{
  "title": "MVA Syndrome & Pediatric Oncology Candidate Gene Burden Matrix",
  "description": "Multi-gene burden analysis across Spindle Assembly Checkpoint, Centrosome, Kinetochore, and Pediatric Cancer loci in Proband EX2312012.",
  "genes": [
    {
      "gene": "BUB1B",
      "omim": "MIM#257300",
      "cytoband": "15q15.1",
      "syndrome": "MVA Syndrome Type 1",
      "complex": "Mitotic Checkpoint Complex (MCC)",
      "role": "SAC Kinase / CDC20 Inhibitor",
      "inheritance": "Autosomal Recessive / Compound Het",
      "patient_variants": 63,
      "highest_vaf": "53.8%",
      "mosaic_candidates": 3,
      "clinical_link": "Rhabdomyosarcoma, Wilms Tumour, Microcephaly, IUGR, Prematurity",
      "pathogenicity_tier": "Tier 1: Primary Diagnostic Candidate"
    },
    {
      "gene": "CEP57",
      "omim": "MIM#614114",
      "cytoband": "11q21",
      "syndrome": "MVA Syndrome Type 2",
      "complex": "Centrosomal Barrel Core",
      "role": "Centrosome Scaffolding / Microtubule Nucleation",
      "inheritance": "Autosomal Recessive",
      "patient_variants": 10,
      "highest_vaf": "50.0%",
      "mosaic_candidates": 0,
      "clinical_link": "Growth Restriction, Rhizomelia, Nephrocalcinosis, Microcephaly",
      "pathogenicity_tier": "Tier 1: Primary Diagnostic Candidate"
    },
    {
      "gene": "TRIP13",
      "omim": "MIM#617598",
      "cytoband": "5p15.33",
      "syndrome": "MVA Syndrome Type 3",
      "complex": "SAC Remodeler AAA+ ATPase",
      "role": "Converts Closed-MAD2 (C-MAD2) to Open-MAD2 (O-MAD2)",
      "inheritance": "Autosomal Recessive",
      "patient_variants": 3,
      "highest_vaf": "28.6% (Mosaic)",
      "mosaic_candidates": 1,
      "clinical_link": "Wilms Tumour, Rhabdomyosarcoma, Variegated Aneuploidy",
      "pathogenicity_tier": "Tier 1: High-Confidence Mosaic Somatic Driver"
    },
    {
      "gene": "CEP192",
      "omim": "MIM#619934",
      "cytoband": "18p11.21",
      "syndrome": "MVA Syndrome Type 4",
      "complex": "Pericentriolar Material (PCM)",
      "role": "AURKA / PLK1 Mitotic Spindle Recruitment",
      "inheritance": "Autosomal Recessive",
      "patient_variants": 219,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 14,
      "clinical_link": "Short Stature, Microcephaly, Failure to Thrive, Aneuploidy",
      "pathogenicity_tier": "Tier 1: High Burden Candidate"
    },
    {
      "gene": "MAD1L1",
      "omim": "MIM#602686",
      "cytoband": "7p22.3",
      "syndrome": "MVA Susceptibility / CIN",
      "complex": "Kinetochore SAC Corona",
      "role": "MAD2 Kinetochore Receptor & Dimerization",
      "inheritance": "Autosomal Dominant / Recessive",
      "patient_variants": 889,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 51,
      "clinical_link": "Mosaic Aneuploidy, Systemic Malignancies, Developmental Delay",
      "pathogenicity_tier": "Tier 2: Major Kinetochore Burden"
    },
    {
      "gene": "MAD2L1",
      "omim": "MIM#601467",
      "cytoband": "4q27",
      "syndrome": "SAC Core Checkpoint",
      "complex": "Mitotic Checkpoint Complex (MCC)",
      "role": "Direct CDC20 Sequestration / Anaphase Clamp",
      "inheritance": "Autosomal Dominant / Somatic",
      "patient_variants": 14,
      "highest_vaf": "52.4%",
      "mosaic_candidates": 1,
      "clinical_link": "Mitotic Arrest Deficiency, CIN, Tumorigenesis",
      "pathogenicity_tier": "Tier 2: Core Checkpoint Regulator"
    },
    {
      "gene": "BUB1",
      "omim": "MIM#602452",
      "cytoband": "2q13",
      "syndrome": "Primary Microcephaly / CIN",
      "complex": "Outer Kinetochore Kinase",
      "role": "H2A Thr120 Phosphorylation / Shugoshin Recruitment",
      "inheritance": "Autosomal Recessive",
      "patient_variants": 15,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 1,
      "clinical_link": "Variegated Aneuploidy, Colorectal & Soft Tissue Tumours",
      "pathogenicity_tier": "Tier 2: Centromeric Cohesion"
    },
    {
      "gene": "BUB3",
      "omim": "MIM#603424",
      "cytoband": "10q26.13",
      "syndrome": "SAC Scaffolding Component",
      "complex": "Kinetochore WD40 Scaffold",
      "role": "MELT Motif Recognition on KNL1",
      "inheritance": "Autosomal Dominant / Somatic",
      "patient_variants": 58,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 2,
      "clinical_link": "Chromosomal Nondisjunction, Embryonic Lethality",
      "pathogenicity_tier": "Tier 2: Kinetochore Docking"
    },
    {
      "gene": "SMC5",
      "omim": "MIM#609313",
      "cytoband": "9q21.11",
      "syndrome": "Atelencephaly / Microcephaly",
      "complex": "Structural Maintenance of Chromosomes",
      "role": "Chromosome Condensation & Decatenation",
      "inheritance": "Autosomal Recessive",
      "patient_variants": 74,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 4,
      "clinical_link": "Chromosomal Instability, Growth Retardation, Facial Dysmorphism",
      "pathogenicity_tier": "Tier 2: Cohesion & DNA Repair"
    },
    {
      "gene": "CENPE",
      "omim": "MIM#117143",
      "cytoband": "4q24",
      "syndrome": "Microcephalic Primordial Dwarfism",
      "complex": "Outer Kinetochore Motor",
      "role": "Kinesin-7 Plus-End Microtubule Translocase",
      "inheritance": "Autosomal Recessive",
      "patient_variants": 76,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 3,
      "clinical_link": "Severe IUGR, Microcephaly, Chromosome Misalignment",
      "pathogenicity_tier": "Tier 2: Motor Translocation"
    },
    {
      "gene": "CENPF",
      "omim": "MIM#600236",
      "cytoband": "1q41",
      "syndrome": "Stromme Syndrome",
      "complex": "Outer Kinetochore Corona",
      "role": "Dynein / Kinetochore Maturation & Spindle Orientation",
      "inheritance": "Autosomal Recessive",
      "patient_variants": 74,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 2,
      "clinical_link": "Intrauterine Growth Restriction, Renal Hypoplasia, Microcephaly",
      "pathogenicity_tier": "Tier 2: Ciliopathy & Kinetochore"
    },
    {
      "gene": "PLK1",
      "omim": "MIM#602098",
      "cytoband": "16p12.2",
      "syndrome": "Mitotic Master Kinase",
      "complex": "Centrosome & Kinetochore Kinase",
      "role": "Centrosome Maturation & Cohesin Release Trigger",
      "inheritance": "Somatic / Oncogenic",
      "patient_variants": 3,
      "highest_vaf": "50.0%",
      "mosaic_candidates": 0,
      "clinical_link": "Rhabdomyosarcoma Oncogenesis, Mitotic Deregulation",
      "pathogenicity_tier": "Tier 3: Mitotic Phospho-Regulator"
    },
    {
      "gene": "AURKA",
      "omim": "MIM#603072",
      "cytoband": "20q13.2",
      "syndrome": "Aurora Kinase A",
      "complex": "Centrosomal Spindle Pole Kinase",
      "role": "Bipolar Spindle Assembly & Centrosome Separation",
      "inheritance": "Somatic / Oncogenic",
      "patient_variants": 16,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 1,
      "clinical_link": "Aneuploidy Induction, Centrosome Amplification, Sarcoma",
      "pathogenicity_tier": "Tier 3: Spindle Pole Kinase"
    },
    {
      "gene": "TP53",
      "omim": "MIM#191170",
      "cytoband": "17p13.1",
      "syndrome": "Li-Fraumeni Syndrome",
      "complex": "Tumor Suppressor Guardian",
      "role": "Tetrameric DNA Damage & Aneuploidy Checkpoint",
      "inheritance": "Autosomal Dominant / Somatic",
      "patient_variants": 16,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 1,
      "clinical_link": "Embryonal Rhabdomyosarcoma, Soft Tissue Sarcomas, Adrenocortical Tumours",
      "pathogenicity_tier": "Tier 3: Sarcoma Driver Candidate"
    },
    {
      "gene": "WT1",
      "omim": "MIM#607102",
      "cytoband": "11p13",
      "syndrome": "Denys-Drash / WAGR Syndrome",
      "complex": "Zinc-Finger Transcription Factor",
      "role": "Nephrogenesis & Mesenchymal-Epithelial Transition",
      "inheritance": "Autosomal Dominant / Recessive",
      "patient_variants": 19,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 0,
      "clinical_link": "Congenital Nephrocalcinosis, Wilms Tumour, Genitourinary Defects",
      "pathogenicity_tier": "Tier 3: Renal Phenotype Corroboration"
    },
    {
      "gene": "DICER1",
      "omim": "MIM#606241",
      "cytoband": "14q32.13",
      "syndrome": "DICER1 Tumour Predisposition",
      "complex": "miRNA Processing Endoribonuclease",
      "role": "MicroRNA Biogenesis & Heterochromatin Maintenance",
      "inheritance": "Autosomal Dominant",
      "patient_variants": 27,
      "highest_vaf": "100.0%",
      "mosaic_candidates": 1,
      "clinical_link": "Embryonal Rhabdomyosarcoma, Pleuropulmonary Blastoma, Cystic Nephroma",
      "pathogenicity_tier": "Tier 3: Pediatric Oncology Predisposition"
    }
  ]
}