CHOPS Syndrome: Comprehensive Disease-Characteristics Report

Evidence cutoff: literature and database searches emphasized 2023–2024 research, while retaining the foundational 2015 disease-discovery study. CHOPS syndrome is exceptionally rare: most disease-specific conclusions still rest on three deeply characterized index patients. Accordingly, fractions such as 3/3 describe that discovery cohort and must not be interpreted as population prevalence.

Executive summary

CHOPS syndrome is a congenital, multisystem disorder of developmental transcription caused by heterozygous gain-of-function missense variants in the degron region of AFF4, a scaffold of the super elongation complex (SEC). The defining phenotype comprises cognitive impairment and coarse facies, heart defects, obesity, pulmonary involvement, and short stature with skeletal dysplasia. The three original variants—NM_014423.4:c.760A>G (p.Thr254Ala), c.761C>G (p.Thr254Ser), and c.772C>T (p.Arg258Trp)—were de novo in three unrelated individuals. Mutant AFF4 resists SIAH1-mediated proteasomal degradation, accumulates on chromatin, and dysregulates SEC-dependent RNA-polymerase-II (Pol II) pause release and transcriptional elongation. Altered AFF4, cohesin, and Pol II occupancy provides a mechanistic explanation for overlap with Cornelia de Lange syndrome (CdLS). (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 4-6, izumi2015germlinegainoffunctionmutations pages 8-10)

No CHOPS-specific natural-history cohort, prevalence estimate, formal diagnostic criteria, disease-modifying treatment, or interventional trial was identified. Diagnosis is molecular, generally through exome/genome sequencing or targeted AFF4 analysis, and care is supportive and organ-directed.

The following structured summary is suitable for knowledge-base ingestion.

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.

1. Disease information

Definition and identifiers

• Preferred name: CHOPS syndrome.
• Expanded name/synonym: Cognitive impairment–coarse facies–heart defects–obesity–pulmonary involvement–short stature–skeletal dysplasia syndrome.
• OMIM: 616368.
• EFO/Open Targets: EFO_0009031; Open Targets associates this entity with one established target, AFF4 (ENSG00000072364), supported principally by PMID 25730767. (OpenTargets Search: CHOPS syndrome-AFF4)
• MONDO: A definitive current MONDO identifier was not established by the retrieved evidence; it should be marked unverified, not guessed. Open Targets separately displays “Cornelia de Lange syndrome 6” as MONDO_0957921, but that label should not automatically be substituted for CHOPS without ontology-level verification. (OpenTargets Search: CHOPS syndrome-AFF4)
• Orphanet, MeSH, ICD-10/ICD-11: No disease-specific identifiers were verified. Clinical coding will usually require broader congenital-malformation, neurodevelopmental, or genetic-syndrome codes.

The landmark report was Izumi et al., Nature Genetics, online March 2015, volume 47:338–344; PMID 25730767, DOI 10.1038/ng.3229. Its abstract states: “Using exome sequencing, we discovered missense mutations in AFF4…in three unrelated probands with a new syndrome…that we have named CHOPS syndrome.” The evidence is aggregated disease-level literature derived from individually phenotyped patients and patient-derived cells, not population EHR statistics. (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 1-3)

2. Etiology, risk, and protective factors

The necessary and currently established cause is a germline heterozygous gain-of-function AFF4 variant affecting a narrow, highly conserved degron/ALF-homology region. All three original variants were absent from all six tested biological parents, establishing de novo occurrence in that cohort. (izumi2015germlinegainoffunctionmutations pages 3-4)

• Genetic risk: A pathogenic activating/degradation-resistant AFF4 allele. No susceptibility loci, modifier genes, founder variants, or polygenic risk scores are established.
• Environmental, lifestyle, occupational, or infectious risk: None established. These factors are not considered primary causes.
• Protective factors: No genetic or environmental protective factors have been reported.
• Gene–environment interaction: Unknown. Obesity may be modified by food intake and activity, but no CHOPS-specific interaction study supports such an effect.
• Family history: Usually negative because known cases arose de novo. A negative family history does not reduce suspicion.

3. Phenotypes

The phenotype begins prenatally or in early childhood and is chronic. Frequencies below are descriptive of the three index cases.

• Neurodevelopment: Cognitive impairment/intellectual disability and developmental delay were shared features (3/3). Severity was clinically meaningful but not quantified by standardized IQ or adaptive-function scales. Suggested terms: HP:0100543 Cognitive impairment, HP:0001249 Intellectual disability, HP:0001263 Global developmental delay. (izumi2015germlinegainoffunctionmutations pages 15-18)
• Craniofacial: Coarse/dysmorphic facial appearance occurred in all index patients. Suggested term: HP:0000280 Coarse facial features. (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 15-18)
• Growth/metabolic: Short stature, obesity, and brachydactyly were shared findings (3/3). Obesity may emerge during childhood; the original authors proposed altered appetite regulation because AFF4 is expressed in hypothalamus, but this remains a hypothesis rather than a demonstrated metabolic pathway. Suggested terms: HP:0004322 Short stature, HP:0001513 Obesity, HP:0001156 Brachydactyly. (izumi2015germlinegainoffunctionmutations pages 15-18, izumi2015germlinegainoffunctionmutations pages 8-10)
• Cardiac: Patent ductus arteriosus was reported in 3/3 and ventricular septal defect in 2/3. Suggested terms: HP:0001643 Patent ductus arteriosus, HP:0001629 Ventricular septal defect, HP:0001627 Abnormal heart morphology. (izumi2015germlinegainoffunctionmutations pages 15-18, piche2019theexpandingphenotypes pages 7-9)
• Pulmonary/upper airway: Pulmonary involvement or chronic lung disease affected all three. Individual manifestations included tracheomalacia, laryngomalacia, narrow oropharynx, and subglottic/tracheal stenosis. Suggested terms: HP:0002783 Tracheomalacia, HP:0001600 Laryngomalacia, HP:0002093 Respiratory insufficiency, and the appropriate HPO stenosis term after clinical confirmation. (izumi2015germlinegainoffunctionmutations pages 15-18, izumi2015germlinegainoffunctionmutations pages 8-10)
• Skeletal: Vertebral abnormalities, kyphoscoliosis, and brachydactyly were reported; severity varies. Suggested terms: HP:0000929 Abnormality of the vertebral column, HP:0002751 Kyphoscoliosis, HP:0002650 Scoliosis, HP:0001156 Brachydactyly. (izumi2015germlinegainoffunctionmutations pages 15-18)
• Gastrointestinal: Gastroesophageal reflux and constipation are reported manifestations. Suggested terms: HP:0002020 Gastroesophageal reflux, HP:0002019 Constipation. (piche2019theexpandingphenotypes pages 7-9)
• Other variable findings: Horseshoe kidney (HP:0000085), cryptorchidism (HP:0000028), hearing loss (HP:0000365), and cataracts (HP:0000518) occurred in individual patients. (izumi2015germlinegainoffunctionmutations pages 15-18)

No CHOPS-specific EQ-5D, SF-36, PROMIS, or caregiver-burden study exists. Nevertheless, developmental disability, respiratory disease, congenital heart disease, skeletal restriction, and communication/motor limitations plausibly impose substantial lifelong effects on schooling, independence, mobility, and caregiver burden; these are clinical inferences rather than measured syndrome-specific outcomes.

4. Genetic and molecular information

AFF4—ALF transcription elongation factor 4, Ensembl ENSG00000072364—is the only established causal gene. The original variants are heterozygous missense substitutions: c.760A>G/p.Thr254Ala, c.761C>G/p.Thr254Ser, and c.772C>T/p.Arg258Trp. They affect highly conserved residues and were germline/de novo, not somatic. (izumi2015germlinegainoffunctionmutations pages 3-4, OpenTargets Search: CHOPS syndrome-AFF4)

The functional classification is gain of function through protein stabilization, not haploinsufficiency. Mutants resist SIAH1-dependent ubiquitination/proteasomal turnover and accumulate particularly in chromatin fractions. Phenotypic differences between CHOPS patients, AFF4 genomic deletions, and Aff4-knockout mice further argue against simple loss of function. (izumi2015germlinegainoffunctionmutations pages 6-8, OpenTargets Search: CHOPS syndrome-AFF4)

Population frequencies were not supplied in the retrieved primary text. For clinical curation, current gnomAD absence or extreme rarity should be checked against the exact transcript/build at interpretation time; absence alone is insufficient because the mechanism and tight positional clustering are critical. ClinVar classifications should likewise be retrieved contemporaneously. No validated modifier gene, disease-specific DNA-methylation episignature, pathogenic structural variant, repeat expansion, mitochondrial variant, or somatic mosaic mechanism has been established.

5. Environmental information

No toxin, radiation, pollution, occupation, diet, smoking, alcohol exposure, exercise pattern, or pathogen has been shown to cause or trigger CHOPS syndrome. Environmental management may influence secondary obesity, cardiopulmonary fitness, reflux, and constipation, but it cannot reverse the congenital AFF4 variant. There is no infectious or zoonotic component.

6. Mechanism and pathophysiology

Causal chain

1. A missense change alters the AFF4 degron/ALF-homology region.
2. Mutant AFF4 interacts inadequately with the SIAH1 degradation machinery and becomes resistant to ubiquitin-dependent proteasomal clearance.
3. Stabilized AFF4 accumulates on chromatin as part of the SEC, whose other components include ELL/ELL2 and P-TEFb (CDK9–cyclin T1).
4. Excess SEC perturbs promoter-proximal Pol II pause release and productive elongation, including altered Ser2-phosphorylated Pol II distribution.
5. Genome-wide AFF4, cohesin/RAD21, SPT5, and Pol II occupancy changes produce developmental transcriptional dysregulation.
6. Misexpression of developmental, skeletal, extracellular-matrix, and immediate-early genes leads to the multisystem phenotype. (izumi2015germlinegainoffunctionmutations pages 4-6, izumi2015germlinegainoffunctionmutations pages 6-8, izumi2016disordersoftranscriptional pages 9-10, izumi2015germlinegainoffunctionmutations pages 1-3)

In patient fibroblasts, one analysis identified 288 downregulated and 445 upregulated genes. Direct AFF4 targets increased 9–127% (mean 48.9%), including MYC, JUN, TMEM100, ZNF711, and FAM13C. Upregulated sets were enriched for homeobox proteins, skeletal-system development, anterior–posterior patterning, and embryonic-organ development; downregulated sets included actin-binding and extracellular-matrix genes. A separately described RNA-seq analysis reported 519 differentially expressed genes. (izumi2015germlinegainoffunctionmutations pages 4-6, izumi2015germlinegainoffunctionmutations pages 11-13)

The primary experimental systems were patient dermal fibroblasts, hTERT-immortalized fibroblasts, HEK293T overexpression assays, and HeLa lysates. Methods included microarray, RNA-seq, qRT-PCR, western blotting, protein interaction assays, and ChIP-seq. This is strong cellular functional evidence, but it does not identify a single affected embryonic cell lineage. (izumi2015germlinegainoffunctionmutations pages 18-22, izumi2015germlinegainoffunctionmutations pages 10-11, izumi2015germlinegainoffunctionmutations pages 11-13)

Recent mechanistic developments

A peer-reviewed 2023 study showed that AFF1 and AFF4 are not interchangeable SEC scaffolds: approximately 74% of AFF4 peaks localized at Pol-II-bound transcription start sites, with AFF4 enriched downstream of the TSS and traveling into highly transcribed gene bodies. AFF4 depletion caused slow elongation/early termination in a subset of bound genes, refining why stabilized AFF4 can distort developmental transcription. Che et al., accepted July 31, 2023, DOI 10.1093/jmcb/mjad049. This was general cell-line biology, not a CHOPS patient cohort. (che2023distinctrolesof pages 2-3, che2023distinctrolesof pages 1-2)

A March 16, 2024 bioRxiv preprint found that acute cohesin depletion reduced promoter Pol II binding and pausing while increasing SEC recruitment; SEC inhibition abolished the pausing reduction. This supports a model in which cohesin normally limits SEC access to promoters. The study used RAD21/SMC1A degron-engineered HCT116 cells, nascent-RNA sequencing, ChIP-seq, and the experimental SEC inhibitor KL-1; it is mechanistically relevant but was not peer reviewed in the retrieved 2024 version and is not therapeutic evidence for CHOPS. DOI 10.1101/2024.03.15.584908. (tei2024cohesinregulatespromoterproximal pages 1-3, tei2024cohesinregulatespromoterproximal pages 14-17)

Suggested annotations include GO:0006368 transcription elongation by RNA polymerase II, GO:0006357 regulation of transcription by RNA polymerase II, protein ubiquitination/proteasomal catabolism, chromatin binding, embryonic organ development, skeletal-system development, and anterior–posterior pattern specification. Relevant cellular compartments are nucleus/chromatin; suggested cell term for the directly assayed human system is CL:0000057 fibroblast. No CHOPS-specific immune, metabolic, lipidomic, metabolomic, single-cell, spatial-transcriptomic, or multi-omic signature has been reported.

7. Anatomical structures affected

Primary systems include the developing central nervous system, craniofacial complex, heart, upper airway/lung, axial and appendicular skeleton, and growth-regulatory tissues. Variable secondary involvement includes gastrointestinal tract, kidney, testes, ear, and lens. Suggested UBERON mappings include brain (UBERON:0000955), heart (UBERON:0000948), lung (UBERON:0002048), trachea (UBERON:0003126), vertebral column (UBERON:0001130), kidney (UBERON:0002113), and eye (UBERON:0000970). Mechanistic localization is nuclear/chromatin-associated rather than mitochondrial, lysosomal, or extracellular. No consistent lateralization has been reported. (izumi2015germlinegainoffunctionmutations pages 15-18, izumi2015germlinegainoffunctionmutations pages 8-10)

8. Temporal development

CHOPS is a congenital/early-childhood developmental disorder with chronic, lifelong manifestations. Heart defects, dysmorphism, airway malacia/stenosis, vertebral anomalies, and growth disturbance may be evident at birth or infancy; developmental impairment becomes clearer with age, and obesity may emerge later. No validated early/intermediate/advanced staging system, remission pattern, progression rate, or critical therapeutic window exists. Early infancy is nevertheless clinically important for detecting airway obstruction, chronic lung disease, feeding/reflux problems, and congenital heart lesions.

9. Inheritance and population

Inheritance is best described as autosomal dominant, usually de novo. Both sexes were affected in the original cohort—two females and one male. Penetrance appears high for proven degron-region activating variants, but the sample is too small to estimate penetrance statistically. Expressivity is variable, particularly for cardiac, airway, renal, genital, auditory, and ocular findings. Anticipation, founder effects, consanguinity effects, carrier frequency, and ethnic/geographic enrichment are unknown. Germline mosaicism has not been demonstrated but cannot be excluded in counseling. (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 15-18)

Neither incidence nor prevalence per 100,000 is known. Published case counts cannot yield a defensible prevalence because ascertainment and molecular testing are incomplete. The condition should be classified as ultra-rare.

10. Diagnostics

There are no consensus clinical criteria or diagnostic biochemical biomarkers. Suspicion should arise in a child with developmental impairment/coarse facies plus the combination of obesity, short stature, skeletal/vertebral abnormalities, congenital heart disease, and chronic pulmonary or structural airway disease—especially when CdLS testing is negative.

Recommended molecular workflow:

1. Trio whole-exome or genome sequencing with phenotype-driven analysis of AFF4, including careful review of missense variants near residues Thr254–Arg258.
2. Confirm by an orthogonal method and test both parents to establish de novo status.
3. If sequencing is nondiagnostic, consider CNV analysis, genome reanalysis, mosaic calling, and broader developmental-disorder/CdLS-like panels. CMA detects large CNVs but will miss the known single-nucleotide variants; karyotype/FISH are not first-line tests.
4. Functional testing—protein stability, chromatin fractionation, or transcriptomic/ChIP-seq studies—remains research-level rather than routine.

Baseline clinical evaluation should include echocardiography/ECG, pulmonology and ENT airway assessment, oxygenation and sleep evaluation as indicated, spine/limb radiographs, hearing and ophthalmic examinations, renal ultrasound, growth/BMI and nutrition assessment, and developmental, speech, motor, feeding, and behavioral evaluation. These recommendations are phenotype-directed expert practice rather than a validated CHOPS guideline.

Principal differentials include classic/nonclassic CdLS (NIPBL, SMC1A, SMC3, RAD21, HDAC8) and other disorders of transcriptional regulation involving AFF3, BRD4, ANKRD11, EP300, TAF1, and related chromatin genes. CHOPS is distinguished molecularly by an activating AFF4 degron variant; clinically, obesity and prominent pulmonary/airway disease may be useful clues. Shared AFF4/cohesin/Pol-II dysregulation explains the overlap rather than making the diseases identical. (izumi2015germlinegainoffunctionmutations pages 1-3, tei2024cohesinregulatespromoterproximal pages 1-3, piche2019theexpandingphenotypes pages 7-9)

Population newborn screening, biochemical carrier screening, repeat-expansion testing, mitochondrial testing, liquid biopsy, and prenatal ultrasound criteria are not established.

11. Outcome and prognosis

There are no survival curves, mortality rates, life-expectancy estimates, validated prognostic scores, or prognostic biomarkers. Morbidity is likely driven by developmental disability, chronic airway/lung disease, congenital heart disease, orthopedic deformity, obesity, reflux/constipation, and sensory deficits. Recovery from the underlying developmental syndrome is not expected, although individual complications may improve with treatment. The small literature does not justify claims about normal or shortened lifespan.

12. Treatment and current applications

No approved disease-modifying pharmacotherapy, AFF4-directed treatment, gene therapy, ASO/siRNA therapy, cell therapy, or genotype-specific clinical pathway exists. ClinicalTrials.gov searches identified no relevant CHOPS interventional trial. Management is therefore multidisciplinary and symptom-directed:

• cardiology surveillance and repair/intervention for hemodynamically significant PDA/VSD;
• pulmonology, ENT, sleep medicine, airway-clearance support, oxygen/ventilatory support, or airway surgery according to anatomy and physiology;
• nutrition and feeding therapy, reflux and constipation treatment, and individualized obesity management;
• physical and occupational therapy, speech/language and augmentative-communication services, educational supports, and developmental pediatrics;
• orthopedic monitoring for vertebral deformity/kyphoscoliosis and mobility impairment;
• audiology, ophthalmology, nephrology/urology, and endocrinology referrals when indicated.

Suggested NCIt concepts include Supportive Care, Physical Therapy, Occupational Therapy, Speech Therapy, Genetic Counseling, Cardiac Surgery, and Airway Management, with exact codes verified against the current NCIt release.

SEC inhibitors such as KL-1 can alter SEC activity experimentally, but global transcriptional elongation is fundamental to normal cells. The available data neither establish a safe therapeutic window nor support off-label use in CHOPS. (tei2024cohesinregulatespromoterproximal pages 14-17, che2023distinctrolesof pages 2-3)

13. Prevention

Primary prevention through lifestyle modification, vaccination, or exposure avoidance is not applicable to a usually de novo monogenic disorder. Secondary prevention consists of prompt molecular diagnosis and early surveillance for airway, pulmonary, cardiac, feeding, developmental, orthopedic, and sensory complications. Tertiary prevention includes respiratory and cardiac management, obesity prevention, reflux/constipation care, therapy services, mobility support, and educational accommodations.

Genetic counseling should explain autosomal-dominant causation, usually de novo occurrence, uncertainty from possible parental germline mosaicism, and a 50% transmission risk for an affected individual’s future pregnancies if reproductive fitness permits. When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are technically possible. CHOPS is not part of routine newborn or population carrier screening.

14. Other species and natural disease

No naturally occurring CHOPS-equivalent veterinary disease, affected breed, zoonotic transmission, or cross-species infectious susceptibility was identified. Orthologous AFF-family proteins and the SEC/proteasomal mechanism are evolutionarily conserved, but conservation should not be conflated with a naturally occurring animal syndrome.

15. Model organisms and experimental systems

The best disease-relevant models are human patient-derived dermal fibroblasts carrying p.Thr254Ala, p.Thr254Ser, or p.Arg258Trp and engineered HEK293T/HeLa systems. These reproduce AFF4 stabilization, chromatin accumulation, downstream target activation, and altered AFF4/cohesin/Pol-II occupancy. (izumi2015germlinegainoffunctionmutations pages 18-22, izumi2015germlinegainoffunctionmutations pages 10-11, izumi2015germlinegainoffunctionmutations pages 11-13)

Aff4-knockout mice have phenotypes unlike CHOPS, an important limitation that supports gain-of-function rather than loss-of-function pathogenesis. An ENU-induced mouse mutation in the homologous degron mechanism of Aff1 provides indirect evidence that altered degradation of AF4/FMR2-family proteins is pathogenic, but it is not a CHOPS knock-in model. (izumi2015germlinegainoffunctionmutations pages 6-8, izumi2015germlinegainoffunctionmutations pages 3-4)

No validated AFF4-CHOPS knock-in mouse, rat, zebrafish, Drosophila, organoid, or patient-derived iPSC model was identified. Priorities for the field are precise p.Thr254/p.Arg258 knock-in models, neural-crest/cardiopulmonary/skeletal organoids, longitudinal registries, and single-cell or spatial profiling during differentiation.

Evidence assessment and research priorities

The causal inference is strong despite the tiny cohort because three unrelated patients had clustered de novo variants and concordant cellular gain-of-function effects. The major weakness is external validity: penetrance, full phenotypic range, variant-specific severity, survival, and treatment outcomes remain unresolved. The most consequential next steps are international case aggregation, standardized HPO phenotyping, natural-history follow-up, contemporary ClinVar/gnomAD reconciliation, development of precise knock-in models, and testing whether AFF4 normalization can be achieved without broadly suppressing essential SEC-dependent transcription.

Principal references

1. Izumi K, et al. Germline Gain-of-Function Mutations in AFF4 Cause a Developmental Syndrome Functionally Linking the Super Elongation Complex and Cohesin. Nature Genetics. Published March 2015;47:338–344. PMID: 25730767. DOI: 10.1038/ng.3229. (izumi2015germlinegainoffunctionmutations pages 3-4)
2. Izumi K. Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes. Molecular Syndromology. Published September 2016;7:262–273. DOI: 10.1159/000448747. (izumi2016disordersoftranscriptional pages 9-10)
3. Piché J, et al. The expanding phenotypes of cohesinopathies: one ring to rule them all! Cell Cycle. Published September 2019;18:2828–2848. DOI: 10.1080/15384101.2019.1658476. (piche2019theexpandingphenotypes pages 7-9)
4. Che Z, et al. Distinct roles of two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA polymerase II transcription elongation. Journal of Molecular Cell Biology. Accepted July 31, 2023;15(8):mjad049. DOI: 10.1093/jmcb/mjad049. (che2023distinctrolesof pages 1-2)
5. Tei S, et al. Cohesin regulates promoter-proximal pausing of RNA Polymerase II by limiting recruitment of super elongation complex. bioRxiv preprint posted March 16, 2024. DOI: 10.1101/2024.03.15.584908. (tei2024cohesinregulatespromoterproximal pages 1-3)

References

1. (izumi2015germlinegainoffunctionmutations pages 3-4): Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, and Ian D Krantz. Germline gain-of-function mutations in aff4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics, 47:338-344, Mar 2015. URL: https://doi.org/10.1038/ng.3229, doi:10.1038/ng.3229. This article has 173 citations and is from a highest quality peer-reviewed journal.

2. (izumi2015germlinegainoffunctionmutations pages 4-6): Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, and Ian D Krantz. Germline gain-of-function mutations in aff4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics, 47:338-344, Mar 2015. URL: https://doi.org/10.1038/ng.3229, doi:10.1038/ng.3229. This article has 173 citations and is from a highest quality peer-reviewed journal.

3. (izumi2015germlinegainoffunctionmutations pages 8-10): Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, and Ian D Krantz. Germline gain-of-function mutations in aff4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics, 47:338-344, Mar 2015. URL: https://doi.org/10.1038/ng.3229, doi:10.1038/ng.3229. This article has 173 citations and is from a highest quality peer-reviewed journal.

4. (izumi2015germlinegainoffunctionmutations pages 1-3): Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, and Ian D Krantz. Germline gain-of-function mutations in aff4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics, 47:338-344, Mar 2015. URL: https://doi.org/10.1038/ng.3229, doi:10.1038/ng.3229. This article has 173 citations and is from a highest quality peer-reviewed journal.

5. (OpenTargets Search: CHOPS syndrome-AFF4): Open Targets Query (CHOPS syndrome-AFF4, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

6. (izumi2015germlinegainoffunctionmutations pages 10-11): Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, and Ian D Krantz. Germline gain-of-function mutations in aff4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics, 47:338-344, Mar 2015. URL: https://doi.org/10.1038/ng.3229, doi:10.1038/ng.3229. This article has 173 citations and is from a highest quality peer-reviewed journal.

7. (izumi2015germlinegainoffunctionmutations pages 11-13): Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, and Ian D Krantz. Germline gain-of-function mutations in aff4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics, 47:338-344, Mar 2015. URL: https://doi.org/10.1038/ng.3229, doi:10.1038/ng.3229. This article has 173 citations and is from a highest quality peer-reviewed journal.

8. (izumi2015germlinegainoffunctionmutations pages 15-18): Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, and Ian D Krantz. Germline gain-of-function mutations in aff4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics, 47:338-344, Mar 2015. URL: https://doi.org/10.1038/ng.3229, doi:10.1038/ng.3229. This article has 173 citations and is from a highest quality peer-reviewed journal.

9. (izumi2015germlinegainoffunctionmutations pages 6-8): Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, and Ian D Krantz. Germline gain-of-function mutations in aff4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics, 47:338-344, Mar 2015. URL: https://doi.org/10.1038/ng.3229, doi:10.1038/ng.3229. This article has 173 citations and is from a highest quality peer-reviewed journal.

10. (izumi2016disordersoftranscriptional pages 9-10): Kosuke Izumi. Disorders of transcriptional regulation: an emerging category of multiple malformation syndromes. Molecular Syndromology, 7:262-273, Sep 2016. URL: https://doi.org/10.1159/000448747, doi:10.1159/000448747. This article has 69 citations and is from a peer-reviewed journal.

11. (tei2024cohesinregulatespromoterproximal pages 1-3): Shoin Tei, Toyonori Sakata, Atsunori Yoshimura, Toyoaki Natsume, Masato T Kanemaki, Masashige Bando, and Katsuhiko Shirahige. Cohesin regulates promoter-proximal pausing of rna polymerase ii by limiting recruitment of super elongation complex. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.15.584908, doi:10.1101/2024.03.15.584908. This article has 3 citations.

12. (piche2019theexpandingphenotypes pages 7-9): Jessica Piché, Patrick Piet Van Vliet, Michel Pucéat, and Gregor Andelfinger. The expanding phenotypes of cohesinopathies: one ring to rule them all! Cell Cycle, 18:2828-2848, Sep 2019. URL: https://doi.org/10.1080/15384101.2019.1658476, doi:10.1080/15384101.2019.1658476. This article has 121 citations and is from a peer-reviewed journal.

13. (izumi2015germlinegainoffunctionmutations pages 18-22): Kosuke Izumi, Ryuichiro Nakato, Zhe Zhang, Andrew C Edmondson, Sarah Noon, Matthew C Dulik, Ramakrishnan Rajagopalan, Charles P Venditti, Karen Gripp, Joy Samanich, Elaine H Zackai, Matthew A Deardorff, Dinah Clark, Julian L Allen, Dale Dorsett, Ziva Misulovin, Makiko Komata, Masashige Bando, Maninder Kaur, Yuki Katou, Katsuhiko Shirahige, and Ian D Krantz. Germline gain-of-function mutations in aff4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nature genetics, 47:338-344, Mar 2015. URL: https://doi.org/10.1038/ng.3229, doi:10.1038/ng.3229. This article has 173 citations and is from a highest quality peer-reviewed journal.

14. (che2023distinctrolesof pages 2-3): Zhuanzhuan Che, Xiaoxu Liu, Qian Dai, Ke Fang, Chenghao Guo, Junjie Yue, Haitong Fang, Peng Xie, Zhuojuan Luo, and Chengqi Lin. Distinct roles of two sec scaffold proteins, aff1 and aff4, in regulating rna polymerase ii transcription elongation. Journal of Molecular Cell Biology, Aug 2023. URL: https://doi.org/10.1093/jmcb/mjad049, doi:10.1093/jmcb/mjad049. This article has 8 citations and is from a peer-reviewed journal.

15. (che2023distinctrolesof pages 1-2): Zhuanzhuan Che, Xiaoxu Liu, Qian Dai, Ke Fang, Chenghao Guo, Junjie Yue, Haitong Fang, Peng Xie, Zhuojuan Luo, and Chengqi Lin. Distinct roles of two sec scaffold proteins, aff1 and aff4, in regulating rna polymerase ii transcription elongation. Journal of Molecular Cell Biology, Aug 2023. URL: https://doi.org/10.1093/jmcb/mjad049, doi:10.1093/jmcb/mjad049. This article has 8 citations and is from a peer-reviewed journal.

16. (tei2024cohesinregulatespromoterproximal pages 14-17): Shoin Tei, Toyonori Sakata, Atsunori Yoshimura, Toyoaki Natsume, Masato T Kanemaki, Masashige Bando, and Katsuhiko Shirahige. Cohesin regulates promoter-proximal pausing of rna polymerase ii by limiting recruitment of super elongation complex. bioRxiv, Mar 2024. URL: https://doi.org/10.1101/2024.03.15.584908, doi:10.1101/2024.03.15.584908. This article has 3 citations.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.