_Syndrome] Hyperammonemia during metabolic crises [Carnitine-Acylcarnitine_Translocase_Deficiency] PRPP and purine nucleotide overproduction [PRPS1_Superactivity] NKH-like secondary hyperglycinemia [Inherited_Threoninemia] RPE Dysfunction and Toxic Metabolite Accumulation [Inherited_Retinal_Dystrophy] Reduced renal oxypurinol clearance [Allopurinol_Induced_SJS_TEN] Phenylketone Accumulation [Phenylketonuria] Multisystem Lysosomal Substrate Accumulation [Mucolipidosis_Type_II] Hypertyrosinemia and systemic tyrosine accumulation [Tyrosinemia_Type_II] Dimethylglycine accumulation [Dimethylglycine_Dehydrogenase_Deficiency] Brain accumulation of GA1 catabolites [Glutaryl-CoA_Dehydrogenase_Deficiency] Abnormal intracellular iron metabolism [neuroferritinopathy] Toxic fumarylacetoacetate and maleylacetoacetate accumulation [Tyrosinemia_Type_I] metabolite depletion Low L-Serine and Downstream Metabolites [3-Phosphoglycerate_Dehydrogenase_Deficiency] Cerebral Creatine Depletion [AGAT_Deficiency] Secondary carnitine depletion [3-Methylcrotonyl-CoA_Carboxylase_Deficiency] Systemic and CSF BCAA depletion [BCKDK_Deficiency] Dolichol-Phosphate-Mannose Depletion [DPM2-congenital_disorder_of_glycosylation] GM3 and downstream ganglioside depletion [GM3_Synthase_Deficiency] Glutamate Excess and Glutamine Depletion [Infantile_Cataract_Skin_Abnormalities_Glutamate_Excess_and_Impaired_Intellectual_Development] Reduced fibroblast selenoprotein levels [EEFSEC_Deficiency] Renal potassium wasting [Liddle_Syndrome] Mitochondrial dNTP Pool Imbalance [Mitochondrial_Neurogastrointestinal_Encephalomyopathy] Glutathione and Inflammatory Metabolomic Signature [ATTR_Amyloidosis] Hepatic glutathione dysregulation in ASL deficiency [Urea_Cycle_Disorder] Secondary Pyridoxal 5-Phosphate Deficiency [Pyridoxine-Dependent_Epilepsy] FGF23-mediated phosphate wasting [Fibrous_Dysplasia] Generalized glutathione deficiency [Glutathione_Synthetase_Deficiency] Secondary Vitamin B6 Deficiency [Hyperprolinemia_Type_2] FGF23-mediated renal phosphate wasting [Arterial_Calcification_of_Infancy] COQ8A-Dependent Coenzyme Q10 Deficiency [Autosomal_Recessive_Ataxia_Due_to_Ubiquinone_Deficiency] protein misfolding / aggregation ADan Misfolding and Beta-Sheet Oligomerization [ADan_amyloidosis] Proteolytic Processing and Beta-Sheet Misfolding of SAA [AA_Amyloidosis] Amyloid-beta Misfolding and Soluble Oligomer Formation [Early-Onset_Autosomal_Dominant_Alzheimer_Disease] Alpha-Synuclein Aggregation and Lewy Body Formation [Dementia_with_Lewy_Bodies] PolyQ-expanded ataxin-3 misfolding and nuclear aggregation [Machado_Joseph_Disease] NOTCH3 Mutation and ECD Aggregation [CADASIL_Type_1] Mutant Myocilin Misfolding and Trabecular Cell Stress [Juvenile_Open_Angle_Glaucoma] DNAJB6b Co-Chaperone Dysfunction and Z-Disc Aggregate Formation [Limb-Girdle_Muscular_Dystrophy_Autosomal_Dominant] Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation [Neuronal_Intranuclear_Inclusion_Disease] Ubiquitin-positive aggregate accumulation [Inclusion_Body_Myopathy_with_Paget_Disease_of_Bone_and_Frontotemporal_Dementia] Mutant Fibrinogen Gamma-Chain Production [Hepatic_Fibrinogen_Storage_Disease] Protein misfolding and aggregation of non-truncating ARID1B variants [Coffin_Siris_Syndrome] 4R-Tau Aggregation with Astrocytic Plaques [Corticobasal_Syndrome] Alpha-actinin-2 protein aggregation [Distal_Myopathy_6_Adult-Onset_Autosomal_Dominant] Impaired Procollagen Chain Association and Collagen Folding [Osteogenesis_Imperfecta_Type_IX] Acquisition of a Conversion-Prone PrP-C State [Fatal_Familial_Insomnia] TDP-43 Proteinopathy [Frontotemporal_Dementia] Polyglutamine-expanded TBP disrupts transcriptional programs [Spinocerebellar_Ataxia_Type_17] Mutant Filamin C Aggregation and Proteostatic Burden [Hypertrophic_Cardiomyopathy_26] protein abundance loss -- the protein is not there, as distinct from being present but inactive (ACTIVITY) or present but misfolded Loss of Cytosolic MSTO1 Protein [MSTO1-Related_Mitochondrial_Myopathy] Loss of Functional MAGEL2 Protein [Schaaf-Yang_Syndrome] Truncated or absent NKCC1 protein [Kilquist_Syndrome] Biallelic MRPL44 Loss of Function and mL44 Protein Depletion [MRPL44_Deficiency] Mitochondrial phosphopantetheinyl-protein loss [Pantothenate_Kinase-Associated_Neurodegeneration] Reduced fibroblast selenoprotein levels [EEFSEC_Deficiency] Loss of beta-IV Spectrin from the Axon Initial Segment and Nodal Membrane Skeleton [SPTBN4-Related_Neurodevelopmental_Disorder] Biallelic Loss of Mitochondrial Gene-Expression and Proteostasis Factors [Perrault_Syndrome] Reduced Fibrinogen Synthesis [Congenital_Hypofibrinogenemia] Von Willebrand Factor Deficiency or Dysfunction [Hereditary_von_Willebrand_Disease] Prosaposin Deficiency and Loss of All Saposins [Combined_Saposin_Deficiency] Loss of the brain-predominant short UGP2 isoform [UGP2-Related_Developmental_and_Epileptic_Encephalopathy_83] Loss of CRB1 at the outer limiting membrane [CRB1_Retinal_Dystrophies] Complete Absence of proalpha2(I) Collagen Chains [Cardiac_Valvular_Ehlers-Danlos_Syndrome] DNAJC5/CSPalpha Functional Depletion and Presynaptic Dysfunction [Adult_Neuronal_Ceroid_Lipofuscinosis] TELO2/TTT complex destabilization [You-Hoover-Fong_Syndrome] E6-Mediated p53 Degradation [HPV_Positive_Head_and_Neck_Cancer] WAPL Deficiency [WAPL-Related_Developmental_Disorder] TFIIH Complex Instability in Photosensitive TTD [Trichothiodystrophy] p.G4310R HUWE1 Destabilization [X-linked_Syndromic_Intellectual_Disability_Turner_Type] Nail Matrix Keratin Deficiency [KRT85_Ectodermal_Dysplasia] POU3F4 Deficiency [Choroideremia-Deafness-Obesity_Syndrome] post-translational modification state -- the molecule is present and correctly folded but chemically altered Tau Hyperphosphorylation [Niemann_Pick_Disease_Type_C] Site-Specific Soluble Tau Hyperphosphorylation [Early-Onset_Autosomal_Dominant_Alzheimer_Disease] Perivascular Hyperphosphorylated Tau Pathology [Chronic_Traumatic_Encephalopathy] PER2 S662-Site Hypophosphorylation [Advanced_Sleep_Phase_Syndrome] CaMKII-Dependent RyR2 Hyperphosphorylation [ANK2_Ankyrin_B_Syndrome] Hypophosphorylation of Secreted Biomineralization Proteins [Raine_Syndrome] AFB1-DNA Adduct Formation [Aflatoxin_Related_HCC] Fatty Aldehyde Schiff-Base Adduct Formation [Sjogren-Larsson_Syndrome] Schiff-base adduction and methylene crosslinking of biomolecules [Formaldehyde_Poisoning] Loss of Ubiquitination of Outer Mitochondrial Membrane Substrates [PRKN-Related_Juvenile_Parkinson_Disease] CHST6 Keratan Sulfate Undersulfation [Stromal_Corneal_Dystrophy] Protein hypoglycosylation [ALG9-congenital_disorder_of_glycosylation] Combined N- and O-glycosylation Defect [COG7-Congenital_Disorder_of_Glycosylation] Increased Substrate Tyrosine Phosphorylation [Congenital_Heart_Defects_and_Skeletal_Malformations_Syndrome] Fibrin homocysteinylation and collagen cross-link deficiency [Homocystinuria] Defective glycoprotein maturation [DK1-congenital_disorder_of_glycosylation] Oxidative stress and 16-kDa prolactin generation [Peripartum_Cardiomyopathy] Retinoid-adduct retention and bisretinoid precursor formation [Stargardt_Disease] NMJ Glycoprotein Glycosylation Defect [Congenital_Myasthenic_Syndrome] PATHWAY EFFECT -- signalling and flux through a pathway signalling reduced / failed Reduced SHH Signaling in Forebrain Patterning [SHH_Holoprosencephaly_Spectrum] DHH paracrine hedgehog signaling failure [46_XY_Partial_Gonadal_Dysgenesis] FSHR Signaling Resistance [46_XX_Gonadal_Dysgenesis] Impaired IHH-Patched1 Receptor Signaling [Brachydactyly_Type_A1] Impaired Norrin/beta-catenin signaling in retinal endothelium [Familial_Exudative_Vitreoretinopathy] Impaired Microglial CSF1R Signaling [Hereditary_Diffuse_Leukoencephalopathy_with_Spheroids] Impaired Go Heterotrimeric G-Protein Signaling [GNAO1-Related_Developmental_and_Epileptic_Encephalopathy] Impaired IGF1R Growth Signaling [IGF1_Deficiency] MC4R pathway signaling failure [Obesity_Due_to_MC4R_Pathway_Disruption] Reduced Hedgehog Signaling and Impaired Chondroinduction [Meier-Gorlin_Syndrome] OSM/IL-31 Receptor Signaling Failure [Primary_Cutaneous_Amyloidosis] Impaired NFAT signaling [CN_Related_DEE] Disrupted Reelin Signaling (CAMRQ1) [Cerebellar_Ataxia_Intellectual_Disability_and_Dysequilibrium] WNT/beta-catenin Signaling Deficiency [Tooth_Agenesis] Altered p53 Signaling [Arboleda-Tham_Syndrome] Attenuated Hedgehog Transcriptional Output [Holoprosencephaly_9] Impaired Neurogenesis via GABAergic Signaling Disruption [Delpire-McNeill_Syndrome] WNT1 Loss-of-Function Abolishes Canonical WNT/Beta-Catenin Signaling [Osteogenesis_Imperfecta_Type_XV] Ciliary and Hedgehog pathway abnormalities in inherited basal-cell-cancer biology [Bazex_Dupre_Christol_Syndrome] Impaired SOX11 Target Gene Transactivation [SOX11-Related_Neurodevelopmental_Disorder] Defective actin-cytoskeletal effector signaling downstream of DCC [Familial_Congenital_Mirror_Movements] Cilium-Dependent Signaling Failure [Cranioectodermal_Dysplasia] Planar Cell Polarity and Non-Canonical Wnt Disruption [Heart_Defect_Tongue_Hamartoma_Polysyndactyly_Syndrome] Reduced and Dominant-Negative AP-2 alpha Transcriptional Activity [Branchiooculofacial_Syndrome] KCTD1-associated WNT-SHH-BMP signaling perturbation [Taurodontism] Visual Cycle and Phototransduction Disruption [Inherited_Retinal_Dystrophy] Impaired innate antiviral interferon signaling [STK4_Deficiency] Disrupted EDA-EDAR-EDARADD-NF-κB Signaling [EDARADD_Hypohidrotic_Ectodermal_Dysplasia] ZNF526-related transcriptional dysregulation [Dentici-Novelli_neurodevelopmental_syndrome] signalling increased Angiogenic Signaling Activation [Angiosarcoma] Somatic CCR4 Gain-of-Function Signaling [Adult_T_Cell_Leukemia_Lymphoma] Constitutive ALK mitogenic and survival signaling [ALK_Rearranged_NSCLC] Constitutive EGFR Signaling [EGFR_Mutant_NSCLC] Constitutive RAS Signaling [KRAS_G12C_Mutant_NSCLC] Constitutive RET Signaling [RET_Rearranged_NSCLC] Constitutive PDGFRB Signaling [Infantile_Myofibromatosis] Constitutive BMP Signaling Activation [Fibrodysplasia_Ossificans_Progressiva] Constitutive type I interferon signaling [COPA_Syndrome] Constitutive STAT6 signaling [STAT6_Gain_of_Function_Disease] TLR2 signaling activation in monocytes and macrophages [Leptospirosis] mTOR pathway hyperactivation [Infantile_Spasms] Mast Cell Supportive Signaling [Waldenstrom_Macroglobulinemia] Serotonergic anorexigen smooth muscle growth signaling [Drug_or_Toxin-Induced_Pulmonary_Arterial_Hypertension] mTOR Pathway Activation [PIK3CA_Mutant_Breast_Cancer] G-alpha-q Pathway Activation [Meningeal_Melanocytoma] Mutation-Driven JAK/STAT Activation (Classic HL) [Hodgkin_Lymphoma] FGFR1 Constitutive Activation [Osteoglophonic_Dysplasia] Pseudohypoxia and HIF Activation [Pheochromocytoma_Paraganglioma] Hypertrophic Signaling and Metabolic Stress [Hypertrophic_Cardiomyopathy_7] NLRP12-associated NF-kappaB dysregulation [Familial_Cold_Autoinflammatory_Syndrome] RAS-MAPK Pathway Hyperactivation [Chronic_Myeloid_Leukemia] RAS-MAPK Pathway Activation [FLT3_Mutant_AML] EBV LMP1-Mediated NF-kappaB Activation [Classic_Hodgkin_Lymphoma] Non-cell-autonomous pAKT activation in adjacent cells [Proteus_syndrome] SMAD4 Gain-of-Function Variants Dysregulating TGF-beta/BMP Signaling [Myhre_Syndrome] Constitutive Mitogenic Pathway Activation [Glomus_Tumor] B-cell receptor signaling activation [Mantle_Cell_Lymphoma] Constitutive STING signaling and type I interferonopathy [STING_Associated_Vasculopathy_with_Onset_in_Infancy] mTORC1 Activation and Apoptosis Resistance [Primary_Pigmented_Nodular_Adrenocortical_Disease] Type I interferon gene signature [Stankiewicz_Isidor_syndrome] GATOR1 Complex Loss and mTORC1 Disinhibition [Familial_Focal_Epilepsy_With_Variable_Foci] Increased pAKT signaling in AKT1-mutant lesion cells [Proteus_syndrome] Receptor Tyrosine Kinase Signaling Activation [Chordoma] cAMP/PKA Pathway Activation [Testicular_Sex_Cord_Stromal_Neoplasm] Salivary Gland JAK-STAT Activation and ISG Upregulation [Sjogrens_Syndrome] MAPK Pathway Hyperactivation [Papillary_Thyroid_Carcinoma] TGF-beta Signaling in Fibrogenesis [Liver_Cirrhosis] PTEN PI3K Pathway Dysregulation [Endometrial_Endometrioid_Adenocarcinoma] Cilium-dependent cyst-promoting signal disinhibition [Autosomal_Dominant_Polycystic_Kidney_Disease] BCL2 Overexpression and Apoptosis Resistance [Diffuse_Large_B_Cell_Lymphoma] Axin1-AKT1-mTORC1-Shh translational dysregulation in HERS [Taurodontism] Dysregulated RAS-MAPK / ERK Signaling [Noonan_Syndrome_with_Multiple_Lentigines] Integrated Stress Response Activation [Progressive_Supranuclear_Palsy] LMP2A-Mediated B Cell Receptor Mimicry [Nasopharyngeal_Carcinoma] metabolic flux block Impaired leucine degradation [3-Hydroxy-3-Methylglutaric_Aciduria] Impaired ketone-body biosynthesis [3-Hydroxy-3-Methylglutaric_Aciduria] Impaired isoleucine catabolism via SBCAD loss-of-function [2-Methylbutyryl-CoA_Dehydrogenase_Deficiency] Impaired valine catabolism and reactive-metabolite accumulation [ECHS1_Deficiency] Impaired lysine degradation causing hyperlysinemia [DECR_Deficiency] Impaired citrulline synthesis and reduced urea cycle flux [Ornithine_Carbamoyltransferase_Deficiency] Impaired Glutamine Catabolism and Glutamine Accumulation [Neonatal_Epileptic_Encephalopathy_Due_to_Glutaminase_Deficiency] Impaired Glycogen Synthesis and Glycogenolysis [PGM1-Congenital_Disorder_of_Glycosylation] Impaired Glycosaminoglycan Biosynthesis [Autism_Spectrum_Disorder-Epilepsy-Arthrogryposis_Syndrome] Impaired Serine Biosynthesis in Neural Progenitors [Siderius_Type_X-Linked_Intellectual_Disability] Impaired Glycosylation [Galactosemia] Impaired Surfactant Catabolism and Macrophage Cholesterol Overload [Autoimmune_Pulmonary_Alveolar_Proteinosis] Peroxisomal Fatty Acid Beta-Oxidation Failure [Perrault_Syndrome] Impaired mitochondrial long-chain fatty acid beta-oxidation [Long-Chain_3-Hydroxyacyl-CoA_Dehydrogenase_Deficiency] Impaired hepatic glycolysis and carbohydrate toxicity [Citrin_Deficiency] Reduced hyaluronic acid synthesis [UGDH-Related_Developmental_and_Epileptic_Encephalopathy_84] H6PD Endoplasmic-Reticulum NADPH Generation Failure [Cortisone_Reductase_Deficiency] Warburg-like Metabolic Reprogramming [Endometriosis] Impaired mitochondrial long-chain fatty acid oxidation [Carnitine_Palmitoyltransferase_II_Deficiency] Urea Cycle Flux Impairment [Hyperornithinemia_Hyperammonemia_Homocitrullinuria_Syndrome] Disrupted Folate One-Carbon Metabolism [Anencephaly] Impaired ureagenesis and hyperammonemia [Argininosuccinic_Aciduria] Urea Cycle Perturbation [Pyruvate_Carboxylase_Deficiency_Disease] CELLULAR EFFECT cell death Centrilobular Oncotic Hepatocyte Necrosis [Acetaminophen_Hepatotoxicity] Rapid Photoreceptor Apoptosis and Congenital Retinal Dystrophy [AIPL1-Related_Retinopathy] Abortive HIV Infection and Caspase-1 Pyroptosis [Acquired_Immunodeficiency_Syndrome] Inflammasome Activation and Pyroptosis [Bacterial_meningitis] p53-Mediated Erythroid Apoptosis [Diamond-Blackfan_Anemia] Combined Rod and Cone Photoreceptor Apoptosis [CERKL-Related_Retinopathy] Retinal Ganglion Cell Degeneration and Apoptosis [Leber_Hereditary_Optic_Neuropathy] Neuronal apoptosis [Nijmegen_breakage_syndrome] Endoplasmic reticulum stress and increased myeloid apoptosis [G6PC3_Deficiency] Defective Fas-mediated apoptosis of activated lymphocytes [FAS-related_Autoimmune_Lymphoproliferative_Syndrome] Apoptosis resistance of leukemic hairy cells [Hairy_Cell_Leukemia] Apoptosis Resistance [Follicular_Lymphoma] Chondrocyte apoptosis [Thanatophoric_Dysplasia_Type_1] Ferroptosis [Wilsons_Disease] Perforin/Granzyme B-Mediated Cytotoxicity [Stevens-Johnson_Syndrome] Gasdermin D-Mediated Pyroptosis [Familial_Mediterranean_Fever] Keratinocyte death by cytotoxic mediators [Allopurinol_Induced_SJS_TEN] Mdm2 mis-splicing activates p53-dependent neural crest apoptosis [Mandibulofacial_Dysostosis_with_Microcephaly] Spinal motor neuron apoptosis [Sandhoff_Disease] Cell Cycle Arrest and Apoptosis [Parvovirus_B19_Infection] Neural Progenitor Apoptosis and Pool Depletion [Congenital_Zika_Syndrome] differentiation / identity Granulocytic Differentiation Arrest [APL_PML_RARA] Interneuron Progenitor Differentiation Failure [ARX-Related_Lissencephaly_and_Interneuronopathy] Differentiation Block [IDH_Mutant_AML] Differentiation Block [NPM1_Mutant_AML] Adipocytic Differentiation Block [Liposarcoma] Oligodendrocyte Differentiation Arrest [POLR-Related_Leukodystrophy] Growth Plate Chondrocyte Differentiation Failure [Cartilage-Hair_Hypoplasia] B-cell terminal differentiation defect [Kabuki_Syndrome] ERK/SOX9-Dependent Osteoprogenitor Differentiation Defect [Osteogenesis_Imperfecta_Type_V] Neural Progenitor Differentiation Failure and Excessive Apoptosis [Shashi_X-Linked_Intellectual_Disability_Syndrome] Distal Nephron Intercalated Cell Origin [Chromophobe_Renal_Cell_Carcinoma] Failure of Lineage Commitment [Mixed_Phenotype_Acute_Leukemia] Primordial Germ Cell-Derived Malignancy [Malignant_Non_Dysgerminomatous_Germ_Cell_Tumor_Of_Ovary] Oxidative Stress and Epithelial-Mesenchymal Transition [Hereditary_Gingival_Fibromatosis] Goblet Cell Amphicrine Differentiation [Appendiceal_Neoplasm] Arrested Osteogenic Differentiation of the Neoplastic Stroma [Bone_Giant_Cell_Tumor] Differentiation Block and Tumor Growth [IDH_Mutant_Cholangiocarcinoma] Impaired osteoblast maturation and cranial mineralization [IRX5-related_Craniofacial_Dysostosis_with_Osteopenia_Intellectual_Disability_and_Dental_Anomalies] Follicular Keratinization Defect [Keratosis_Follicularis_Spinulosa_Decalvans] Impaired Osteoblast Differentiation and Bone Matrix Deposition [Osteogenesis_Imperfecta_Type_XII] GTF2I-driven thymic epithelial transformation [Thymoma] SOX10 neural crest and glial lineage dysfunction [SOX10_Neurocristopathy_Spectrum] Abnormal Epidermal Homeostasis and Keratinization [Erythrokeratodermia_Variabilis] Disrupted Cortical Neurogenesis and Neuronal Maturation [THOC2-Related_Intellectual_Disability] Dysregulated neural progenitor development [Costello_Syndrome] Cranial Suture Osteoblast Differentiation [Crouzon_Syndrome_with_Acanthosis_Nigricans] Proliferation-Differentiation Imbalance [Pineoblastoma] Self-Renewal Maintenance [Core_Binding_Factor_AML] EMT and Mesenchymal Plasticity [Ovarian_High-Grade_Serous_Carcinoma] Abnormal Megakaryopoiesis [Primary_Myelofibrosis] Megakaryocyte proplatelet formation dysregulation [Platelet-Type_von_Willebrand_Disease] metaplasia -- a differentiated tissue replaced by another differentiated type. From MeSH Metaplasia (D008679); conceptually sharp and distinct from a differentiation block. Gastric Intestinal Metaplasia [Gastric_Adenocarcinoma] Intestinal Metaplasia [Gastric_Cancer_H_pylori_Associated] Barrett Metaplasia to EAC Sequence [Esophageal_Carcinoma] Barrett's Esophagus Metaplastic Adaptation [Gastroesophageal_Reflux_Disease] haemolysis -- erythrocyte destruction as its own leaf; MeSH gives Hemolysis (D006461) top-level pathologic-process billing Chronic Hemolysis [Beta_Thalassemia] Acute Hemolytic Anemia [Glucose-6-Phosphate_Dehydrogenase_G6PD_Deficiency] Shortened Red Cell Survival and Hemolysis [Hereditary_Elliptocytosis] Acanthocytosis and Hemolysis [Abetalipoproteinemia] Hemolytic erythrocyte injury [Lead_Poisoning] Erythroid Uroporphyrin I Accumulation and Hemolysis [Inherited_Porphyria] Bartonella erythrocyte infection and hemolysis [Oroya_Fever] proliferation / expansion SHH-Responsive Cerebellar Progenitor Expansion [Gorlin_Syndrome] Uncontrolled Proliferation [HER2_Positive_Breast_Cancer] Uncontrolled Melanocyte Proliferation [KIT_Mutant_Melanoma] Enhanced Cell Proliferation [BRAF_V600E_Mutant_Colorectal_Cancer] Myelomonocytic Progenitor Expansion [Juvenile_Myelomonocytic_Leukemia] Loss of p57 and Trophoblast Hyperproliferation [Gestational_Trophoblastic_Neoplasm] Pulmonary Artery Smooth Muscle Cell Proliferation and Vasoconstriction [Idiopathic_Pulmonary_Arterial_Hypertension] EBV-driven lymphoproliferation and hyperinflammation [CD27-related_lymphoproliferative_and_immune_disorder] Impaired DNA Replication and Reduced Cell Proliferation [DTYMK-Related_Neurodegeneration] Melanocytic Tumor Cell Proliferation [Meningeal_Melanocytoma] Nephron Progenitor Self-Renewal [Wilms_Tumor] Dermal and Ocular Melanocyte Accumulation [Nevus_of_Ota] Malignant Lymphoid Proliferation [Lymphoma] Monoclonal Immunoglobulin Production [Plasma_Cell_Neoplasm] Malignant NK-Cell Survival and Expansion [Aggressive_NK-cell_Leukemia] Uncontrolled Intestinal Epithelial Proliferation [Familial_Adenomatous_Polyposis] Clonal Plasma Cell Proliferation [Multiple_Myeloma] Uncontrolled Cell Proliferation [Glioblastoma_IDH_Wildtype] Congenital Gingival Granular Cell Proliferation [Congenital_Epulis] Sustained Proliferation [Dermatofibrosarcoma_Protuberans] Driver Mutation-Initiated Clonal Transformation [Uterine_Leiomyoma] Neural Progenitor Overgrowth and Brain Enlargement [Bannayan-Riley-Ruvalcaba_Syndrome] Increased Tumor Cell Proliferation [Esophageal_Squamous_Cell_Carcinoma] Cell Proliferation and Migration [Meningioma] MYCN-Driven Proliferation [Neuroblastoma] Myeloid kinase-driven clonal eosinophilopoiesis [Hypereosinophilic_Syndrome] Systemic CD30-Positive Malignant T-Cell Expansion [Anaplastic_Large_Cell_Lymphoma] Dysregulated Progenitor Growth and Proliferation [Hemimegalencephaly] Loss of Merlin-Dependent Contact Inhibition and Receptor Control [Acoustic_Neuroma] Cyclin D1-CDK4 Cell-Cycle Dependency [Alveolar_Soft_Part_Sarcoma] Localized benign epithelial or smooth muscle proliferation in tubal/adnexal tissue [Fallopian_Tube_Benign_Neoplasm] Cerebellar Granule Cell Proliferation [Medulloblastoma_SHH_Activated] senescence Neural Stem Cell Senescence-Like State [Arts_syndrome] Cellular Senescence [Chronic_Obstructive_Pulmonary_Disease] Senescence Escape [Li-Fraumeni_Syndrome] Cellular senescence [Hutchinson-Gilford_Progeria_Syndrome] Oncogene-Induced Melanocytic Growth-Arrest Barrier [BRAF_V600_Mutant_Melanoma] Senescence-Constrained Low-Grade Progression Barrier [Pilocytic_Astrocytoma] cell activation -- a cell type switching into an effector state; the single most common CELLULAR node kind in immune and neuro entries Microglial Activation and Neuroinflammation [Early-Onset_Autosomal_Dominant_Alzheimer_Disease] Reactive Microglial and Macrophage Activation [ADan_amyloidosis] ANCA-Mediated Neutrophil Activation [Glomerulonephritis] Excess Effector T Cell Activation [CTLA4_Haploinsufficiency] Cytokine-mediated endothelial activation [Hantavirus_Pulmonary_Syndrome] Th1-Polarized Cell-Mediated Response and Macrophage Activation [Leishmaniasis] Classical Complement Activation on Astrocytes [Neuromyelitis_Optica_Spectrum_Disorder_with_Anti-AQP4_Antibodies] Complement activation at the glomerular capillary wall [Membranous_Nephropathy] Rho GTPase-Mediated Osteoclast Activation [Camurati-Engelmann_Disease] Neutrophil Activation and NLRP3 Inflammasome [Adult-Onset_Still_Disease] Retinal ceramide storage and macrophage activation [Farber_Disease] NETosis and Neutrophil Extracellular Trap Formation [Systemic_Lupus_Erythematosus] Endothelial dysfunction [Migraine_with_Aura] Macrophage Calcitriol Production [Sarcoidosis] Th1 and TNF-Driven Macrophage Recruitment and Activation [Chronic_Beryllium_Disease] Endothelial activation and damage [Viral_Hemorrhagic_Fever] Epithelial Alarmin Release [Eosinophilic_Esophagitis] GalCer-Driven Macrophage Pathology [Krabbe_Disease] Type 2 Immune Response [Atopic_Dermatitis] Macrophage-Mediated Treponemal Response [Bejel] RANKL-Mediated Osteoclast Overactivation [Osteogenesis_Imperfecta_Type_VI] T Cell Dysregulation [Immune_Thrombocytopenia] Innate Immune Activation [Vitiligo] Excessive Microglial Synaptic Pruning [Tourette_Syndrome] Endothelial COX-2 prostaglandin activation [Boutonneuse_Fever] IL-15 and Tissue-Resident Memory T Cells [Vitiligo] Th1 Effector Cytokine Response [Vogt-Koyanagi-Harada_Disease] Enhanced Cell-Mediated Immunity in Type 1 Reaction [Leprosy] Interferon-Gamma-Dependent Cell-Autonomous Immune Control [Toxoplasmosis] Antigen Presentation and Th1-Th17 Activation [Neurosarcoidosis] Alveolar Macrophage Phagocytosis of Respirable Silica [Silicosis] B Cell Dysregulation [Autoimmune_Hemolytic_Anemia] Eosinophil subset heterogeneity and tissue-specific dysfunction [Hypereosinophilic_Syndrome] Constitutive Fibroblast IL-6 Production [MSMO1_Deficiency] organelle dysfunction Cardiac Mitochondrial Dysfunction [Adult_Refsum_Disease] Failure of Poly(ADP-Ribose) Turnover under Stress [ADPRS-Related_Stress-Induced_Neurodegeneration] Mitochondrial dysfunction and oxidative stress [Danon_disease] Oxidative Stress and Mitochondrial Dysfunction in Nigral Dopaminergic Neurons [PARK7-Related_Early-Onset_Parkinson_Disease] Cardiomyocyte autophagy impairment and oxidative stress [Fabry_Disease] Autophagic Block and Proteostasis Failure [GNE_Myopathy] Intracellular Procollagen Retention and ER Stress [Kniest_Dysplasia] Impaired 26S Proteasome Assembly [OTUD6B-Related_Neurodevelopmental_Disorder] Escape from Antizyme-Mediated Proteasomal Degradation [Bachmann-Bupp_Syndrome] MT-ATP6 complex V respiratory defect [Myopathy_Lactic_Acidosis_and_Sideroblastic_Anemia] Left-right organizer ciliary dysfunction [Visceral_Heterotaxy] Mitochondrial Translation and OXPHOS Deficiency [Kearns-Sayre_Syndrome] Impaired Mechanotransduction and Nuclear Mechanical Fragility [Emery_Dreifuss_Muscular_Dystrophy] Inner Hair Cell Ribbon Synapse Exocytosis Defect [MYO6_Hearing_Loss] Collagen Retention, ATF6-UPR, and FGFR3 Overactivation [Atelosteogenesis_Type_II] Mitochondrial Respiratory Chain Subunit Defect [Histiocytoid_Cardiomyopathy] Aberrant Endolysosome Accumulation [Hereditary_Spastic_Paraplegia_48] Desmosomal Disruption [PKP2_Cardiomyopathy] Impaired Endosome-Lysosome Tethering and Fusion [Mucopolysaccharidosis-Plus_Syndrome] Disrupted ER Protein-Interaction Network [CPT1C-Related_Hereditary_Spastic_Paraplegia] Cutaneous and hair-follicle desmosome failure [Naxos_disease] Ciliary Dysfunction [Polycystic_Kidney_Disease] Neural stem-cell ER stress and unfolded-protein response [UGP2-Related_Developmental_and_Epileptic_Encephalopathy_83] Macrophage Autophagy Dysfunction [Crohn_Disease] Oxidative Stress [Vitiligo] Oxidative and Mitochondrial Stress [Succinic_Semialdehyde_Dehydrogenase_Deficiency] Centrosome, Cilium and Mitotic Spindle Perturbation in Apical Radial Glia [EML1_Ribbon_Heterotopia] BSCL2 seipin lipid-droplet dysregulation [Berardinelli_Seip_Congenital_Lipodystrophy] Mitochondrial redox imbalance from copper accumulation [Menkes_Disease] Mitochondrial bioenergetic failure and lipid peroxidation [Lipoyl_Transferase_1_Deficiency] Biallelic DSP Deficiency — Desmosome-IF Uncoupling [Carvajal_Syndrome] Mitochondrial Dysfunction and Oxidative Stress [Lathyrism] Substrate Limitation of ATP Synthase and Impaired Oxidative Phosphorylation [Cardiomyopathy-Hypotonia-Lactic_Acidosis_Syndrome] Abnormal mitochondrial energy metabolism [Fontaine_Progeroid_Syndrome] Oxidative Stress-Linked Autophagy [Smith-Lemli-Opitz_syndrome] Centrosome, Spindle, and Kinetochore Dysfunction [Autosomal_Recessive_Primary_Microcephaly] Impaired Autophagosome-Lysosome Fusion [Vici_Syndrome] ER-Associated Neutral Lipid Dyshomeostasis [Autosomal_Recessive_Spinocerebellar_Ataxia_20] Intraflagellar Transport and Ciliogenesis Defects [Short-Rib_Polydactyly_Syndrome] COXFA4/NDUFA4 Subunit Loss and Failed Complex IV Assembly [COXFA4-Related_COX_Deficiency] Impaired Mitochondrial Fission and Mitophagic Completion [AR_Cerebellar_Ataxia-Saccadic_Intrusion_Syndrome] Cardiac oxidative stress via circulating propionate [Propionic_Acidemia] PRKCSH and SEC63 ER protein biogenesis defects [Autosomal_Dominant_Polycystic_Liver_Disease] COX20 Loss and Defective COX2 Maturation [COX20-Related_COX_Deficiency] Dysregulated Autophagy and Endolysosomal Trafficking [Autosomal_Recessive_Spinocerebellar_Ataxia_15] morphogenesis, migration and positioning Impaired Dendritic and Synaptic Morphogenesis [TRIO-Related_Neurodevelopmental_Disorder] Impaired Neurogenic Division and Migration [TUBB_TUBB5-related_Microcephaly] Ciliary membrane protein trafficking defect [Bardet-Biedl_Syndrome] Impaired Mitochondrial Axonal Transport [Charcot-Marie-Tooth_Disease_Type_2] Impaired intraciliary transport [Joubert_syndrome] Impaired lysosome transport and autophagy [BLOC1S1-related_Complex_Neurodevelopmental_Disorder_with_Leukodystrophy] Membrane Contact Site Dysfunction with Impaired Lipid Transport [Chorea-acanthocytosis] Impaired CNS Synaptic Development and Network Maturation [UNC13A_Congenital_NDD_with_Epilepsy] Impaired Axon Guidance and Neurite Outgrowth [L1_Syndrome] Neuroplasticity Deficits [Major_Depressive_Disorder] Dendritic spine abnormalities [ZTTK_syndrome] Actin-Dependent Apical Progenitor Cleavage-Plane Defect [Baraitser-Winter_Cerebrofrontofacial_Syndrome] Defective Cytokinetic Abscission [VPS4A-Related_Neurodevelopmental_Syndrome] Impaired Neuronal Development and Function [PUS7-Related_Neurodevelopmental_Disorder] Cortical Midline Guidepost-Cell Mispatterning [Acrocallosal_Syndrome] Impaired hippocampal synaptic plasticity [Bosch-Boonstra-Schaaf_Optic_Atrophy_Syndrome] Impaired neurogenesis and neuronal migration [Schinzel-Giedion_Syndrome] Disrupted Neuronal Maturation and Dendritic Arborization [PPM-X_Syndrome] protein trafficking and localization -- the protein is made and folded but does not reach where it works. 69 nodes; distinct from ACTIVITY (it would work if it got there) and from SUBSTANCE (nothing is misfolded or depleted). Impaired Outer Segment Protein Trafficking and Opsin Mislocalization [Leber_Congenital_Amaurosis_10] Ciliary membrane protein trafficking defect [Bardet-Biedl_Syndrome] IFT-A Retrograde Intraflagellar Transport Failure [IFT140-related_Recessive_Ciliopathy] Impaired COPI Retrograde Golgi-to-ER Trafficking [CALFAN_Syndrome] AMPA Receptor Trafficking Disruption [Epilepsy] Impaired Receptor Trafficking and Postsynaptic Clustering [GABRB3-Related_Developmental_and_Epileptic_Encephalopathy] Mutant DNMT1 Mislocalization and Aggresome Formation [ADCA-DN] Lysosomal Mislocalization of Mutant Pol III Subunits [POLR-Related_Leukodystrophy] Procollagen Processing and Intracellular Trafficking Defect [Osteogenesis_Imperfecta_Type_IV] Impaired cytosolic deglycosylation of ERAD substrates [NGLY1-congenital_disorder_of_deglycosylation] Increased CTLA4 lysosomal turnover [LRBA_Deficiency] Cochlear glia-like supporting cell vesicle trafficking dysfunction [DOORS_Syndrome] TBC1D32/BROMI Ciliary Trafficking and IFT Turnaround Defect [Alsahan-Harris_Syndrome] Failure of KCNQ2 and KCNQ3 Potassium Channel Clustering [SPTBN4-Related_Neurodevelopmental_Disorder] Impaired Connexin 30 Trafficking [Clouston_Syndrome] ADAMTS17 Secretion Loss and Microfibril Dysregulation [Weill-Marchesani_Syndrome] Abnormal Cholesterol and Lipid Trafficking [Pelizaeus_Merzbacher_Disease] B0AT1 endoplasmic-reticulum retention [Hartnup_Disease] Impaired Rubicon Endolysosomal Localization [Autosomal_Recessive_Spinocerebellar_Ataxia_15] Collagen Retention in Endoplasmic Reticulum [Diastrophic_Dysplasia] Reduced TIM22-mediated import of inner-membrane carrier proteins [Sengers_syndrome] Impaired Procollagen Quality Control and Defective Secretion [Osteogenesis_Imperfecta_Type_X] Partial Peroxisomal Matrix Protein Import Failure [Peroxisome_Biogenesis_Disorder_1B] RAB5C GTPase regulatory defect [RAB5C-Related_Neurodevelopmental_Disorder_with_Macrocephaly] TISSUE / ORGAN EFFECT inflammation Early and Sustained Pilosebaceous Inflammation [Acne_Vulgaris] CNS-Directed Autoimmune Inflammation [Acute_Disseminated_Encephalomyelitis] Microglial Activation and Neuroinflammation [Early-Onset_Autosomal_Dominant_Alzheimer_Disease] Vascular Inflammation [Kawasaki_Disease] Leukocytoclastic Vasculitis in Skin and Systemic Organs [IgA_Vasculitis] Systemic Autoinflammation (sJIA) [Juvenile_Idiopathic_Arthritis] Reactive astrogliosis and neuroinflammation [Lafora_Disease] Chronic Biliary Inflammation [Gallbladder_Cancer] Granulocyte-Rich Neuroinflammation [Neuromyelitis_Optica_Spectrum_Disorder_with_Anti-AQP4_Antibodies] Cognate T-Cell Mediated Inflammation [MOGAD] Spinal Cord Inflammation [Transverse_Myelitis] Complement-dependent capillaritis [Anti-GBM_Disease] Inflammatory demyelinating optic neuropathy [Optic_Neuritis] Ocular Inflammation [Blau_Syndrome] Immune-mediated neuroinflammation [Carbon_Monoxide_Poisoning] Urogenital inflammation and scarring [Schistosomiasis] Alveolar Pneumonia and Respiratory Compromise [Pneumocystis_Pneumonia] Microglial Dysfunction and Neuroinflammation [Peroxisome_Biogenesis_Disorder] Cutaneous small-vessel inflammation [Wissler_syndrome] Nervous System Granulomatous Inflammation [Neurosarcoidosis] Inflammatory Mediator Release at the Wound [Acute_Post-Surgical_Pain] fibrosis / remodelling Fibroproliferative Remodeling and Fibrosis [Acute_Respiratory_Distress_Syndrome] Lesional Fibrosis and Myofibroblast Transdifferentiation [Adenomyosis] Cutaneous Fibrosis and Multiorgan Involvement [H_Syndrome] Hepatic Ductal Plate Malformation and Progressive Fibrosis [MPI-Congenital_Disorder_of_Glycosylation] Renal Tubular Cystic and Fibrotic Disease [IFT140-related_Recessive_Ciliopathy] Labyrinthine fibrosis [Labyrinthitis] Cardiomyocyte Hypertrophy and Concentric Left Ventricular Remodelling [KLHL24-Related_Hypertrophic_Cardiomyopathy] Structural Cardiac Remodeling [ANK2_Ankyrin_B_Syndrome] Subchondral Bone Remodeling [Osteoarthritis] Immune Activation and ECM Remodeling [CADASIL_Type_1] Excessive ECM Deposition [Volumetric_Muscle_Loss] Disordered Bone Remodeling [Psoriatic_Arthritis] Fibrofatty myocardial replacement [Arrhythmogenic_Right_Ventricular_Cardiomyopathy] Cardiomyocyte Hypertrophy [Hypertrophic_Cardiomyopathy_25] Deficient Chondroitin Sulfate Proteoglycan Matrix [Schneckenbecken_Dysplasia] Proteoglycan depletion and cartilage matrix disorganization [Spondylodysplastic_Ehlers-Danlos_Syndrome] Deficient Uterine Spiral Artery Remodeling [Fetal_Growth_Restriction] Vascular Remodeling [Pulmonary_hypertension] Tubulointerstitial Fibrosis [Chronic_Kidney_Disease] Excessive Hepatic Extracellular Matrix Deposition [Alcoholic_Liver_Disease] Fibroblast Activation and Fibrosis [Systemic_Sclerosis] Chorioretinal Scarring and Bruch Membrane Disruption [Choroiditis] Impaired fibroblast elastogenesis [Costello_Syndrome] pathological structure formed Platelet-rich intraluminal thrombus [Abdominal_Aortic_Aneurysm] Amyloid Plaque Formation [Alzheimer_Disease] Fibrillar Amyloid-beta Plaque Formation and Deposition [Early-Onset_Autosomal_Dominant_Alzheimer_Disease] Advanced Atheroma with Necrotic Core and Fibrous Cap [Peripheral_Artery_Disease] Renal Cyst Formation [Nephronophthisis] Follicular Cyst Formation [Bachmann-Bupp_Syndrome] Non-caseating granulomatous inflammation with epithelioid histiocytes [Melkersson_Rosenthal_syndrome] VEGF-Driven Retinal Neovascularization [Diabetic_Retinopathy] Angiogenic Switch and VEGF-Driven Neovascularization [Gastric_Adenocarcinoma] Ectopic arterial and periarticular calcification [Hereditary_Arterial_and_Articular_Multiple_Calcification_Syndrome] Ectopic Intracranial and Soft Tissue Calcification [Raine_Syndrome] Vitelliform Material Accumulation [BEST1-Related_Dominant_Retinopathy] Hamartoma Formation [Cowden_Syndrome] Periosteal New Bone Formation [Primary_Hypertrophic_Osteoarthropathy] Hepatic cyst formation [Cystic_Echinococcosis] VEGF-Driven Angiogenesis [Clear_Cell_Renal_Cell_Carcinoma] Severe infantile pan-enteric polyposis and enteropathy [Juvenile_Polyposis_Syndrome] Adenoma Formation [Familial_Adenomatous_Polyposis] Angiogenesis and VEGF Signaling [Hepatocellular_Carcinoma] Angiogenesis [Non-Small_Cell_Lung_Cancer] Cortical Glioneuronal Tumor Formation [Dysembryoplastic_Neuroepithelial_Tumor] Atrial Thrombus Formation [Atrial_Fibrillation] Differentiated Vulvar Intraepithelial Neoplasia (dVIN) [Vulvar_Carcinoma] Granuloma formation and containment [Coccidioidomycosis] Atherosclerotic carotid plaque formation [Carotid_Artery_Occlusion] Opticin Loss and Pathologic Retinal Neovascularization [CAPN5-Related_Vitreoretinopathy] Hypothalamic Hamartoma Formation [Hypothalamic_Hamartoma_with_Gelastic_Seizures] Pulmonary cavitary disease [Coccidioidomycosis] degeneration / atrophy Cerebellar Degeneration [ADCA-DN] Medial smooth muscle cell depletion and wall thinning [Abdominal_Aortic_Aneurysm] Progressive rod-first photoreceptor degeneration [BBSome-Related_Retinitis_Pigmentosa] Motor neuron degeneration [Kennedy_Disease] Posterior Column Sensory Neuron Degeneration [FLVCR1-Related_Retinopathy] Leigh-like basal ganglia neurodegeneration [ECHS1_Deficiency] Progressive Neurodegeneration [GM1_Gangliosidosis_Type_1] Spiral ganglion neuron degeneration [Labyrinthitis] Distal axonal degeneration [Organophosphate_Poisoning] Progressive Cerebral Hemiatrophy [Hemiconvulsion-Hemiplegia-Epilepsy_Syndrome] Demyelination and Connexin Dysfunction [Multiple_System_Atrophy] Retinal Ganglion Cell and CNS Neuron Degeneration [Wolfram_Syndrome] Neurodegeneration [Multiple_Mitochondrial_Dysfunctions_Syndrome_9B] Enteric nervous system denervation [Chagas_Disease] Neostriatal neuronal loss [X-linked_Dystonia-Parkinsonism] Osteolytic Bone Disease [Multiple_Myeloma] Motor Speech Network Degeneration [Primary_Progressive_Apraxia_of_Speech] Vascular smooth muscle cell depletion [Thoracic_Aortic_Aneurysm] Bulbar Lower Motor Neuron Degeneration [Progressive_Bulbar_Palsy] Skeletal Muscle Denervation and Atrophy [Progressive_Muscular_Atrophy] Vestibular Ganglion Sensory Neuron Degeneration [Autosomal_Dominant_Sensory_Ataxia_1] Skeletal and Bulbar Mitochondrial Myopathy [Autosomal_Dominant_Progressive_External_Ophthalmoplegia] Auditory pathway degeneration [PHARC_syndrome] Extracerebellar Neurodegeneration [Autosomal_Dominant_Cerebellar_Ataxia_Type_I] Progressive White Matter Rarefaction and Cavitation [Leukoencephalopathy_With_Vanishing_White_Matter] Regional Neuronal Loss and Clinical Syndrome [Gerstmann-Straussler-Scheinker_Syndrome] Exocrine Pancreatic Tissue Destruction [Cystic_Fibrosis] Length-Dependent Distal Motor Axonopathy [Distal_Hereditary_Motor_Neuronopathy_Autosomal_Dominant] Posterior Column Degeneration [Autosomal_Dominant_Sensory_Ataxia_1] Lower Motor Neuron and Motor Axon Degeneration [Scapuloperoneal_Spinal_Muscular_Atrophy] Retinal Ganglion Cell Loss and Optic Nerve Involvement [ALG3-Congenital_Disorder_of_Glycosylation] Accelerated Ovarian Germ Cell Attrition and Follicular Atresia [Turner_Syndrome] Progressive Skeletal Muscle Fiber Degeneration [Myofibrillar_Myopathy] Length-Dependent Corticospinal-Tract Axonal Degeneration [Hereditary_Spastic_Paraplegia] Secondary Demyelination [Neuromyelitis_Optica_Spectrum_Disorder] Hippocampal Subfield Abnormality in Dissociative Amnesia [Dissociative_Identity_Disorder] Neuronal Dysfunction and Neurodegeneration [Salla_Disease] Retinal and Auditory Degeneration [Multiple_Sulfatase_Deficiency] Neurodegeneration and neuronal cell death [Fragile_X-Associated_Tremor_Ataxia_Syndrome] developmental malformation Impaired Forebrain Midline Separation [SHH_Holoprosencephaly_Spectrum] Craniofacial Midline Deficiency [SHH_Holoprosencephaly_Spectrum] Impaired endochondral ossification and chondrodysplasia [Achondroplasia] Cobblestone Cortical Malformation [LAMB1-Related_Cobblestone_Lissencephaly] Reduced Cortical Output and Microlissencephaly [KATNB1-related_Cortical_Malformation] Dysmorphic Neurons and Focal Cortical Dysplasia [DEPDC5-Related_Epilepsy] Structural Midline Brain Malformation and Neurodevelopmental Impairment [CDH2-Related_ACOG_Syndrome] Anorectal Malformation [FG_Syndrome_1] Sweat Gland Aplasia/Hypoplasia [EDAR_Hypohidrotic_Ectodermal_Dysplasia] Skeletal Dysplasia with Thoracic Constriction [IFT140-related_Recessive_Ciliopathy] Cervical Vertebral Fusion [Klippel-Feil_Syndrome] Biliary ductal plate malformation via ciliary tight junction defect [Joubert_syndrome] Disrupted optic-cup and globe morphogenesis [Microphthalmia_with_Coloboma] Cardiac Developmental Defects [Mediator_Complex_Neurodevelopmental_Disorder] Skeletal Development Disruption [Loeys-Dietz_Syndrome] Skeletal and dentoalveolar mineralization failure [Hypophosphatasia] Disrupted Somite Formation [Spondylocostal_Dysostosis] Impaired lymphatic valve development [Deafness-Lymphedema-Leukemia_Syndrome] Corpus Callosum Developmental Agenesis [Aicardi_Syndrome] Abnormal enteric nervous system development [Mowat-Wilson_syndrome] Prenatal skeletal and hydrops involvement [ALG9-congenital_disorder_of_glycosylation] Pigmentary developmental abnormality [PCWH_syndrome] Cochlear Melanocyte Absence [MITF_Waardenburg_Tietz_Spectrum] Impaired Ocular Development [Temtamy_Syndrome] Altered Sonic hedgehog-dependent limb patterning [McKusick-Kaufman_Syndrome] Ectodermal and Visceral Mosaic Anomalies [CLOVES_Syndrome] Thyroid Gland Dysgenesis [Congenital_Hypothyroidism] Abnormal eye development [STRA6-related_syndromic_microphthalmia] Impaired Craniofacial and Digital Morphogenesis [Filippi_Syndrome] Anterior Segment Dysgenesis [Peters_Plus_Syndrome] Disrupted Neural Development [PRR12-Related_Neuroocular_Syndrome] Corticospinal Tract and Commissural Defects [L1_Syndrome] Hypomyelination [Fucosidosis] Generalized Skeletal Dysplasia [Fountain_Syndrome] Tooth Developmental Defects [X-linked_Hypohidrotic_Ectodermal_Dysplasia] Impaired Limb Bud Patterning [Hartsfield_Syndrome] Cochlear Melanocyte Deficiency [Craniofacial-Deafness-Hand_Syndrome] Reduced Cortical Neuron Output and Postnatal Microcephaly [Filippi_Syndrome] Defective Joint Interzone Specification [Humeroradial_Synostosis] Hindbrain Hypoplasia [Cri-du-Chat_Syndrome] Cranial Motor Nerve Maldevelopment and Ocular Dysmotility [TUBB3-related_Tubulinopathy] Craniofacial, ocular, and sensory developmental dysregulation [MED13_Syndrome] Perisylvian Cortical Organization Failure [SRPX2-related_Speech_Epilepsy_Polymicrogyria] Failure of Optic Fissure Closure [Uveal_Coloboma-Cleft_Lip_and_Palate-Intellectual_Disability_Syndrome] Structural brain injury and cortical malformation [NELABA] Deficient Neural-Crest-Derived Skeletogenic Mesenchyme in the First and Second Arches [Craniofacial_Microsomia] Primary mesodermal developmental arrest [Prune_Belly_Syndrome] Spondyloepimetaphyseal Skeletal Dysplasia [Spondyloepimetaphyseal_Dysplasia_Bieganski_Type] Randomized Organ Laterality [Primary_Ciliary_Dyskinesia] Impaired lymphatic valve morphogenesis [Hennekam_Lymphangiectasia-Lymphedema_Syndrome_2] Disrupted Enteric Nervous System Development [Hirschsprung_Disease] Hemivertebrae and Congenital Scoliosis [TBX6-Associated_Congenital_Scoliosis] Gonadal Dysgenesis with Hypergonadotropic Hypogonadism [PPP2R3C-Related_Gonadal_Dysgenesis_Syndrome] Ectopia Lentis [Weill-Marchesani_Syndrome] Reduced Fetal Lung Development [Achondrogenesis_Type_II] Growth-Plate Architectural Disorganization [Achondrogenesis_Type_II] Impaired Cortical Sculpting with Megalencephaly and Thin Lissencephaly [CRADD-Related_Thin_Lissencephaly] CHN1 Hyperactivation and MAFB Loss Disrupt Abducens Motor Neuron Development [Duane_Retraction_Syndrome] Failure of Diaphragm Closure and Visceral Herniation [Congenital_Diaphragmatic_Hernia] Impaired Cerebellar Development and Progressive Degeneration [Pontocerebellar_Hypoplasia] SMN-Dependent Neurodevelopmental Disruption [Spinal_Muscular_Atrophy] Serial Craniofacial Arch-Derivative Maldevelopment [Treacher_Collins_Syndrome] Callosal commissural development failure [Familial_Congenital_Mirror_Movements] RASopathy Developmental Program [Neurofibromatosis-Noonan_Syndrome] Palatal morphogenesis disruption [Apert_Syndrome] Abnormal neurodevelopment [Oculogastrointestinal-Neurodevelopmental_Syndrome] Defective Bone Matrix, Reduced Mineralization, and Skeletal Fragility [Osteogenesis_Imperfecta_Type_XXII] Skeletal Overgrowth [Kosaki_Overgrowth_Syndrome] Congenital Macular Developmental Disruption [North_Carolina_Macular_Dystrophy] Ureterovesical Junction Incompetence [Familial_Vesicoureteral_Reflux] Failed Endochondral Ossification [Hypochondrogenesis] Gain-of-Function Cortical Maldevelopment [GRIN1-Related_Neurodevelopmental_Disorder] barrier failure Blood-Brain Barrier Disruption [Bacterial_meningitis] Glomerular Filtration Barrier Disruption [AA_Amyloidosis] Podocyte damage and filtration barrier failure [IgA_Nephropathy] Epidermal barrier breakdown and increased transepidermal water loss [Netherton_Syndrome] Inner Blood-Retinal Barrier Dysfunction [Familial_Exudative_Vitreoretinopathy] Endothelial Dysfunction and Vascular Leak [Ebola_Virus_Disease_EVD] Blood-brain barrier dysfunction in cerebral malaria [Malaria] Blood-labyrinth barrier disruption [Labyrinthitis] Epidermal Lipid-Barrier Defect [Triglyceride_Storage_Disease_Type_1] GBM Structural Deterioration [Alport_Syndrome] Epidermal Barrier Failure and Systemic Complications [Staphylococcal_Scalded_Skin_Syndrome] Plasma leakage leading to shock in severe dengue [Dengue] Epidermal Lipid Processing and Transport Defect [Autosomal_Recessive_Congenital_Ichthyosis] Abnormal Stratum Corneum and Barrier Phenotype [Autosomal_Recessive_Congenital_Ichthyosis] Blood-Labyrinth Barrier Dysfunction and Oxidative Stress [Menieres_Disease] injury -- generic tissue damage where the entry names no more specific process; "injury" is the 8th commonest head noun in the KB Cerebral White Matter Injury [ABCC9-Related_Intellectual_Disability_and_Myopathy_Syndrome] Renal tubulointerstitial injury [Bardet-Biedl_Syndrome] ER Stress and Complement-Mediated Vessel Wall Injury [CADASIL_Type_1] Renal glycosphingolipid storage and podocyte injury [Fabry_Disease] H. pylori and NSAID-associated mucosal injury [Gastric_Ulcer] Cochlear hair cell injury [Labyrinthitis] Upper Motor Neuron and Corticospinal Tract Injury [Konzo] Early Thalamic Injury [DEE_with_Spike-Wave_Activation_in_Sleep] Cerebral and cerebellar developmental injury [Huppke-Brendel_syndrome] Progressive airway injury [Activated_PI3K-delta_Syndrome] Retinal and optic nerve toxicity [Methanol_Poisoning] Endothelial Damage and Vasculopathy [Deficiency_of_Adenosine_Deaminase_2] Basal Ganglia and Thalamic Injury [Cerebral_Palsy] Structural V5/MT Network Injury [Akinetopsia] Subretinal/Intraretinal Exudative Injury [Age_Related_Macular_Degeneration] Endothelial Cell Injury in Lucio Phenomenon [Leprosy] Oxidative stress and neuronal injury [Neurodegeneration_With_Brain_Iron_Accumulation] Podocyte Injury and Loss [Focal_Segmental_Glomerulosclerosis] Skeletal and respiratory myofiber injury [Pompe_Disease] Putative Immune Boundary Injury [Acute_Annular_Outer_Retinopathy] Carcinogen-Induced Sinonasal Epithelial Injury [Paranasal_Sinus_Squamous_Cell_Carcinoma] Methylmercury CNS Accumulation and Neuronal Injury [Mercury_Poisoning] circulatory disturbance -- haemorrhage, fluid shift and vessel/chamber dilatation. Added because MPATH gives circulatory disorder TOP-LEVEL billing (MPATH:105) while we had scattered it: thrombus under structure-formed, ischemia in its own leaf, and ~70 haemorrhage/oedema/dilatation nodes nowhere at all. Cutaneous livedo [Sneddon_syndrome] Choroidal Engorgement and Vascular Congestion [Spaceflight_Associated_Neuro-Ocular_Syndrome] Cerebrovascular Autoregulation Failure and Eclampsia [Preeclampsia] Neurovascular vasodilation [Rosacea] Trigger-dependent thromboinflammatory amplification [Antiphospholipid_Syndrome] OCCC-Associated Hypercoagulability [Clear_Cell_Ovarian_Carcinoma] Progressive Arterial Aneurysm and Tortuosity [Aneurysm-Osteoarthritis_Syndrome] ALCAPA coronary steal and low-pressure perfusion [Coronary_Artery_Congenital_Malformation] Retinal hemorrhage episodes [Retinal_Arterial_Tortuosity] Endolymphatic Hydrops [Menieres_Disease] Ductal-Dependent Systemic Perfusion in Critical Coarctation [Coarctation_of_the_Aorta] Circulatory collapse on ductal closure [Hypoplastic_Left_Heart_Syndrome] mechanical obstruction and stenosis -- from SNOMED Mechanical abnormality (107658001). 75 nodes; the single largest gap any external source found. Bladder Outlet Obstruction [Benign_Prostatic_Hyperplasia] Left Ventricular Outflow Tract Obstruction [Hypertrophic_Cardiomyopathy] Intracranial Tumor Mass Effect and Cerebrospinal Fluid Obstruction [Central_Nervous_System_Germ_Cell_Tumor] Trabecular Meshwork Immaturity and Outflow Obstruction [Juvenile_Open_Angle_Glaucoma] Bile Duct Fibrostenosis [IgG4-Related_Sclerosing_Cholangitis] Flow-limiting carotid lumen narrowing [Carotid_Stenosis] Vascular Smooth Muscle Cell Dysfunction and Arterial Stenosis [Grange_syndrome] Lacrimal Canal Stenosis [Dacryocystitis-Osteopoikilosis_Syndrome] Intracanalicular compression and conduction block of cranial nerve VII [Bells_Palsy] Obliterative Endarteritis [Syphilis] Cortical Irritation and Mass Effect [oligoastrocytoma] Proximal Duodenal Obstruction and Gastroduodenal Stasis [Superior_Mesenteric_Artery_Syndrome] Mass effect and local invasion [Polycystic_Echinococcosis] Cauda equina nerve root compression [Cauda_Equina_Syndrome] Neurological compression from calvarial thickening [Morgagni-Stewart-Morel_Syndrome] Dynamic left ventricular outflow tract obstruction [Takotsubo_Cardiomyopathy] Pulmonary Venous Obstruction [Congenital_Total_Pulmonary_Venous_Return_Anomaly] Other rare stenotic and nonstenotic renal artery obstruction [Renal_Artery_Obstruction] abnormal communication -- fistula, septal defect, shunt. From SNOMED Abnormal communication (783804002). These are the cardiac-shunt nodes an earlier regex sweep mistook for metabolic flux blocks and discarded. Malalignment ventricular septal defect with overriding aorta [Tetralogy_of_Fallot] Left-to-Right Shunt and Pulmonary Overcirculation [Ventricular_Septal_Defect] Right-to-left shunting through an interatrial communication [Ebstein_Anomaly] Hemodynamically significant ductal shunting [Patent_Ductus_Arteriosus] Uncorrected non-restrictive systemic-to-pulmonary shunt [Eisenmenger_Syndrome] Abnormal coronary artery-to-chamber or vessel shunt [Coronary_Arterial_Fistulas] Single arterial trunk overriding a ventricular septal defect [Persistent_Truncus_Arteriosus] Associated atrial septal defect [Scimitar_Syndrome] Chronic Fistula Inflammation [Anal_Canal_Adenocarcinoma] Shunt Physiology and Hypoxemic Respiratory Failure [Acute_Respiratory_Distress_Syndrome] Cardiac Septation Defect [Ellis-van_Creveld_Syndrome] vascular malformation -- from SNOMED Vascular malformation (783806000); small but mechanistically distinct from developmental malformation generally RAS-MAPK/ERK-driven arteriovenous malformation formation [Capillary_Malformation-Arteriovenous_Malformation_Syndrome] VEGF-Triggered AVM Formation [Hereditary_Hemorrhagic_Telangiectasia] Diffuse proliferative cerebral arteriovenous malformation [Cerebral_Proliferative_Angiopathy] Vascular Shunting Through Visceral AVMs [Hereditary_Hemorrhagic_Telangiectasia] Retinal Vascular Dysgenesis and Neovascularization [Incontinentia_Pigmenti] material deposition -- material laid down IN tissue, as opposed to a discrete structure being built. SNOMED makes Deposition (46595003) a top-level morphologic category; we had split these between structure-formed and substance-accumulation. Microvascular Fragility and Iron Deposition [CADASIL_Type_1] Neurovascular calcium-phosphate deposition [Bilateral_Striopallidodentate_Calcinosis] Ocular glycosphingolipid deposition [Fabry_Disease] Excessive Collagen Deposition and Cord Formation [Dupuytrens_Contracture] Corneal cystine crystal deposition [Cystinosis] Crystal Deposition [Gout] Hyaline Material Deposition [Lipoid_Proteinosis] Vessel Wall Fragility and Intracerebral Haemorrhage [Early-Onset_Autosomal_Dominant_Alzheimer_Disease] Cerebral Small-Vessel Fragility and Hemorrhage [Brain_Small_Vessel_Disease_1_With_Or_Without_Ocular_Anomalies] Alveolar hemorrhage and hemosiderin accumulation [Lane_Hamilton_Syndrome] Massive Obstetric Haemorrhage [Placenta_Accreta_Spectrum] Haemorrhagic manifestations [Hantavirus_Hemorrhagic_Fever_with_Renal_Syndrome] Protein-Rich Alveolar Edema and Loss of Aerated Lung [Acute_Respiratory_Distress_Syndrome] Noncardiogenic pulmonary edema [Hantavirus_Pulmonary_Syndrome] Cytotoxic edema in callosal white matter [Marchiafava_Bignami_Disease] Stromal Imbibition and Acute Corneal Oedema [Keratoconus] Progressive aortic dilatation [Abdominal_Aortic_Aneurysm] Left Ventricular Dilation and Systolic Dysfunction [Dilated_Cardiomyopathy_1AA] Thoracic aortic dilatation and dissection [Familial_Thoracic_Aortic_Aneurysm_and_Aortic_Dissection] Intestinal lymphangiectasia [Hennekam_Lymphangiectasia-Lymphedema_Syndrome_1] Aneurysm rupture [Intracranial_Berry_Aneurysm] Secondary amyloidosis [CINCA_Syndrome] Glomerular Immune Complex Deposition [Lupus_Nephritis] 2,8-dihydroxyadenine crystalluria [Adenine_Phosphoribosyltransferase_Deficiency] Bronchial microfibril accumulation and epithelial dysplasia [Geleophysic_Dysplasia] Arterial Wall Calcification and Vasculopathy [Pseudoxanthoma_Elasticum] ischemia and infarction -- perfusion failure and its tissue consequence Thrombotic Occlusion and Ischemic Tissue Injury [Heparin-Induced_Thrombocytopenia] Microvascular Occlusion and Ischemic Organ Injury [Acquired_Thrombotic_Thrombocytopenic_Purpura] Small Vessel Arteriopathy and Hypoperfusion [CADASIL_Type_1] Ischemic osteocyte and marrow cell death [Osteonecrosis] Venous infarction and intracranial hypertension [Sagittal_Sinus_Thrombosis] Fetal Hypoxic-Ischemic Injury [Placental_Abruption] Atherosclerotic vertebral artery occlusion [Vertebral_Artery_Insufficiency] Oxidative Stress and Ischemia-Reperfusion Injury [Raynaud_Disease] Context-Dependent Organ Hypoperfusion [Acute_Hypotension] Ischemic and Focal Neurologic Injury [CNS_Vasculitis] Ischemia-Reperfusion Injury [Myocardial_Infarction] Nerve root ischemia and demyelination [Cauda_Equina_Syndrome] Ischemic penumbra and energy failure [Ischemic_Stroke] Triggering of Acute Myocardial Infarction [Influenza] Anterior Horn Motor Neuron Ischemic Injury [Monomelic_Amyotrophy] Myocardial Ischemia [Hypertensive_Heart_Disease] Thromboembolism and Cerebral Ischemia [Cervical_Artery_Dissection] Central Retinal Arterial Obstruction [Central_Retinal_Artery_Occlusion] Local Oxyhemoglobin Oxidation and Oxygen Deprivation [Acatalasia] inflammatory infiltration -- cells or material entering tissue; distinct from the inflammatory response itself IgG4-Positive Plasma Cell Infiltration [IgG4-Related_Disease] Synovial Leukocyte Infiltration [Juvenile_Idiopathic_Arthritis] Perivascular Inflammation and Immune Cell Infiltration [Dermatomyositis] Eosinophil tissue infiltration and degranulation [Eosinophilic_Granulomatosis_with_Polyangiitis] Lymphocytic Tissue Infiltration [CTLA4_Haploinsufficiency] Oxidized LDL Infiltration of Arterial Intima [Familial_Hypercholesterolemia] Histiocyte Activation and Tissue Infiltration [H_Syndrome] Microfilarial Skin and Ocular Infiltration [Onchocerciasis] Pulmonary Neutrophil Recruitment [Alpha_1_Antitrypsin_Deficiency] Macrophage Recruitment to Arterial Intima [Hyperlipidemia] Chemokine-Mediated Effector Recruitment [Alopecia_Areata] Visceral Reticuloendothelial Infiltration [Gaucher_Disease] functional disturbance -- an organ working wrongly without a structural lesion: excitability, conduction, contractility, motility Neuronal Hyperexcitability [Epilepsy] UBE3A-dependent neuronal hyperexcitability [15q11q13_Microduplication_Syndrome] Neuronal Hyperexcitability and Thalamocortical Hypersynchrony [GABRB3-Related_Developmental_and_Epileptic_Encephalopathy] Loss of Dendritic Excitability Constraint [HCN1-Related_Developmental_and_Epileptic_Encephalopathy] Cardiac repolarization disturbance [Arsenic_Poisoning] Enhanced Thalamic T-type Calcium Current [Childhood_Absence_Epilepsy] Gastrointestinal Dysmotility and Nutritional Impact [AL_Amyloidosis] Intestinal Pseudo-obstruction and Dysmotility [FLNA_Intestinal_Pseudoobstruction] Glycogen-Independent Early Electrophysiological Abnormality [PRKAG2_Cardiac_Syndrome] Autonomic Dysfunction [Aromatic_L_Amino_Acid_Decarboxylase_Deficiency] Gain-of-Function Neurotransmission [UNC13A_NDD_with_Seizures_and_Movement_Disorder] Atrial Electrical Remodeling [Atrial_Septal_Defect] Altered Neuronal Excitability and Neurotransmitter Release [CACNA1E-Related_Developmental_and_Epileptic_Encephalopathy] Progressive respiratory functional decline [Hypersensitivity_Pneumonitis] Neuronal Hyperexcitability and Seizure Substrate [Claes-Jensen_Type_X-Linked_Intellectual_Disability] Failure of Upper Esophageal Sphincter Relaxation [Retrograde_Cricopharyngeus_Dysfunction] Sleep-Activated Centrotemporal Epileptiform Discharges [Self-Limited_Epilepsy_with_Centrotemporal_Spikes] Glutamatergic Signaling Imbalance [Obsessive-Compulsive_Disorder] Disrupted Neurotransmission and Impaired Neurodevelopment [VAMP2-Related_Disorder] Cortical Excitation-Inhibition Imbalance [SYNGAP1-Related_Developmental_and_Epileptic_Encephalopathy] Central Sensitization [Migraine] Sinoatrial Node Dysfunction [RYR2_CPVT] Trigger-Dependent Breach of the Motor Network Attack Threshold [Paroxysmal_Dyskinesia] Impaired Myocardial Stress Adaptation [SNIP1-Related_Neurodevelopmental_Disorder] Poor urinary-tract contractility [Prune_Belly_Syndrome] Impaired Cardiomyocyte Contractile Performance [Dilated_Cardiomyopathy_1Z] Distributed Psychomotor Network Destabilization [Catatonia] Generalized Polyspike-Wave Discharges [Juvenile_Myoclonic_Epilepsy] Carbohydrate malabsorption and intestinal symptoms [Congenital_Sucrase-Isomaltase_Deficiency] Age-Dependent Hyperexcitability of the Occipital Cortex [Childhood_Occipital_Visual_Epilepsy] Cortical Excitation-Inhibition Imbalance and Seizures [SNAP25_Encephalopathy] Macrophage dysfunction and malabsorption [Whipple_Disease] Cortical network hyperexcitability with abnormal EEG background [Angelman_Syndrome] Thalamocortical Excitation-Inhibition Imbalance and Generalized Seizures [SLC6A1-Related_Disorder] Posterior electrocardiographic injury pattern [Posterior_Myocardial_Infarction] Intrinsic Factor Deficiency and B12 Malabsorption [Autoimmune_Gastritis] Peripheral Nociceptor Sensitization [Acute_Post-Surgical_Pain] Synaptic dysfunction in KANSL1-deficient neurons [Koolen_de_Vries_syndrome] PREPL-related neuromuscular transmission defect [Hypotonia-Cystinuria_Syndrome] Axial Muscle Imbalance [Spinal_Muscular_Atrophy] Chronic Motor Neuron and Terminal Axon Metabolic Overload [Postpoliomyelitis_Syndrome] Impaired nociceptor excitability [Congenital_Insensitivity_to_Pain] Fetal Akinesia [Camptodactyly] Atrial Triggered Activity [CASQ2_CPVT] Retrograde Urine Flow and Intrarenal Reflux [Familial_Vesicoureteral_Reflux] Heritable Sinoatrial Node Pacemaker Dysfunction [Familial_Sick_Sinus_Syndrome] Choroid plexus CSF hypersecretion [pseudotumor_cerebri] Bradycardia and Low Cardiac Output [Sinoatrial_Block] Testicular Microenvironment Dysfunction [Klinefelter_Syndrome] Palmoplantar Epidermal and Sweat Gland Dysfunction [Odonto-Onycho-Dermal_Dysplasia] neoplastic invasion and metastasis Invasion and Metastatic Dissemination [BRAF_V600E_Mutant_NSCLC] Neurotropic Perineural Invasion [Adenoid_Cystic_Carcinoma] Local Invasion and Nodal Spread [Laryngeal_Squamous_Cell_Carcinoma] Peritoneal, Nodal, and Distant Dissemination [Malignant_Germ_Cell_Tumor_of_Ovary] Haematogenous Dissemination Without Lymphatic Drainage [Ocular_Melanoma] Diffuse Infiltrative Growth and Linitis Plastica [Gastric_Adenocarcinoma] EMT-Linked Invasive Dissemination [Colon_Adenocarcinoma] Unrestrained Trophoblast Invasion of the Tubal Wall [Ectopic_Pregnancy] BAP1 Loss and Metastatic Progression [Uveal_Melanoma] Locoregional Peritoneal Tumor Expansion [Malignant_Peritoneal_Mesothelioma] MAPK-Driven Metastatic Fitness [Cutaneous_Melanoma] EMT-Driven Dissemination [Breast_Carcinoma] Diffusely Infiltrative Signet-Ring Cell Carcinoma [CDH1-Related_Hereditary_Diffuse_Gastric_Cancer] Invasive Squamous Cell Proliferation and Nodal Spread [Penile_Cancer] Early Dissemination and EMT [Pancreatic_Ductal_Adenocarcinoma] Diffuse Infiltrative Growth [Glioma] Distant Metastatic Dissemination [Ameloblastoma] Silva Pattern of Invasion [Cervical_Adenocarcinoma] Invasive Growth and Metastasis [Mixed_Germ_Cell_Tumor] Local Invasion and Metastatic Dissemination [Epithelioid_Sarcoma] Inguinofemoral Nodal Metastasis [Vulvar_Carcinoma] Fibroblast-Supported Tumor Invasion [Vulvar_Carcinoma] pathogen spread and tissue invasion -- the host-side counterpart of the ENVIRONMENTAL agent node Viremia and CNS Invasion [Paralytic_Poliomyelitis] Viremia and systemic dissemination [Hand_Foot_and_Mouth_Disease] Endothelial Cell Invasion and Intracytoplasmic Replication [Rocky_Mountain_Spotted_Fever] Dentin Invasion and Pulpal Inflammation [Dental_Caries] Cytotoxic T Cell Invasion of Non-Necrotic Myofibres [Inclusion_Body_Myositis] CadF/FlpA-mediated epithelial adhesion [Campylobacteriosis] Hematogenous endothelial infection [Murine_Typhus] Host Lipid Scavenging and Membrane Biogenesis [Lyme_Disease] Productive Life Cycle Coupled to Keratinocyte Differentiation [Human_Papillomavirus_Infection] Direct or contiguous vessel-wall infection [Postinfectious_Vasculitis] Larval infection of the nervous system (neurocysticercosis) [Taeniasis_Cysticercosis] Gonococcal Mucosal Attachment and Microcolony Formation [Gonorrhea] Excystation and invasion of small-intestinal enterocytes [Cyclosporiasis] Viral Neuroinvasion [Viral_Encephalitis] immune evasion and immunosuppressive microenvironment Immunosuppressive Microenvironment and Immune Evasion [Gallbladder_Cancer] PD-L1 Upregulation and Immune Evasion [MSI_High_Colorectal_Cancer] PD-L1/PD-1 Immune Evasion [BRAF_Mutant_Thyroid_Cancer] T cell exhaustion and immune checkpoint evasion [Langerhans_Cell_Histiocytosis] NS3/4A-mediated innate immune evasion [Acute_Hepatitis_C_Virus_Infection] Biofilm-associated immune evasion [Cat-Scratch_Disease] Immune Evasion and Viral Replication [Ebola_Virus_Disease_EVD] Tumor Immune Microenvironment Remodeling [Osteosarcoma] Adaptive Immune Resistance [Oral_Cavity_Squamous_Cell_Carcinoma] Immune-Suppressive Tumor Microenvironment [Prostate_Adenocarcinoma] PD-L1-Mediated Adaptive Immune Resistance [Choriocarcinoma] Immune Evasion [Nasopharyngeal_Carcinoma] Immune Tolerance and T-Cell Exhaustion [Chronic_Myelomonocytic_Leukemia] impaired repair Wound Healing Impairment and Chronic Wounds [Epidermolysis_Bullosa] Repetitive alveolar epithelial injury and aberrant repair [Idiopathic_Pulmonary_Fibrosis] Impaired Keratinocyte Migration and Wound Healing [Kindler_Epidermolysis_Bullosa] Fascial Microinjury and Aberrant Wound Healing [Dupuytrens_Contracture] Dermal collagen VI deficiency and abnormal wound healing [Bethlem_Myopathy] AT2 progenitor exhaustion and impaired alveolar regeneration [Idiopathic_Pulmonary_Fibrosis] Exuberant Granulation Tissue Formation [Junctional_Epidermolysis_Bullosa] Epidermal and Dermal Wound-Repair Response [Ainhum] neural circuit and network dysfunction -- a distributed multi-region circuit misbehaving as a circuit: hyperexcitability, hypersynchrony, dysconnectivity, oscillation. 137 nodes, the second-largest gap any method has found. Distinct from functional disturbance, which is one organ working wrongly; here the lesion IS the network property, and no single region is at fault. Hypersynchronous Three-Hertz Thalamocortical Spike-Wave Oscillation [Epilepsy_with_Myoclonic_Absences] Cortico-Striato-Thalamo-Cortical Circuit Dysfunction [Obsessive-Compulsive_Disorder] Aberrant Long-Range Functional Connectivity [CHD8-Related_Neurodevelopmental_Disorder_with_Overgrowth] Left Hemisphere Reading Network Dysfunction [Dyslexia] Collapse of Thalamocortical Sleep Oscillation [Fatal_Familial_Insomnia] Cerebello-thalamo-cortical oscillatory propagation [Essential_Tremor] Threat-Circuit and Fear-Extinction Dysregulation [Post-Traumatic_Stress_Disorder] Distributed Visual-Attentional-Salience Network Dysconnectivity [Visual_Snow_Syndrome] Basal Ganglia Circuit Dysfunction [Parkinsons_Disease] Brainstem Respiratory Circuit Dysregulation [Rett_Syndrome] Progressive Language Network Degeneration [Primary_Progressive_Aphasia] Large-Scale Network Reorganization [Mesial_Temporal_Lobe_Epilepsy_with_Hippocampal_Sclerosis] Suppression of Central Sexual Arousal and Reward Signaling [Post-SSRI_Sexual_Dysfunction] Generalized Epileptiform Discharge Time-Locked to the Jerk [Myoclonic_Epilepsy_in_Infancy] COQ8A-Related Hyperkinetic Motor Circuit Dysfunction [Autosomal_Recessive_Ataxia_Due_to_Ubiquinone_Deficiency] pathological angiogenesis -- the vessel-building program running where, when or as much as it should not, and occasionally failing where it should run. 36 nodes and the tree held none of them. Not vascular malformation (that is congenital architecture), not fibrosis/remodelling (that is matrix), and not structure formed: the vessels themselves are ordinary, the program driving them is not. VEGF-Driven Macular Neovascularization [Age_Related_Macular_Degeneration] Angiogenic Switch and VEGF-Driven Neovascularization [Gastric_Adenocarcinoma] Hypoxia-Driven Pathological Neovascularization [Retinopathy_of_Prematurity] Placental Anti-Angiogenic Factor Release [Preeclampsia] Failed Pulmonary Microvascular Angiogenesis [Alveolar_Capillary_Dysplasia_with_Misalignment_of_Pulmonary_Veins] Impaired angiogenesis-osteogenesis coupling [Osteonecrosis] AKT overactivation induces excessive vasculogenesis [Proteus_syndrome] vGPCR-Mediated Angiogenic Signaling [Kaposi_Sarcoma] compression and mass effect -- one structure pressing on its neighbour. Not obstruction (no lumen is narrowed) and not invasion (nothing crosses a boundary); the damage is transmitted force, so the lesion and the injured tissue are different tissues. Cerebellopontine-Angle Expansion and Advanced Mass Effect [Acoustic_Neuroma] Cranial Nerve Compression from Skull Thickening [Autosomal_Recessive_Osteopetrosis] Cauda equina nerve root compression [Cauda_Equina_Syndrome] Optic-Hypothalamic-Pituitary Mass Effect [Craniopharyngioma] Extrinsic Compression of the Third Part of the Duodenum [Superior_Mesenteric_Artery_Syndrome] Cardiac tamponade [Pericarditis] Circumferential Tissue Compression [Amniotic_Band_Syndrome] Extrinsic bony compression of the vertebral artery [Vertebral_Artery_Insufficiency] Fetal Hydrops from Cardiac Compression [Congenital_Pulmonary_Airway_Malformation] Flexion-Induced Cervical Cord Compression [Monomelic_Amyotrophy] Compression-Sensitive Conduction Failure [Hereditary_Neuropathy_with_Liability_to_Pressure_Palsies] SYSTEMIC EFFECT metabolic crisis Acute hypoketotic metabolic decompensation [3-Hydroxy-3-Methylglutaric_Aciduria] Illness-associated acute neurometabolic decompensation [3-Hydroxyisobutyryl-CoA_Hydrolase_Deficiency] Episodic metabolic decompensation [Beta-Ketothiolase_Deficiency] Lactic Acidosis and Metabolic Decompensation [PET100-Related_COX_Deficiency] Lactic acidosis [Leigh_Syndrome] Systemic hyperammonemia and glutamine diversion [N-Acetylglutamate_Synthase_Deficiency] Hypoketotic hypoglycemia mechanism [MCAD_Deficiency] Impaired glucose-6-phosphate hydrolysis and fasting hypoglycemia [Glycogen_Storage_Disease_Type_I] Acute Febrile Encephalopathy and Cerebellar Decompensation [CAPOS_Syndrome] Cellular Energy Deficit and Lactate Overproduction [MTO1_Deficiency] Metabolic alkalosis [Liddle_Syndrome] Hyperinsulinemic Hypoglycemia and Neuroglycopenia [Congenital_Isolated_Hyperinsulinism] Secondary urea cycle impairment and hyperammonemia [Isovaleric_Acidemia] Hyperammonemic Encephalopathy [Hyperornithinemia_Hyperammonemia_Homocitrullinuria_Syndrome] Exertional Muscle Energy Failure [Glycogen_Storage_Disease_Type_V] Hypoketotic hypoglycemia [Carnitine_Palmitoyltransferase_1A_Deficiency] Systemic metabolic decompensation [Multiple_Acyl-CoA_Dehydrogenase_Deficiency] organ failure Shunt Physiology and Hypoxemic Respiratory Failure [Acute_Respiratory_Distress_Syndrome] Valproate-Precipitated Fulminant Hepatic Failure [Alpers-Huttenlocher_Syndrome] Progressive Kidney Failure [AA_Amyloidosis] Nephron Loss and Progressive Kidney Failure [Glomerulonephritis] Bone Marrow Failure [Fanconi_Anemia] Heart Failure and Sudden Cardiac Death [Dilated_Cardiomyopathy_1AA] Congestive heart failure [Endomyocardial_Fibrosis] Skeletal Muscle Respiratory Failure [MERRF_Syndrome] Rapidly Progressive Lactic Acidosis and Multiorgan Failure [COQ4-Related_Neonatal_Encephalomyopathy] Acute kidney injury with oliguric renal failure [Hantavirus_Hemorrhagic_Fever_with_Renal_Syndrome] Progressive Kidney Failure and Systemic Oxalosis [Primary_Hyperoxaluria_Type_1] Renal Impairment [Multiple_Myeloma] Pulmonary Vascular and Ventricular Complications [Atrial_Septal_Defect] Ventricular Dilation and End-Stage Heart Failure [Hypertrophic_Cardiomyopathy_21] Right Ventricular Pressure Overload and Failure [Congenital_Diaphragmatic_Hernia] Perinatal respiratory failure [Renal_Agenesis] Respiratory And Cardiovascular Decompensation [Myxedema] Bone marrow failure due to marrow space obliteration [Osteopetrosis] endocrine / homeostatic derangement Hypothalamic Autonomic and Homeostatic Dysfunction [SHH_Holoprosencephaly_Spectrum] Central Diabetes Insipidus [SHH_Holoprosencephaly_Spectrum] End-Organ Hormone Resistance [Acrodysostosis] Thyroid Hormone Deficiency [Hashimotos_Thyroiditis] Low-renin mineralocorticoid hypertension [Familial_Hyperaldosteronism_Type_I] Precapillary Pulmonary Arterial Hypertension with Right Ventricular Failure [Idiopathic_Pulmonary_Arterial_Hypertension] Cytotoxic cerebral edema and intracranial hypertension [N-Acetylglutamate_Synthase_Deficiency] Impaired Redox Homeostasis [Glucose-6-Phosphate_Dehydrogenase_G6PD_Deficiency] Hypovolaemic Shock [Ectopic_Pregnancy] Cardiopulmonary shock [Hantavirus_Pulmonary_Syndrome] Placental CRH Elevation [Postpartum_Depression] Cardiometabolic Dysfunction and Adipose Insulin Resistance [Metabolic_Dysfunction-Associated_Steatotic_Liver_Disease] HPA Axis Dysregulation [Generalized_Anxiety_Disorder] Severe Refractory Pulmonary Arterial Hypertension [Alveolar_Capillary_Dysplasia_with_Misalignment_of_Pulmonary_Veins] Hypothalamic hypogonadism and genital hypoplasia [Warburg_Micro_Syndrome] Disturbed serotonin homeostasis [Myoclonus_Dystonia_Syndrome] Gonadal dysfunction [adrenoleukodystrophy] Perinatal Stress Lowering of the Beta-Cell Glucose Threshold [Hyperinsulinemic_Hypoglycemia] Mild Autonomous Cortisol Secretion [Adrenal_Cortex_Adenoma] Excessive Sympathetic Activation [Postural_Orthostatic_Tachycardia_Syndrome] Reduced IGF-1 Production and Action [Growth_Hormone_Insensitivity_Syndrome] Impaired thyroid hormone metabolism [SECISBP2_Deficiency] Early HPG Axis Activation and Premature Gonadarche [Central_Precocious_Puberty] Estrogen-Driven Epiphyseal Maturation [Aromatase_Excess_Syndrome] Hypothalamic-pituitary-ovarian axis dysregulation in selected adenofibromas [Fallopian_Tube_Benign_Neoplasm] Reduced Cortisol Production [Addisons_Disease] Excess Bone-Derived FGF23 Signaling [X-Linked_Hypophosphatemia] systemic inflammatory state Systemic Autoinflammation [TNF_Receptor-Associated_Periodic_Syndrome] Uncontrolled T-cell and Macrophage Activation and Cytokine Storm [Hemophagocytic_Lymphohistiocytosis] Systemic Hyperinflammation and Multiorgan Involvement [Adult-Onset_Still_Disease] IL-1 Driven Autoinflammation [Schnitzler_Syndrome] Innate immune activation and sepsis [Melioidosis] Innate immune activation and systemic inflammatory response [Infective_Endocarditis] VEXAS-Type Somatic Myeloid Autoinflammation [Relapsing_Polychondritis] Systemic inflammation and cytopenias [Babesiosis] Cytokine Storm [Multisystem_Inflammatory_Syndrome_in_Children_MIS-C] Autoinflammatory recurrence loop [Pericarditis] Systemic inflammatory manifestations [Boutonneuse_Fever] haematological deficit -- circulating cell-count failure. From SNOMED Abnormal cellular component of blood (89615005). Peripheral neutropenia [Chemotherapy_Induced_Neutropenia] Cytopenia-Associated Complications [Acute_Myeloid_Leukemia_with_CEBPA_Somatic_Mutations] Persistence of autoreactive lymphocytes and autoimmune cytopenias [FAS-related_Autoimmune_Lymphoproliferative_Syndrome] Chronic hypoxaemia and secondary erythrocytosis [Eisenmenger_Syndrome] Platelet dysfunction [Viral_Hemorrhagic_Fever] Reduced oxygen transport and cyanosis [Hereditary_Methemoglobinemia] Macrothrombocytopenia [Sitosterolemia] Megaloblastic erythropoietic failure [Hereditary_Intrinsic_Factor_Deficiency] Cytopenias and Autoimmune Complications [Splenic_Marginal_Zone_Lymphoma] Release of Fewer, Abnormally Large Platelets [Bernard-Soulier_Syndrome] Ineffective Erythropoiesis [Alpha_Thalassemia] Microthrombocytopenia and platelet dysfunction [Wiskott_Aldrich_Syndrome] Platelet Dense-Granule Deficiency and Bleeding [Chediak-Higashi_Syndrome] autoimmune response -- loss of self-tolerance and the autoreactive response itself. 122 nodes, the largest gap found by any method so far. The tissue damage it causes still goes to TISSUE/inflammation or inflammatory infiltration; this leaf is the immune claim, not the lesion. Anti-Hemidesmosomal Autoantibody Formation [Bullous_Pemphigoid] Anti-C1-INH Autoantibody-Mediated Inactivation [Acquired_Angioedema] Myositis-Specific Autoantibodies [Dermatomyositis] Anti-myocardial autoantibody response [Endomyocardial_Fibrosis] ECM1-Directed Humoral Autoimmune Response [Genital_Lichen_Sclerosus] Cartilage-Directed Adaptive Autoimmunity [Relapsing_Polychondritis] Multi-Organ Autoimmune Attack [IPEX_Syndrome] Tolerance perturbation and autoimmunity [MHC_Class_II_Deficiency] Autoimmune Destruction [Narcolepsy] Pathogenic Autoantibody-Mediated Synaptic Dysfunction (Surface Antigen PNS) [Paraneoplastic_Neurological_Syndromes] Cross-Reactive Anti-Ganglioside IgG Response [Acute_Motor_and_Sensory_Axonal_Neuropathy] Germinal Center Autoantibody Production [Graves_Disease] Autoimmune-mediated inner ear damage [Labyrinthitis] AIRE Deficiency and Thymic Tolerance Failure [Autoimmune_Polyendocrine_Syndrome_Type_1] Low-Titer Insulin Receptor Agonism [Type_B_Insulin_Resistance_Syndrome] Immune Dysregulation and Autoimmunity [Common_Variable_Immunodeficiency] Chronic Chorioamnionitis and Maternal Anti-Fetal Rejection [Chorioamnionitis] Antigen-antibody immune-complex formation [Allergic_Cutaneous_Vasculitis] Autoimmune Neuroinflammation [Neuropsychiatric_SLE] High-Titer Insulin Receptor Antagonism [Type_B_Insulin_Resistance_Syndrome] Anti-Desmoglein Autoantibodies [Pemphigus_Vulgaris] Autoantibody Production and Immune Complex Formation [Lupus_Nephritis] Molecular mimicry and cross-reactive immune priming [Rheumatic_Heart_Disease] Anti-Nephrin Autoantibody-Associated Podocyte Injury [Minimal_Change_Disease] Intracellular-Antigen Cytotoxic T-Cell Injury [Autoimmune_Encephalitis] Immune-Mediated Orexin Neuron Injury [Narcolepsy-Cataplexy_Syndrome] Breakdown of regulatory T-cell-mediated hapten tolerance [Contact_Dermatitis] CD8+ T Cell-Mediated Cytotoxicity [Polymyositis] Neuronal Antigen Humoral Autoimmunity [Limbic_Encephalitis] Anti-Mitochondrial Antibody Response [Primary_Biliary_Cholangitis] Autoimmune Destruction of Beta Cells [Type_I_Diabetes] immune deficiency -- the defect in immune function itself, as opposed to the susceptibility it confers (DISPOSITION) or the infection that follows (ENVIRONMENTAL) Impaired T Cell Development and Function [Ectodermal_Dysplasia_and_Immunodeficiency_2] FOXP3-Associated Treg Deficiency [Autoimmune_Enteropathy] behavioural and cognitive mechanism -- a psychological process doing mechanistic work. Small but unmistakable, and the psychiatric corpus has nowhere else to go: this is not tissue function, not a network lesion, and not an outcome. Impaired Inhibitory Control [Binge_Eating_Disorder] Impaired Inhibitory Control and Habit Formation [Obsessive-Compulsive_Disorder] Executive attention and inhibitory-control variability [Attention_Deficit-Hyperactivity_Disorder] Automatic Sensory Reinforcement [Pica] Reward and Inhibitory-Control Dysregulation [Bulimia_Nervosa] Cognitive-Behavioral Maintenance Processes [Social_Anxiety_Disorder] Hypokinetic Psychomotor Output [Catatonia] Negative Appearance Appraisal and Rumination [Body_Dysmorphic_Disorder] nutritional deficit -- whole-body undernutrition as a state. Rejected on an earlier pass because the search for it collided with renal salt and phosphate "wasting"; with those separated, the real nodes are few but unambiguous. Low Weight and Malnutrition [Anorexia_Nervosa] Protein-Calorie Malnutrition [Cystic_Fibrosis] Malnutrition and Growth Failure [Dystrophic_Epidermolysis_Bullosa] Progressive Weight Loss and Malnutrition [Superior_Mesenteric_Artery_Syndrome] Insulin deficiency from beta-cell impairment in undernutrition [Malnutrition-related_Diabetes_Mellitus] Agammaglobulinemia (Absent Antibody Production) [Immunodeficiency_131] Panhypogammaglobulinemia from Absent Plasma Cells [X-linked_Agammaglobulinemia] Severe Cell-Mediated Immunodeficiency [Acquired_Immunodeficiency_Syndrome] Defective Lymphocyte Proliferation and Combined Immunodeficiency [Cartilage-Hair_Hypoplasia] Hypogammaglobulinemia [Roifman-syndrome] Immunodeficiency from malnutrition and infection [Noma] Waning of Maternal IgG Unmasks the Antibody Defect [Autosomal_Agammaglobulinemia] Chronic Fetal Hypoxemia and Nutrient Deprivation [Fetal_Growth_Restriction] Pre-refeeding malnutrition state [Refeeding_Syndrome] OUTCOME -- what happens to the patient clinical endpoint Neurological Impairment [SHH_Holoprosencephaly_Spectrum] Left Ventricular Decompensation and Symptom Onset [Aortic_Valve_Stenosis] Death in Infancy From Central Respiratory Failure [Severe_Neonatal-Onset_Encephalopathy_With_Microcephaly] Neurodevelopmental malformation and cognitive phenotype [MAN2C1-congenital_disorder_of_deglycosylation_2] Developmental and Epileptic Encephalopathy [KCNH1_Associated_Disorder] Multi-System Clinical Phenotype [Zellweger_Spectrum_Disorders] FOXG1 Static Neurodevelopmental Encephalopathy [FOXG1_Disorder] Circulatory Failure and Sudden Cardiac Death [Histiocytoid_Cardiomyopathy] Abnormality of Terminal Sexual Hair [Androgen_Insensitivity_Syndrome] Recurrent Acute Pancreatitis [Familial_Chylomicronemia_Syndrome] ARCL3A neurocutaneous disease [ALDH18A1_De_Barsy_Spectrum] Profuse Watery Diarrhea [Cholera] Neurologic and multisystem dysfunction [VPS51-Related_Pontocerebellar_Hypoplasia-CDG] Acute Progressive Encephalomyelitis [Rabies] Respiratory muscle involvement [Ullrich_Congenital_Muscular_Dystrophy] Paroxysmal Coughing Illness [Pertussis] Late Unprovoked Seizures [Post-Traumatic_Epilepsy] Progeroid craniofacial and somatic growth phenotype [Ogden_syndrome] Early-Onset Intractable Epilepsy [CDKL5_Deficiency_Disorder] Lower Respiratory and Complicated Infection [Seasonal_Coronavirus_Infection] Desquamation [Transient_Neonatal_Pustular_Melanosis] Genetically Heterogeneous Spastic-Ataxia Syndrome [Spasticity-Ataxia-Gait_Anomalies_Syndrome] Absence Seizures [Juvenile_Absence_Epilepsy] Impaired Somatic Development [ZNF407-Related_Neurodevelopmental_Disorder] Subacute monophasic inflammatory neuropathy course [Subacute_Inflammatory_Demyelinating_Polyneuropathy] Extrapyramidal and neuropsychiatric involvement [Cerebrotendinous_Xanthomatosis] Recurrent Visually Provoked Reflex Seizures [Photosensitive_Occipital_Lobe_Epilepsy] Multisystem Developmental and Hematologic Disease [VPS4A-Related_Neurodevelopmental_Syndrome] Muscle weakness and central nuclei phenotype [Centronuclear_Myopathy] Atypical Pneumonia and Systemic Illness [Psittacosis] Episodic Neurovascular Pain Flares [Primary_Erythermalgia] B6-Vitamer-Responsive Neonatal Seizures [PNPO_Deficiency] Systemic manifestations of glycosaminoglycan storage [Sanfilippo_syndrome] Multisystem Pleiotropic Ciliopathy Phenotype [Orofaciodigital_Syndrome_17] Progressive Encephalopathy [TRAPPC12-Related_Encephalopathy] Neurological Dysfunction [Peroxisome_Biogenesis_Disorder] Brief Generalized Myoclonic Seizures [Myoclonic_Epilepsy_in_Infancy] Joint Contracture [Camptodactyly] Unresolved multisystem tissue dysfunction [Woodhouse-Sakati_Syndrome] Multisystem somatic disease [Maroteaux-Lamy_syndrome] Airway soft-tissue disease [Hunter_syndrome] Extreme Disproportionate Short-Limb Short Stature [Anauxetic_Dysplasia] Progressive Neurological Decline [Rasmussen_Encephalitis] Seizures and movement disorders [Pyruvate_Dehydrogenase_Deficiency] Diaphragmatic and Respiratory Muscle Weakness [Distal_Hereditary_Motor_Neuronopathy_Autosomal_Recessive] Progressive Neurologic Decline [Neuronal_Ceroid_Lipofuscinosis_2] progression and transformation -- a transition to a DIFFERENT disease state. Not a cascade step: it asserts where the disease goes next, and is the shape that keeps OUTCOME from being nearly empty. Malignant Transformation [Dermoid_Cyst] Smooth Muscle Lineage Malignant Transformation [Leiomyosarcoma] Transformation to Aggressive Lymphoma [Heavy_Chain_Disease] Barrett Metaplasia to EAC Sequence [Esophageal_Carcinoma] Progression to Secondary Osteoarthritis [Focal_Articular_Cartilage_Defect_of_the_Knee] Cholestasis and Progression to Biliary Cirrhosis [Biliary_Atresia] Maternal Progression to Type 2 Diabetes [Gestational_Diabetes_Mellitus] Progression to Systolic Failure and Transplantation [KLHL24-Related_Hypertrophic_Cardiomyopathy] Age-Dependent Evolution from Infantile Spasms [Lennox-Gastaut_Syndrome] Stepwise Mucinous Tumor Progression [Ovarian_Mucinous_Carcinoma] Seizure Evolution and Intractability [Aicardi_Syndrome] Cervical Intraepithelial Neoplasia Progression [Cervical_Cancer] Chronic Kidney Disease Progression [Cadmium_Poisoning] Accelerated Tumor Development [Lynch_Syndrome] Malignant Progression to High-Grade Carcinoma [Choroid_Plexus_Neoplasm] Secondary Peripheral Malignant Transformation [Chondrosarcoma] CF-Related Diabetes [Cystic_Fibrosis] Clonal Evolution and Leukemic Transformation [Myelodysplastic_Syndrome] DISPOSITION -- a standing susceptibility rather than an event. Not a cascade tier: a disposition can sit at any tier, and it is the one node kind that describes what COULD happen rather than what did. genetic predisposition Germline APC loss-of-function predisposition [Classic_Familial_Adenomatous_Polyposis] Complex Genetic Predisposition [Jeavons_Syndrome] Somatic Second Hit and JMML Predisposition [CBL-related_Disorder] Somatic genome instability and germ cell tumor predisposition [MCM8-related_gametogenic_failure] Heterozygous EDNRB susceptibility [EDN3_EDNRB_Waardenburg_Shah] Polygenic Corneal Matrix Susceptibility [Keratoconus] Candidate 2q37.1 Wilms tumor susceptibility [2q37_Microdeletion_Syndrome] ERAP2 Evolutionary Selection [Plague] WT1 haploinsufficiency and Wilms tumor predisposition [WAGR_Syndrome] PRKCD-Associated Immune Susceptibility [Vogt-Koyanagi-Harada_Disease] Neurodevelopmental Pathway Enrichment [Oppositional_Defiant_Disorder] Germline Tumor Suppressor Inactivation (First Hit) [Neurofibromatosis] Variant-class-dependent subtype severity [Blepharophimosis_Ptosis_and_Epicanthus_Inversus_Syndrome] DICER1 Syndrome Predisposition [Sarcoma_Of_Cervix_Uteri] Gonadal Sex-Cord Tumor Predisposition [Peutz_Jeghers_Syndrome] Lifelong Multiorgan Cancer Predisposition [Bannayan-Riley-Ruvalcaba_Syndrome] trigger-specific susceptibility -- latent until a named stimulus arrives; pairs with an ENVIRONMENTAL/physiological stressor node Anesthetic-Triggered Malignant Hyperthermia Susceptibility [Bailey-Bloch_Congenital_Myopathy] Possible catabolic-stress susceptibility [2-Methylbutyryl-CoA_Dehydrogenase_Deficiency] Increased Seizure Susceptibility [ABCC9-Related_Intellectual_Disability_and_Myopathy_Syndrome] Opportunistic Infection Susceptibility [Acquired_Immunodeficiency_Syndrome] Susceptibility to severe infections [IKBKG_Ectodermal_Dysplasia_with_Immunodeficiency] Opportunistic pulmonary infection susceptibility [Hepatic_Veno-occlusive_Disease-Immunodeficiency_Syndrome] Fever-associated increased seizure susceptibility [Timothy_Syndrome] Abnormal Sensitivity to Cyclic Ovarian Steroids [Premenstrual_Dysphoric_Disorder] tissue vulnerability -- a tissue that will fail first, without yet having failed White-matter vulnerability and progressive leukoencephalopathy [L-2-Hydroxyglutaric_Aciduria] TBX1-associated pharyngeal developmental vulnerability [22q11.2_Deletion_Syndrome] Neural cell signaling vulnerability [GM3_Synthase_Deficiency] Bioenergetic Failure in Cells With Low Metabolic Reserve [SDHA-Related_Neurodegeneration_With_Ataxia_And_Optic_Atrophy] Endocrine energy vulnerability [NARP_syndrome] Tract-Selective White Matter Involvement [CLCN2-Related_Leukoencephalopathy] Selective Extraocular and Levator Muscle Vulnerability [Autosomal_Recessive_Progressive_External_Ophthalmoplegia_1] outcome risk -- a named adverse endpoint stated as a standing probability Elevated Risk of Sudden Unexpected Death in Epilepsy [DEPDC5-Related_Epilepsy] Gonadal germ-cell neoplasia risk [46_XY_Partial_Gonadal_Dysgenesis] SUZ12 Haploinsufficiency and Elevated MPNST Risk [NF1_Microdeletion_Syndrome] Platelet Dysfunction and Thrombosis Risk [Essential_Thrombocythemia] Cardiac Valvular Insufficiency and Heart Failure Risk [Cardiac_Valvular_Ehlers-Danlos_Syndrome] penetrance and expressivity modifier -- what decides whether a disposition is expressed at all, and how severely. Not the disposition and not the effect: a second locus, a background, or a residual activity level standing between them. Modifier-Dependent Variable Expressivity [SHH_Holoprosencephaly_Spectrum] Penetrance Modulation by Genetic Background and Environmental Triggers [Leber_Hereditary_Optic_Neuropathy] Proposed Residual FLVCR1 Function in Ataxia-Sparing Genotypes [FLVCR1-Related_Retinopathy] Modifier-dependent penetrance and phenotype variability [SMAD6-related_Craniosynostosis] Enzyme redundancy and low clinical penetrance [Isobutyryl-CoA_Dehydrogenase_Deficiency] Connexin 40 Modifier of Atrial Conduction Reserve [Atrial_Standstill] IFNL3 rs12979860 host-clearance modifier [Acute_Hepatitis_C_Virus_Infection] MED13/MED13L paralog redundancy [MED13_Syndrome] Usually Benign Biochemical Disorder [HAO1-Related_Glycolate_Oxidase_Deficiency] mRNA Cleavage-Dependent Spectrum Modulation [Anauxetic_Dysplasia] ALSO CLASSES -- answer a different question than the tiers; a node here is also a molecular/cellular/tissue effect COMPENSATION -- the body pushing back Compensatory Gonadotropin Elevation [46_XX_Gonadal_Dysgenesis] ATP deficit and compensatory lactate production [ACAD9_Deficiency] P2Y12-Dependent Protective Microglial Response [Alexander_Disease] Compensatory Distal Sodium Reabsorption and Potassium Wasting [Bartter_Syndrome] Compensatory Mitochondrial Proliferation in Skeletal Muscle [MERRF_Syndrome] Compensatory Epidermal Hyperproliferation [KRT1_Keratinopathies] Fetal Anemia and Compensatory Extramedullary Erythropoiesis [Hemolytic_Disease_of_the_Fetus_and_Newborn] ETV6 GGAA Counter-Regulation [Ewing_Sarcoma] Preserved Phytanic Acid Alpha-Oxidation [Rhizomelic_Chondrodysplasia_Punctata_Plasmalogen_Synthesis_Defect] Compensatory nitrogen buffering as glutamine [Carbamoyl_Phosphate_Synthetase_I_Deficiency] exhausted compensation -- the reserve running out is its own node, and is where disease becomes manifest Beta-Cell Compensatory Failure [Gestational_Diabetes_Mellitus] Febrile Illness Unmasking of Pump Reserve Failure [CAPOS_Syndrome] QT-Prolonging Drug Unmasking of Reduced Repolarization Reserve [Long_QT_Syndrome] Bioenergetic Failure in Cells With Low Metabolic Reserve [SDHA-Related_Neurodegeneration_With_Ataxia_And_Optic_Atrophy] INTERVENTION POINT -- where a drug acts drug target Bacterial Peptidoglycan Cross-Linking (Beta-Lactam Target) [Bacterial_meningitis] Staphylococcal Peptidoglycan Cross-Linking (Beta-Lactam Target) [Furunculosis] Salmonella Peptidoglycan Cross-Linking (Beta-Lactam Target) [Paratyphoid_Fever] Bacterial Ribosomal Translation (Clindamycin/Linezolid Target) [Toxic_Shock_Syndrome] Streptococcal Ribosomal Translation (Clindamycin/Macrolide Target) [Scarlet_Fever] Coxiella Ribosomal Translation (Tetracycline Target) [Q_Fever] Rickettsial Ribosomal Translation [Rocky_Mountain_Spotted_Fever] Candida beta-1,3-Glucan Synthesis by Fks Glucan Synthase [Invasive_Candidiasis] SARS-CoV-2 Mpro-Dependent Processing of pp1a/pp1ab [COVID-19] HCV NS3/4A-Dependent Processing of the Nonstructural Polyprotein [Acute_Hepatitis_C_Virus_Infection] Adenoviral DNA Polymerase Activity [Adenovirus_Respiratory_Infection] Receptor Tyrosine Kinase Amplification [Gastric_Adenocarcinoma] gp100-Directed T-Cell Redirection [Ocular_Melanoma] Exquisite Platinum Chemosensitivity [Malignant_Germ_Cell_Tumor_of_Ovary] MFSD8 Intron 6 SVA-Induced Cryptic Splicing (Milasen Patient) [Neuronal_Ceroid_Lipofuscinosis_7] Exon-Skipping-Amenable DMD Pre-mRNA Processing Vulnerability [Duchenne_Muscular_Dystrophy] Requirement for Cell-Penetrant Antimicrobials [Legionnaires_Disease] Molecularly Stratified Therapeutic Vulnerabilities [Bladder_Urothelial_Carcinoma] resistance / escape EMT-associated ALK TKI resistance [ALK_Rearranged_NSCLC] TKI Resistance Mechanisms [EGFR_Mutant_NSCLC] Acquired Resistance to Kinase Inhibition [Inflammatory_Myofibroblastic_Tumor] Acquired Resistance to GD2-CAR T Cell Therapy [H3_K27_Altered_Diffuse_Midline_Glioma] Drug Resistance Mechanisms [Tuberculosis] POLQ-Mediated Microhomology Repair Escape [Ovarian_High-Grade_Serous_Carcinoma] TP53-Mutant Senescence Escape [Adult_T_Cell_Leukemia_Lymphoma] T Cell Exhaustion and Immune Escape [Postcricoid_Region_Cancer] HDAC3-SMARCA4-miR-27a Chemotherapy Resistance Circuit [Alveolar_Rhabdomyosarcoma] Acquired Penicillin Resistance via Altered PBPs [Pneumococcal_Pneumonia] ESR1 Mutation-Driven Endocrine Resistance [ER_Positive_Breast_Cancer] DEBUNDLE TARGETS -- the payoff, not a failure of the tree: a node needing two classes is making two claims, and naming which two makes the split obvious found by name -- the node name itself says "and", or "or". The "and" case bundles two claims that both hold; the "or" case bundles two ALTERNATIVE routes to the same effect, which is a different shape and just as splittable. Amyloid Fibril Formation and Extracellular Deposition [AL_Amyloidosis] :split SUBSTANCE = Amyloid Fibril Formation :split TISSUE = Extracellular Amyloid Deposition Eosinophil expansion and tissue infiltration [Autoinflammation_Immune_Dysregulation_and_Eosinophilia] :split CELLULAR = Eosinophil Expansion :split TISSUE = Eosinophil Tissue Infiltration FXN GAA Repeat Expansion and Epigenetic Silencing [Friedreich_Ataxia] :split GENOMIC = FXN GAA Repeat Expansion :split GENOMIC = FXN Epigenetic Silencing Adult Adverse Genomic Landscape and Therapy Resistance [Acute_Megakaryoblastic_Leukemia] :split GENOMIC = Adverse Genomic Landscape :split INTERVENTION = Therapy Resistance HPRT1 Enzyme Deficiency and Purine Overproduction [Lesch-Nyhan_Syndrome] :split ACTIVITY = HPRT1 Enzyme Deficiency :split SUBSTANCE = Purine Overproduction Impaired valine catabolism and reactive-metabolite accumulation [ECHS1_Deficiency] :split PATHWAY = Impaired Valine Catabolism :split SUBSTANCE = Reactive Metabolite Accumulation ZRS or pZRS Regulatory Gain of Ectopic Expression [ZRS-Related_Limb_Malformation] :split GENOMIC = ZRS Duplication (a dosage change) :split GENOMIC = pZRS Point Variant (a regulatory sequence variant, no dosage change) :note An "or" bundle, and both arms land in GENOMIC -- so unlike the others :note here it is not a cross-tier split. Filing it exposed a missing leaf: :note it sat under `dosage`, true of the duplication arm and false of the :note point-variant arm, and now sits under `cis-regulatory variant`, which :note is true of both. The bundle is still real and still worth splitting. found by GO term -- node class disagrees with its GO annotation's usual class; 55/333 (17%) of scale-labelled nodes carrying a confident GO term SCN5A Sodium-Channel Loss of Function [Atrial_Standstill] :evidence curated MOLECULAR, annotated GO:0061337 cardiac conduction (usually TISSUE) :split ACTIVITY = SCN5A Sodium-Channel Loss of Function :split TISSUE = Impaired Cardiac Conduction Loss of Cardiomyocyte KATP Conductance [ABCC9-Related_Intellectual_Disability_and_Myopathy_Syndrome] :evidence curated CELLULAR, annotated GO:0071805 potassium ion transmembrane transport (usually MOLECULAR) :split ACTIVITY = Loss of KATP Channel Conductance :split CELLULAR = Cardiomyocyte Excitability Change White-Matter Oxidative Stress [Alexander_Disease] :evidence curated TISSUE, annotated GO:0006979 response to oxidative stress (usually CELLULAR) :split CELLULAR = Glial Oxidative Stress Response :split TISSUE = White-Matter Injury Impaired Cortical Circuit Formation and Connectivity [Autosomal_Recessive_Non-Syndromic_Intellectual_Disability] :evidence curated TISSUE, annotated GO:0030182 neuron differentiation (usually CELLULAR) found by conflicting GO terms -- the node's OWN annotations span two classes; needs no curated class at all; 762 nodes (6.2%) Serine-Dependent CNS Biosynthetic and Signaling Insufficiency [3-Phosphoglycerate_Dehydrogenase_Deficiency] :evidence PATHWAY + SUBSTANCE Oocyte-Granulosa Growth and Estrogen Signaling Failure [46_XX_Gonadal_Dysgenesis] :evidence PATHWAY + TISSUE Neuronal Overmigration and Cortical Dyslamination [ADGRG1_Bilateral_Frontoparietal_Polymicrogyria] :evidence CELLULAR + TISSUE Altered B-cell Development and Signaling [B-Lymphoblastic_Leukemia_Lymphoma_With_Recurrent_Genetic_Abnormality] :evidence CELLULAR + PATHWAY Matrisome Sequestration and HTRA1 Loss-of-Function [CADASIL_Type_1] :evidence ACTIVITY + TISSUE Disrupted Cortical Neurogenesis and Cell-Cycle Control [DYRK1A_Syndrome] :evidence CELLULAR + TISSUE Autophagy and Proteostasis Dysfunction [Ehlers-Danlos_Syndrome] :evidence ACTIVITY + CELLULAR Reduced GABA-Gated Chloride Current and Phasic Inhibition [GABRG2-Related_Epilepsy] :evidence ACTIVITY + CELLULAR Epigenetic Derepression and Aberrant Gene Activation [H3_K27_Altered_Diffuse_Midline_Glioma] :evidence CELLULAR + GENOMIC 2-HG Accumulation and Epigenetic Dysregulation [IDH_Mutant_Astrocytoma] :evidence CELLULAR + GENOMIC Mutant Myocilin Misfolding and Trabecular Cell Stress [Juvenile_Open_Angle_Glaucoma] :evidence ACTIVITY + CELLULAR Mitochondrial dysfunction and metabolic reprogramming [L-2-Hydroxyglutaric_Aciduria] :evidence CELLULAR + SUBSTANCE MECP2 Overexpression and Neurodegeneration [MECP2_Duplication_Syndrome] :evidence CELLULAR + GENOMIC Cortical Dyslamination and Lissencephaly [NDE1-related_Microcephaly_Lissencephaly] :evidence CELLULAR + TISSUE Osteoclast and protein-glycosylation dysfunction [RAB33B-Related_Smith-McCort_Dysplasia_2] :evidence ACTIVITY + TISSUE TACO1 Loss and Defective Mitochondrial COX I Translation [TACO1-Related_COX_Deficiency] :evidence ACTIVITY + CELLULAR VCP Dysfunction and Proteostasis Failure [VCP-associated_Multisystem_Proteinopathy] :evidence ACTIVITY + CELLULAR rDNA chromatin and RNA polymerase I transcription defect [Warsaw_breakage_syndrome] :evidence ACTIVITY + GENOMIC Impaired Axonogenesis and Commissural Tract Formation [USP9X_Female-Restricted_Syndromic_Intellectual_Disability] :evidence CELLULAR + TISSUE not a bundle, do not split -- a molecular event with an anatomical site is ONE claim; UBERON is a location qualifier, not a second tier. Fires on 368 nodes (3.0%), mostly wrongly. ANK2 Haploinsufficiency in Neurons [ANK2_Related_Complex_Neurodevelopmental_Disorder] Developmental Forebrain Ank2 Loss [ANK2_Related_Complex_Neurodevelopmental_Disorder] SHOX haploinsufficiency in growth plate chondrocytes [Leri-Weill_Dyschondrosteosis] Impaired Serine Biosynthesis in Neural Progenitors [Siderius_Type_X-Linked_Intellectual_Disability] STILL UNPLACED -- genuine scope questions, not bundles not an effect at all -- no tier applies Modifier-Dependent Variable Expressivity [SHH_Holoprosencephaly_Spectrum] :note a statement about penetrance, not a step in a cascade Requirement for Cell-Penetrant Antimicrobials [Brucellosis] :note a therapeutic constraint, not pathophysiology Exquisite Platinum Chemosensitivity [Malignant_Germ_Cell_Tumor_of_Ovary] :note a treatment-response property of the tumour, not a mechanism step Unknown Etiology with Negative Riboflavin-Transporter and C9ORF72 Genetics [Madras_Motor_Neuron_Disease] :note a negative finding recorded as a node Molecular Reclassification [oligoastrocytoma] Lone star tick bite-associated syndrome of unknown etiology [Southern_Tick-Associated_Rash_Illness] Clinical detection by imaging, surgery, or pathology [Fallopian_Tube_Benign_Neoplasm] normal biology, not pathology -- healthy pathogen physiology, in the graph only because a drug hits it; every antimicrobial drug-target node has this shape Bacterial Peptidoglycan Cross-Linking (Beta-Lactam Target) [Bacterial_meningitis] Coxiella Ribosomal Translation (Tetracycline Target) [Q_Fever] Candida beta-1,3-Glucan Synthesis by Fks Glucan Synthase [Invasive_Candidiasis] aetiology unresolved -- the entry drawing a node for a cause it cannot name. A statement about the state of knowledge, not about the patient, so no tier can apply; worth keeping visible because it marks exactly where the pathograph stops. Aetiologic Fork - Infectious versus Non-Infectious Choroidal Inflammation [Choroiditis] Heterogeneous Genetic Etiology [DEE_with_Spike-Wave_Activation_in_Sleep] Unknown Molecular Etiology [Fountain_Syndrome] Heterogeneous Etiologic Brain Insult [Lennox-Gastaut_Syndrome] Unknown Etiology with Negative Riboflavin-Transporter and C9ORF72 Genetics [Madras_Motor_Neuron_Disease] Lone star tick bite-associated syndrome of unknown etiology [Southern_Tick-Associated_Rash_Illness] Etiologic Lesion of the Immature Brain [Early-Infantile_Developmental_and_Epileptic_Encephalopathy] Heterogeneous developmental brain etiologies [Infantile_Spasms] # ---- NOTES FROM BUILDING THIS # # 1. The SHH/holoprosencephaly example does not curate as a genomic node. # SHH_Holoprosencephaly_Spectrum opens at "Reduced SHH Signaling in Forebrain # Patterning" -- a PATHWAY effect. The allele is in the `genetic:` section, # not the pathograph. Common pattern: many entries start the cascade at # pathway or molecular level and never draw the lesion. # # 2. "Deficiency" is the most overloaded word in the KB. It names a genomic LoF, # a molecular activity loss, a flux block, and a nutrient depletion -- and # sometimes several of those in one node name. # # 3. DEVELOPMENTAL MALFORMATION was not in the original 8-tier sketch and had to # be added. Malformation is not inflammation, fibrosis, or degeneration, and a # large share of the Mendelian KB lands there. # # 3b. MOLECULAR ACTIVITY vs MOLECULAR SUBSTANCE was the second addition, and the # corpus backs it hard. Mean topological depth: nodes grounded in a GO # molecular_function sit at 0.81, nodes grounded in CHEBI at 1.78 -- a full # causal step apart. WITHIN the nodes curators tagged `biological_scale: # MOLECULAR`, MF nodes sit at 0.87 and CHEBI nodes at 1.90, so that one tag # was already covering two tiers. Curators had also invented a naming # convention for the activity tier without a slot to put it in: 31 nodes are # literally named " molecular function deficiency", and 394 node names # (3.4%) are activity-shaped overall. # # 3c. But ACTIVITY is NOT between GENOMIC and SUBSTANCE in depth. Gene-grounded # nodes sit at 0.94 and MF-grounded nodes at 0.81 -- statistically the same # place. GENOMIC and ACTIVITY are ALTERNATIVE ENTRY POINTS, not sequential # steps: an entry either opens on the lesion or opens on the broken activity, # rarely both. That is the same pattern as note 1. # # 3d. Expanding from 108 to 420 examples forced five NEW subclasses that the # small sample had hidden: ENVIRONMENTAL/physical exposure (acoustic, aerosol # -- not chemical), ACTIVITY/structural-protein activity (a collagen or # filament failing to ASSEMBLE is not an enzyme failing to catalyse), # CELLULAR/migration-positioning, TISSUE/barrier failure, and # COMPENSATION/exhausted compensation (the reserve running out is its own # node, and is usually where the disease becomes clinically manifest). # # 3e. OUTCOME is nearly empty -- 4 examples against 62 for TISSUE/ORGAN. That is # not a sampling artifact: patient-level outcomes are curated in the # `phenotypes:` section, so the pathograph's pathophysiology chain mostly # stops at the systemic tier. If OUTCOME stays this thin it may not be a # tier of this classification at all. # # 3f. Examples were harvested with an alphabet spread deliberately. A plain # regex sweep returns whichever diseases sort first, which is how the earlier # 108-example draft ended up dominated by A-named entries. The 420 now cover # 334 distinct entries. # # 3g. METHOD CHANGE, and it mattered more than any single addition. Examples up # to 420 were harvested by regex per subclass, which can only ever find what # the taxonomy already expects -- it confirms, it cannot falsify. Switching to # a RANDOM sample of 70 nodes drawn from entries not yet cited broke the # taxonomy in nine places in one pass. Every gap below came from that sample: # # GENOMIC/pathogenic sequence variant -- a plain miss. The tree had dosage, # structural variant, epigenetic and transcript-level but no home for # "Biallelic COL7A1 Pathogenic Variants", the commonest genomic node of all. # CELLULAR/cell activation -- microglial, neutrophil, macrophage, endothelial, # osteoclast, complement. Recurs across every immune and neuro entry. # TISSUE/injury -- "injury" is the 8th commonest head noun in the KB and had # no leaf. # TISSUE/ischemia and infarction -- perfusion failure, entirely absent. # TISSUE/functional disturbance -- an organ working wrongly with no structural # lesion (excitability, conduction, motility). The whole epilepsy and # arrhythmia corpus lands here. # TISSUE/inflammatory infiltration, neoplastic invasion and metastasis, # pathogen spread and tissue invasion, immune evasion, impaired repair # SYSTEMIC/systemic inflammatory state -- autoinflammation, cytokine storm, sepsis # SUBSTANCE/protein abundance loss and post-translational modification state # ENVIRONMENTAL/microbiome state -- dysbiosis as an exposure # # Regex harvesting is still the right way to POPULATE a leaf once it exists. # It is the wrong way to discover that a leaf is missing. # # 3h. DISPOSITION was promoted from STILL UNPLACED to a top-level class. Nodes # asserting a standing susceptibility rather than an event ("Anesthetic- # Triggered Malignant Hyperthermia Susceptibility", "Germline APC loss-of- # function predisposition", "White-matter vulnerability") turned out to be # common and to have four distinct shapes. It is explicitly NOT a cascade # tier: a disposition can sit at any tier, and it is the only node kind that # describes what COULD happen rather than what did. This is the DISPOSITION # facet from the very first sketch, which was dropped and has now earned its # way back on evidence. # # 3i. TISSUE/ORGAN now holds 121 of 556 examples across 13 leaves -- nearly a # quarter of the tree. That is partly real (it is where most pathology is # described) and partly a sign it should eventually split. OUTCOME is still # at 4, unchanged by a random sample, which strengthens note 3e. # # 3j. EXTERNAL SOURCES AS A GAP-FINDER (MPATH, MeSH, SNOMED, NCIT, via OLS). # Used purely to mine for missing categories -- not for structure, not for # mapping. Method: take each external pathology category, count matching # dismech nodes, keep the ones with no leaf here. Nine leaves came out of it: # # MPATH:105 circulatory disorder -> TISSUE/circulatory disturbance (~70 nodes) # SNOMED:107658001 mechanical abnorm. -> TISSUE/mechanical obstruction (75 nodes, # the largest single gap any source found) # SNOMED:783804002 abnormal communic. -> TISSUE/abnormal communication (20) # SNOMED:46595003 deposition -> TISSUE/material deposition (74) # SNOMED:783806000 vascular malform. -> TISSUE/vascular malformation (5) # SNOMED:89615005 abn. blood cells -> SYSTEMIC/haematological deficit (24) # MeSH:D042822 genomic instability -> GENOMIC/genome instability (41) # MeSH:D008679 metaplasia -> CELLULAR/metaplasia (4) # MeSH:D006461 hemolysis -> CELLULAR/haemolysis (16) # # The mechanical-obstruction gap is the embarrassing one: 75 nodes -- bladder # outlet, LV outflow tract, biliary, CSF, lacrimal, carotid -- and the tree had # nowhere to put any of them. Obstruction is not inflammation, fibrosis, # degeneration, malformation or barrier failure. # # The abnormal-communication leaf is a direct RETRACTION. An early regex sweep # for "metabolic flux block" matched cardiac shunt nodes ("Left-to-Right Shunt", # "ductal shunting"), and I dismissed them as false positives instead of asking # what class they DID belong to. SNOMED had the answer. # # 3k. What the external sources did NOT justify, checked before assuming: # NCIT Ulceration matches 2 nodes here, Hyalinization 1. Their absence is # correct. MPATH's process/structure MIRROR was also declined for now -- it is # a structural choice, and this phase is gap-filling only. # # 3l. Second random draw (80 nodes, seed 77) found four more gaps, one of them # the largest yet: # # SYSTEMIC/autoimmune response 122 nodes -- biggest gap any method # has found. Autoantibody formation, # autoreactive lymphocytes, loss of # tolerance had nowhere to go; the tree # could describe the tissue damage but # not the immune claim causing it. # CELLULAR/protein trafficking and 69 nodes -- the protein is made and # localization folded but never reaches where it # works. Not ACTIVITY (it would work if # it arrived), not SUBSTANCE (nothing # misfolded or depleted). # OUTCOME/progression and transformation 20 nodes # SYSTEMIC/immune deficiency 15 nodes -- the defect itself, as # opposed to the susceptibility it # confers (DISPOSITION) or the # infection that follows (ENVIRONMENTAL) # # 3m. PARTIAL RETRACTION of notes 3e and 3i. OUTCOME being stuck at 4 examples was # twice read as evidence that patient-level outcomes live in `phenotypes:` and # that OUTCOME might not be a tier at all. That was half right. The tier was # also missing a LEAF: "progression and transformation" -- Barrett-to-EAC, # malignant transformation, progression to secondary osteoarthritis. Those # assert where the disease goes NEXT, which is not a cascade step and not a # phenotype. With that leaf OUTCOME holds 15. The original reading survives in # weakened form: OUTCOME is still the smallest tier and still mostly deferred # to `phenotypes:`, but "not a tier at all" was too strong. # # 3n. Checked and NOT added: neoplastic cell-of-origin (2 nodes only), and a # nutritional-wasting leaf -- the regex for it conflated renal salt/phosphate # "wasting" (a SUBSTANCE loss via the kidney) with nutritional wasting, and # once separated the latter is thin. Two different things sharing a word. # # 3o. Third pass: 300 random nodes (seed 300300) classified in one batch. # 294 placed, 1 duplicate, 5 deliberately left out. Examples 666 -> 958, # entries 492 -> 757. NO new subclasses were needed -- the first time a draw # has not forced one. Taken with 3l (four new leaves from 80 nodes) and 3j # (nine from the external ontologies), that is the first sign the leaf # vocabulary is starting to saturate. One draw is not proof; a fourth should # be run before anyone relies on it. # # Placement was done by index into the sample and inserted programmatically # rather than by hand-editing ~50 places in the file. Worth repeating: it # removes transcription error entirely, and the --verify-kb check then # confirms every leaf against kb/. # # Left unplaced on purpose, all of them too vague to classify honestly rather # than hard to classify: "Epithelial Cell Dysfunction" [Sjogrens_Syndrome], # "Neurological involvement" [MGAT2-CDG], "Retinal Pigment Epithelium # Dysfunction" [Central_Serous_Chorioretinopathy], "Reduced amniotic fluid # volume" [Prune_Belly_Syndrome], "Transient Exogenous Motion-Network # Interference" [Akinetopsia]. A node this generic is a curation signal in its # own right -- it says almost nothing a reader could act on. # # 3p. Correction worth recording. Six sampled nodes were initially skipped as # "already in the tree" from memory. Checked, five were not, and were then # placed. Only "Microbiome Dysbiosis" was a genuine duplicate. Do not assert a # duplicate without grepping for it -- the file is now large enough that # recall is unreliable. # # 3q. Fourth random draw (300 nodes, seed 444444). 296 placed, 4 already present. # Examples 958 -> 1263, entries 757 -> 1024. This PARTIALLY REFUTES 3o. The # third draw needed zero new leaves; the fourth needed two, so saturation is # slowing but is not reached: # # SYSTEMIC/behavioural and cognitive a psychological process doing # mechanism mechanistic work -- avoidance, # restriction, compulsion, catastrophic # appraisal. The psychiatric and # functional-disorder entries had # nowhere to put the step that actually # drives the disease. # SYSTEMIC/nutritional deficit whole-body undernutrition as a state, # distinct from the single-nutrient # depletion that is a SUBSTANCE node. # # The trend across draws: external ontologies 9 new leaves, 80-node draw 4, # 300-node draw 0, 300-node draw 2. Read it as decelerating, not finished. # # Also checked and NOT added: malabsorption (~11 nodes) -- it is a specific # failure of an organ doing its job, so it folds into TISSUE/functional # disturbance rather than earning a leaf. # # REVERSAL of 3n. That note rejected a nutritional leaf, and the rejection was # an artifact: the regex that measured it had swept in renal salt/phosphate # "wasting" nodes, I noticed the conflation, and then wrongly concluded the # remainder was too thin instead of re-measuring it cleanly. It was not. This # is the same failure mode as the shunt retraction in 3j -- a bad regex was # allowed to settle a question about the taxonomy. Both times the fix came from # looking at the nodes rather than at the match count. # # 3r. Fifth random draw (300 nodes, seed 555555). 285 placed, 11 name-collisions, # 4 already used as seeds for the new leaves below. Examples 1263 -> 1592, # entries 1024 -> 1275. # # This REFUTES the saturation reading outright. The draw forced FIVE new # leaves, more than any previous draw, and two of them are among the largest # gaps found by any method: # # TISSUE/neural circuit and network 137 nodes -- second only to the # dysfunction autoimmune leaf. Distributed # multi-region circuits misbehaving AS # circuits: hyperexcitability, # hypersynchrony, dysconnectivity, # oscillation. The whole epilepsy, # movement-disorder and psychiatric # corpus was landing in `functional # disturbance`, which describes ONE # organ working wrongly. # TISSUE/pathological angiogenesis 36 nodes and the tree held NONE of # them. Every tumour entry with a VEGF # node, every proliferative # retinopathy. # TISSUE/compression and mass effect 28 nodes -- one structure pressing # on its neighbour. Not obstruction # (no lumen narrows) and not invasion # (no boundary is crossed). # STILL UNPLACED/aetiology unresolved 8 nodes -- the entry drawing a node # for a cause it cannot name. # DISPOSITION/penetrance and expressivity 7 nodes -- what stands between a # modifier disposition and its expression. # # New leaves per draw, in order: external ontologies 9, 80-node draw 4, # 300-node draw 0, 300-node draw 2, 300-node draw 5. The trend I reported in # 3o and 3q was not a trend. Two draws of the same size differ by 5 leaves, # which says the variance between draws is larger than any decline across # them -- so nothing here supports a claim about saturation in either # direction, and I should not have made one from a single draw. # # Why this draw found more: the four biggest finds are all TISSUE/ORGAN, the # tier that already had the most leaves and the most examples. Coverage of a # tier does not predict coverage of its vocabulary. `functional disturbance` # and `pathological structure formed` were acting as sinks -- broad enough to # accept anything, so nothing looked missing until the sink was measured. # # Checked and NOT added, with the nodes read rather than the counts trusted: # - drug pharmacokinetics. 15 regex hits, 2 genuine ("Reduced renal # oxypurinol clearance"); the rest are immune clearance, protein # clearance, or CYP enzymes acting as ordinary catalytic nodes. # - hypersecretion (11). Splits cleanly between endocrine derangement # (hormone) and functional disturbance (mucus, CSF); no shared claim. # - detection and diagnosis (2). Goes to `not an effect at all`. # # 11 of 300 sampled node NAMES (3.7%) were already in the tree from a # DIFFERENT disease -- "Bone Marrow Failure", "Genomic Instability", # "RAS-MAPK Pathway Activation". The tree holds representatives, so these add # nothing, but the rate is worth knowing: node names are reused across entries # often enough that name alone is not an identifier. # # 3s. Merging main into this branch broke 7 of 1592 examples (0.4%), all from # ordinary recuration on main while this file was being written -- entries # renamed (Triphalangeal_Thumb_Polysyndactyly -> ZRS-Related_Limb_Malformation), # entries merged (Complete_ and Partial_Androgen_Insensitivity_Syndrome -> one # Androgen_Insensitivity_Syndrome), and nodes renamed inside surviving entries. # Two of the seven were placed in this same session from a node snapshot that # was already stale. # # This is the cost of citing nodes by name, and it is why --verify-kb exists. # Budget for it: a tree of this size will drift by a few examples per week of # normal curation, and the check is a second to run. # # One break was not a rename. `PRRX1/OTX2 Loss of Function in First-Arch Neural # Crest` was filed here under "not a bundle, do not split" -- and main has since # SPLIT it, into `PRRX1 Loss of Function`, `OTX2 Loss of Function` and # `First-Arch Neural Crest Patterning Failure`. The rule survives: the split # curators made was on the GENE axis (two genes, two claims), not the anatomy # axis the rule is about. The example was simply a bad one -- it bundled two # genes as well as a site, so it could never have shown what it was chosen to # show. Removed rather than re-pointed. # # 4. Ontology grounding predicts the class well enough to seed it, but only # from the RIGHT slot. GO MF present -> 91% MOLECULAR. Gene present -> 81%. # CL+UBERON -> 70% TISSUE. GO BP present -> no signal at all (40/24/13/23 # across the four scales), because BP spans every tier; for BP you need the # term identity, not its presence. Details and measurements in the spec doc. # # 5. The GO seed table works. 640 hand-classified GO BP terms # (pathograph_node_class_go_seed.tsv) assign an unambiguous class to 5,536 # nodes (45.0% of 12,290) and flag another 762 (6.2%) whose own GO terms # disagree -- i.e. debundle candidates. With the MF/gene rule, 60.1%. # On MODULE nodes specifically: 63.8% seeded, 76.4% combined. # # 6. Frequency-ranked seeding has a systematic blind spot. The first 200 terms # seeded ~21 nodes each; terms 201-500 only ~3.7 each. But a third tranche # chosen by TARGET rather than rank -- every GO BP term used in kb/modules # that the first two missed -- barely moved the corpus number (43.6 -> 45.0%) # while taking module coverage from ~44% to 63.8%. Whole specialist # vocabularies (viral lifecycle, meiosis, fungal/bacterial cell wall, # cortical migration) were absent because each term is rare KB-wide while # being central to the module using it. Extend by target, not by rank.