| { | |
| "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" | |
| } | |
| ] | |
| } |