| { | |
| "title": "Proband Phenotypic Constellation vs Syndromic Differential Matrix", | |
| "description": "Cross-referencing observed clinical HPO findings against competing pediatric rare disease and cancer predisposition syndromes.", | |
| "phenotypes": [ | |
| { | |
| "feature": "Rhabdomyosarcoma (RMS)", | |
| "hpo": "HP:0002859", | |
| "mva_syndrome_match": "High (Hallmark embryonal malignancy in MVA Type 1 & 3)", | |
| "mva_genes": "BUB1B, TRIP13, DICER1, TP53", | |
| "competing_syndromes": "Li-Fraumeni (TP53), DICER1 Syndrome, Costello Syndrome (HRAS), Beckwith-Wiedemann (11p15)", | |
| "molecular_mechanism": "Mitotic checkpoint leakage triggers chromosome 15/11/8 aneuploid nondisjunction, leading to somatic loss of heterozygosity (LOH) and oncogenic transformation of skeletal myoblasts.", | |
| "discriminatory_power": "Very High: Isolated RMS doesn't cause nephrocalcinosis or premature IUGR, but MVA links all three." | |
| }, | |
| { | |
| "feature": "Congenital Nephrocalcinosis", | |
| "hpo": "HP:0000121", | |
| "mva_syndrome_match": "High (Characteristic in MVA Type 2 and centrosomal ciliopathies)", | |
| "mva_genes": "CEP57, WT1, CEP192", | |
| "competing_syndromes": "Dent Disease (CLCN5), Bartter Syndrome (SLC12A1), Primary Hyperoxaluria, Familial Hypomagnesemia", | |
| "molecular_mechanism": "Centrosomal dysfunction (CEP57/CEP192) impairs primary cilia formation in renal collecting duct epithelium, causing calcium phosphate precipitation and medullary calcification.", | |
| "discriminatory_power": "Critical: Distinguishes MVA2/centrosomal etiology from standard pediatric sarcoma syndromes." | |
| }, | |
| { | |
| "feature": "Intrauterine Growth Restriction (IUGR, 1.0 kg)", | |
| "hpo": "HP:0001518", | |
| "mva_syndrome_match": "Pathognomonic (Severe primordial growth retardation)", | |
| "mva_genes": "BUB1B, CEP57, CENPE, CENPF, CEP192", | |
| "competing_syndromes": "Silver-Russell Syndrome (11p15), Meier-Gorlin Syndrome (ORC1), Seckel Syndrome (ATR)", | |
| "molecular_mechanism": "Systemic cellular attrition due to mitotic catastrophe and p53-mediated apoptosis in rapidly dividing embryonic stem cells.", | |
| "discriminatory_power": "High: Corroborates global embryonic cell cycle failure." | |
| }, | |
| { | |
| "feature": "Premature Delivery (32 Weeks)", | |
| "hpo": "HP:0001622", | |
| "mva_syndrome_match": "Consistent (Placental insufficiency & fetal distress)", | |
| "mva_genes": "BUB1B, CEP57", | |
| "competing_syndromes": "Maternal vascular malperfusion, Pre-eclampsia", | |
| "molecular_mechanism": "Aneuploid mosaicism within trophoblast and placental villi impair maternal-fetal gas and nutrient exchange.", | |
| "discriminatory_power": "Moderate: Supports placental aneuploid involvement." | |
| }, | |
| { | |
| "feature": "Parental Recurrent Miscarriages", | |
| "hpo": "HP:0200067", | |
| "mva_syndrome_match": "Strong (Familial segregation defect & meiotic instability)", | |
| "mva_genes": "BUB1B, TRIP13, MAD1L1", | |
| "competing_syndromes": "Balanced reciprocal translocations, Inversions, Antiphospholipid Syndrome", | |
| "molecular_mechanism": "Heterozygous carrier parents can exhibit subclinical meiotic chromosome missegregation, generating nonviable aneuploid zygotes resulting in recurrent first-trimester spontaneous abortions.", | |
| "discriminatory_power": "Very High: Points specifically to germline spindle checkpoint vulnerability." | |
| }, | |
| { | |
| "feature": "Skeletal Muscle Atrophy & Low Mass", | |
| "hpo": "HP:0003202", | |
| "mva_syndrome_match": "Consistent (Myoblast exhaustion & cachexia)", | |
| "mva_genes": "BUB1B, CENPF, MAD1L1", | |
| "competing_syndromes": "Spinal Muscular Atrophy (SMN1), Congenital Myopathies", | |
| "molecular_mechanism": "Impaired myoblast proliferative expansion during myogenesis combined with tumor-associated catabolic microenvironment.", | |
| "discriminatory_power": "Moderate: Secondary consequence of both syndromic myogenesis defect and sarcoma burden." | |
| } | |
| ] | |
| } |