| Domain | Established finding | Evidence/quantity | Suggested ontology |
|---|---|---|---|
| Disease name/definition | CHOPS syndrome is a multisystem developmental disorder named for cognitive impairment/coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia | Initially delineated in 3 unrelated probands; phenotype overlaps Cornelia de Lange syndrome spectrum but is molecularly distinct via AFF4 gain-of-function (pqac-00000001, pqac-00000006) | OMIM:616368; EFO:0009031; MONDO: unavailable/unverified |
| Synonyms | Cognitive impairment–coarse facies–heart defects–obesity–pulmonary involvement–short stature–skeletal dysplasia syndrome; CHOPS syndrome | Acronym-based syndrome name used in primary literature and disease-target resources (pqac-00000001, pqac-00000002) | Exact synonym mapping to disease record |
| Evidence source type | Knowledge is derived primarily from aggregated disease-level literature plus deep molecular analysis of patient-derived fibroblasts; not from large registry or trial datasets | 3 published probands in landmark study; fibroblast transcriptomics/ChIP-seq/cell-line functional assays (pqac-00000001, pqac-00000004, pqac-00000014, pqac-00000015) | ECO: human clinical evidence; in vitro functional evidence |
| Causal gene | AFF4 (ALF transcription elongation factor 4), core scaffold component of the super elongation complex (SEC) | Single established causal gene for classic CHOPS syndrome in available evidence (pqac-00000001, pqac-00000016) | HGNC: AFF4; NCBI Gene/Ensembl gene record |
| Pathogenic variants | Recurrent de novo missense variants in the degron/ALF homology region: c.760A>G (p.Thr254Ala), c.761C>G (p.Thr254Ser), c.772C>T (p.Arg258Trp) | 3/3 probands had heterozygous de novo missense variants; all affected highly conserved residues (pqac-00000001, pqac-00000012) | Sequence Ontology: missense_variant |
| Inheritance | Autosomal dominant disorder usually arising de novo | Variants absent in all 6 biological parents in the discovery cohort; no inherited multigeneration pedigree established (pqac-00000001, pqac-00000003) | HP:0000006 Autosomal dominant inheritance; HP:0025352 De novo mutation |
| Molecular class/mechanism | Gain-of-function caused by impaired SIAH1-mediated ubiquitin/proteasome degradation of AFF4 | Mutant AFF4 resists degradation and behaves opposite to AFF4 knockdown/LoF models (pqac-00000004, pqac-00000010, pqac-00000012) | GO: positive regulation of transcription by RNA polymerase II; GO: protein ubiquitination |
| Causal chain | Degron-region AFF4 missense mutation → reduced SIAH1 binding/degradation → chromatin-associated AFF4 accumulation → altered SEC activity and RNAP2 pause-release/elongation → altered cohesin/RNAP2 genome-wide binding → developmental transcriptional dysregulation → multisystem phenotype | Supported by patient fibroblasts, overexpression systems, transcriptomics, and ChIP-seq (pqac-00000004, pqac-00000005, pqac-00000009, pqac-00000010, pqac-00000013, pqac-00000017) | GO: protein stabilization; GO: chromatin binding; GO: transcription elongation by RNA polymerase II |
| Core phenotype: cognitive/developmental | Cognitive impairment/intellectual disability/developmental delay | Present across all 3 index cases as core naming feature (pqac-00000001, pqac-00000003) | HP:0100543 Cognitive impairment; HP:0001249 Intellectual disability |
| Core phenotype: facial | Coarse facies/dysmorphic facial features | Core naming feature; dysmorphic/coarse facial appearance reported in all 3 probands (pqac-00000001, pqac-00000003) | HP:0000280 Coarse facial features |
| Core phenotype: cardiac | Congenital heart disease, especially PDA and/or VSD | Cardiac defects in all 3 probands; PDA reported in 3/3, VSD in 2/3 from available case descriptions (pqac-00000003) | HP:0001644 Congenital heart defect; HP:0001643 Patent ductus arteriosus; HP:0001629 Ventricular septal defect |
| Core phenotype: obesity | Obesity/abnormal weight gain | Common syndrome-defining feature; described in all 3 probands and considered a core component of the acronym (pqac-00000001, pqac-00000003, pqac-00000005) | HP:0001513 Obesity |
| Core phenotype: pulmonary/airway | Chronic lung disease/airway involvement including tracheomalacia, laryngomalacia, subglottic-tracheal stenosis | Pulmonary involvement in 3/3 probands; chronic lung disease noted as universal in initial cohort (pqac-00000003, pqac-00000005) | HP:0002093 Respiratory insufficiency; HP:0002783 Tracheomalacia; HP:0001600 Laryngomalacia |
| Core phenotype: growth/skeletal | Short stature and skeletal dysplasia with vertebral anomalies, kyphoscoliosis, brachydactyly | Short stature and brachydactyly in all 3; vertebral/skeletal anomalies in multiple probands (pqac-00000003) | HP:0004322 Short stature; HP:0001156 Brachydactyly; HP:0002650 Scoliosis; HP:0000929 Abnormality of the vertebral column |
| Additional phenotypes | Gastroesophageal reflux, constipation, hearing loss, horseshoe kidney, cryptorchidism, cataracts | Present in subsets rather than all cases; evidence remains case-based (pqac-00000003, pqac-00000021) | HP:0002020 Gastroesophageal reflux; HP:0002019 Constipation; HP:0000084 Horseshoe kidney; HP:0000028 Cryptorchidism; HP:0000518 Cataract |
| Age/onset/course | Congenital or early-childhood onset developmental disorder with chronic multisystem manifestations | Discovery cases were pediatric/developmental presentations; no formal staging system or long-term natural history study identified (pqac-00000001, pqac-00000003) | HP:0003577 Congenital onset |
| Key cell/tissue systems | Brain/neurodevelopment, craniofacial tissues, heart, airway/lung, skeleton, gastrointestinal tract, kidney, gonads, eye | Multisystem developmental syndrome inferred from human phenotype distribution; mechanistic studies mainly in dermal fibroblasts (pqac-00000003, pqac-00000014, pqac-00000015) | UBERON: brain, heart, lung, vertebral column; CL: fibroblast |
| Omics evidence | Patient fibroblast transcriptomics showed 288 downregulated and 445 upregulated genes in one analysis; RNA-seq identified 519 differentially expressed genes in CHOPS samples | Disease-relevant direct targets include MYC, JUN, TMEM100, ZNF711, FAM13C; direct AFF4 targets upregulated by 9–127% (mean 48.9%) (pqac-00000004, pqac-00000015) | GO: embryonic organ development; GO: skeletal system development |
| Chromatin evidence | ChIP-seq showed altered genome-wide binding of AFF4, cohesin, and RNAP2 with AFF4 accumulation around TSS/gene regions and excess chromatin-associated AFF4 | Mechanistic link to SEC–cohesin–RNAP2 dysregulation supported in patient cells (pqac-00000005, pqac-00000007, pqac-00000013) | GO: chromatin organization; GO: RNA polymerase II CTD phosphorylation |
| Differential diagnosis | Cornelia de Lange syndrome and related disorders of transcriptional regulation/cohesinopathy spectrum | Overlapping phenotype and partially shared transcriptomic signature, but CHOPS is distinguished by AFF4 GOF rather than classic cohesin-gene LoF (pqac-00000001, pqac-00000006, pqac-00000017) | MONDO/CdLS spectrum cross-reference |
| Diagnosis | Molecular diagnosis is best established by exome/genome sequencing or targeted AFF4 analysis in a patient with CdLS-like features plus obesity/pulmonary involvement/short stature-skeletal findings | Discovery was by exome sequencing; no disease-specific biochemical biomarker or formal consensus criteria identified (pqac-00000001, pqac-00000003) | NCIT: Whole Exome Sequencing; NCIT: Molecular Genetic Testing |
| Treatment status | No disease-modifying or targeted CHOPS therapy established; management is supportive and organ-specific | No relevant CHOPS interventional trials identified; care inferred from phenotype burden rather than syndrome-specific evidence (pqac-00000021) | NCIT: Supportive Care; NCIT: Physical Therapy; NCIT: Cardiology Referral; NCIT: Pulmonology Referral |
| Prevention/genetic counseling | Primary prevention not established; recurrence risk generally low when variant is de novo, but standard counseling should address possible germline mosaicism uncertainty | No CHOPS-specific recurrence studies or prevention trials found (pqac-00000001) | NCIT: Genetic Counseling |
| Epidemiology | Extremely rare; prevalence and incidence not established | Only a handful of published patients identified in available literature; no population-based estimate (pqac-00000001) | Orphan disease epidemiology field: unknown |
| Prognosis | Long-term survival, life expectancy, and prognostic factors are unknown | No longitudinal cohort, survival analysis, or validated prognostic biomarker identified (pqac-00000001, pqac-00000003) | Prognosis field: unknown |
| Environment/risk modifiers | No established environmental, lifestyle, infectious, or protective factors | Current evidence supports primary monogenic etiology without defined gene-environment interaction data (pqac-00000001) | Exposure ontology: not established |
| Model/functional systems | Main disease models are patient-derived fibroblasts and transfected cell lines; Aff4 knockout differs phenotypically from CHOPS, supporting GOF; an ENU Aff1 mouse with related degron mechanism is supportive but indirect | Functional evidence is strong for cellular mechanism, limited for organismal CHOPS-specific modeling (pqac-00000010, pqac-00000012) | CL: fibroblast; model type: in vitro human cell model |
| Recent developments (2023–2024) | Recent work strengthens the SEC/cohesin pause-release framework relevant to CHOPS: AFF4 shown to have distinct TSS-proximal elongation roles, and cohesin depletion increases SEC recruitment and reduces RNAP2 pausing | Mechanistic context from 2023 AFF1/AFF4 SEC study and 2024 cohesin/SEC preprint supports the CHOPS pathogenic model, though not CHOPS-patient cohorts directly (pqac-00000019, pqac-00000020, pqac-00000017) | GO: promoter-proximal RNA polymerase II pausing; GO: transcription elongation |
| Evidence gaps | No validated MONDO ID confirmed here, no syndrome-specific trials, no robust prevalence, no natural-history registry, no single-cell/spatial/proteomic/metabolomic datasets, and no known natural disease in other species | Important for knowledge-base curation to mark as unavailable rather than absent disease biology (pqac-00000001, pqac-00000017) | Evidence status annotation: not available/unverified |


*Table: This table condenses the highest-confidence knowledge-base fields for CHOPS syndrome, including identifiers, causal AFF4 variants, mechanism, key phenotypes, diagnostic approach, and major evidence gaps. It is designed for rapid downstream curation into a structured rare-disease entry.*