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Classifications

Harrison's Part

👪

Inheritance

1

Autosomal dominant, de novo HP:0000006

CHOPS syndrome is autosomal dominant. Every reported proband whose parents were tested carries a de novo AFF4 variant; no vertically transmitted family has been described, and sib recurrence risk is quoted at roughly 1% on the basis of possible parental gonadal mosaicism.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:41712746 SUPPORT Human Clinical

"AFF4-related CHOPS syndrome is an autosomal dominant disorder."

GeneReviews states the mode of inheritance directly.

PMID:41712746 SUPPORT Human Clinical

"All probands reported to date with AFF4-related CHOPS syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant."

Establishes that the disorder arises de novo rather than being inherited.

PMID:41712746 SUPPORT Human Clinical

"There is, however, a recurrence risk (~1%) to sibs based on the possibility of parental gonadal mosaicism."

Quantifies the residual sib recurrence risk that follows from gonadal mosaicism, which is what makes prenatal testing a discussable option.

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Discussions and Knowledge Gaps

4

By what mechanism does AFF4 gain of function produce chronic lung disease?

KNOWLEDGE GAP OPEN gap_pulmonary_mechanism_unknown

Attached to

pathophysiology#Multisystem Developmental Malformation and Growth Dysregulation

Pulmonary involvement is one of the two features that most reliably separate CHOPS syndrome from CdLS, and it carries much of the morbidity - a third of the largest cohort required tracheostomy. Yet the largest clinical series states plainly that the aetiology of the chronic lung disease is undetermined, and it is not attributed to the cardiac lesions, prematurity, or aspiration. Nothing in the published transcriptomic work identifies a lung-specific programme downstream of excess AFF4. The pathograph therefore stops at the organism-level malformation node rather than inventing a pulmonary mechanism.

Proposed experiments

Airway and alveolar transcriptomics in AFF4 gain-of-function models

exp_lung_lineage_aff4_transcriptomics

Profile AFF4 occupancy and transcription in lung epithelial and mesenchymal lineages carrying a knock-in CHOPS allele (for example p.Arg258Trp), to test whether excess chromatin-bound AFF4 dysregulates a lung developmental or airway-remodelling programme rather than acting through a systemic route.

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Pulmonary issues most commonly manifested as chronic lung disease, of as yet undetermined etiology"

The source states the gap in its own words.

How does a transcriptional-elongation defect produce hyperphagia and impaired satiety?

KNOWLEDGE GAP OPEN gap_appetite_mechanism_unknown

Attached to

pathophysiology#Food-Seeking Behaviour and Impaired Satiety

The obesity of CHOPS syndrome is behaviourally driven: satiety items score highest on a Prader-Willi-derived questionnaire, and families lock food away. But no hypothalamic, leptin-melanocortin, or other appetite-pathway link to AFF4 has been demonstrated, and the phenotypic resemblance to Prader-Willi syndrome is not evidence of a shared mechanism. The causal edge into this node is therefore curated as INDIRECT and the node makes no anatomical claim.

Proposed experiments

Hypothalamic appetite-circuit assessment in a CHOPS knock-in model

exp_hypothalamic_appetite_circuit_knockin

Measure food intake, satiety responses, and AFF4-dependent transcription in hypothalamic arcuate neurons of a mouse carrying a CHOPS AFF4 allele, to test whether the appetite phenotype has a central origin at all.

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"The group of questions pertaining to impairment of satiety category had the highest average scores ranging from 3 to 4.5."

Establishes that the phenotype is one of impaired satiety, which is what a mechanism would need to explain.

Is systemic vasculopathy, including moyamoya, part of the CHOPS syndrome phenotype?

KNOWLEDGE GAP OPEN gap_vasculopathy_association_unconfirmed

Attached to

phenotypes#Moyamoya Phenomenon and Systemic Vasculopathy

One individual with a p.Pro253Leu AFF4 variant developed moyamoya disease and diffuse narrowing of the renal arteries and infrarenal aorta. The observation is confounded: the same individual carried the RNF213 p.Arg4810Lys moyamoya susceptibility allele inherited from an unaffected mother. With n=1 and a competing explanation in the same genome, this cannot be curated as a CHOPS feature; the report's own authors ask for more observation. The phenotype is recorded with PARTIAL evidence so that a second case would be recognised as confirmatory rather than novel.

Proposed experiments

Systematic vascular imaging in a CHOPS syndrome cohort

exp_cohort_vascular_imaging_rnf213

Cerebral and abdominal vascular imaging across an unselected CHOPS syndrome cohort, with RNF213 genotyping, to establish whether vasculopathy occurs above background in AFF4 variant carriers independently of known susceptibility alleles.

Show evidence (1 reference)

PMID:33248856 SUPPORT Human Clinical

"More clinical observations and functional studies are required to clarify this association."

The authors explicitly decline to assert the association.

Which of the CHOPS phenotypes are driven by enhancer-complex loss shared with CdLS, and which by the CHOPS-specific elongation gain of function?

KNOWLEDGE GAP OPEN gap_shared_vs_specific_arm_partition

Attached to

pathophysiology#Attenuation of Enhancer Complexes and Enhancer-Promoter Looping

CHOPS and CdLS patient cells converge on the same enhancer and looping defect, which plausibly accounts for the shared features - synophrys, arched eyebrows, long eyelashes, developmental delay, heart defects, hearing loss. But obesity, pulmonary involvement and skeletal dysplasia are CHOPS-specific and would have to arise from something the shared mechanism does not explain, presumably the elongation-side gain of function. No study has yet partitioned the phenotype between the two arms, so the pathograph runs both into a single convergence node rather than assigning phenotypes to one arm or the other.

Proposed experiments

Allele-resolved comparison of CHOPS and CdLS transcriptomes by lineage

exp_isogenic_lineage_enhancer_comparison

Differentiate isogenic CHOPS-allele and NIPBL-haploinsufficient iPSC lines into lung, cartilage and hypothalamic lineages and compare enhancer occupancy and transcription, to identify which programmes diverge between the two disorders and therefore which phenotypes belong to the CHOPS-specific arm.

Show evidence (1 reference)

PMID:39983729 SUPPORT In Vitro

"These findings reveal a shared molecular mechanism in these syndromes and highlight unexpected roles for cohesin, cohesin loaders, and the SEC in maintaining the enhancer complexes."

Establishes the shared arm whose phenotypic scope is the open question.

⚙

Pathophysiology

8

De Novo AFF4 ALF-Homology-Domain Missense Variant

A single heterozygous de novo missense variant in AFF4 (chromosome 5q31.1). The reported alleles cluster in a 14-amino-acid stretch (residues ~251-263) of the ALF (AF4/LAF4/FMR2) homology domain: p.Pro253Arg, p.Pro253Leu, p.Thr254Ala, p.Thr254Ser, p.Ala255Thr, p.Ala255Val, p.Arg258Trp, p.Met260Thr and p.Met260Val. p.Arg258Trp is the recurrent allele. This node records the genomic lesion only; no truncating or whole-gene-deletion allele has been implicated, which is itself an argument against haploinsufficiency.

Genetic context AFF4 hgnc:17869 allele_type: missense variant_origin: DE_NOVO allelic_event: MISSENSE_VARIANT zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

A single de novo heterozygous missense allele in the AFF4 ALF homology domain. The consequence is gain of function - escape from SIAH1-mediated degradation - not haploinsufficiency; no truncating allele has been implicated.

Downstream

Loss of SIAH1-Mediated Degradation of AFF4 The substituted residues sit in the degron that SIAH1 must recognise, so the variant protein is no longer efficiently ubiquitinated and degraded.

Show evidence (6 references)

PMID:25730767 SUPPORT Human Clinical

"All of the missense mutations found in AFF4 (c.760A>G (p.Thr254Ala), c.761C>G (p.Thr254Ser) and c.772C>T (p.Arg258Trp)) were de novo"

Reports the three founding alleles and their de novo status.

PMID:25730767 SUPPORT Human Clinical

"All 3 missense mutations were located within the ALF (AF4/LAF4/FMR2) homology domain of AFF4, and these missense mutations altered highly evolutionarily conserved amino acids"

Localises the lesion to the ALF homology domain and notes the conservation of the affected residues.

PMID:31058441 SUPPORT Human Clinical

"All the mutations identified in CHOPS syndrome were de novo, and those clustered in the ALF homology domain"

Confirms clustering and de novo origin across an eleven-individual cohort.

+ 3 more references

Loss of SIAH1-Mediated Degradation of AFF4

Wild-type AFF4 is cleared by the SIAH1 ubiquitin E3 ligase through the proteasome. Co-expression experiments in HEK293T cells show that each CHOPS allele resists SIAH1-driven degradation, and proteasome inhibition with MG132 restores wild-type AFF4 levels - confirming the route being escaped is proteasomal. The same escape was demonstrated independently for the later alleles p.Ala255Thr and p.Pro253Arg. This is a protein-turnover defect, distinct from the abundance change it produces.

proteasomal degradation of AFF4 GO:0043161 ↓ DECREASED

SIAH1 ubiquitin ligase binding GO:0031625 ↓ DECREASED

Experimental models

HEK293T AFF4/SIAH1 co-overexpression assay CELL LINE Directly tests whether each variant escapes SIAH1-driven degradation, and is the standard functional-validation step for a candidate CHOPS allele.

Animal models

robotic mouse (ENU Aff1 ALF-homology-domain missense) Mouse partially recapitulates Demonstrates in a whole organism that a missense change in this domain of an ALF-family protein produces gain of function via escape from SIAH1-mediated degradation.

Downstream

Accumulation of Chromatin-Associated AFF4 Protein Reduced clearance raises the steady-state amount of AFF4 protein.

Show evidence (3 references)

PMID:25730767 SUPPORT In Vitro

"the AFF4 constructs containing the missense mutations found in the three CHOPS syndrome probands hindered the degradation of AFF4 with SIAH1 overexpression"

Direct demonstration that the CHOPS alleles escape SIAH1-mediated degradation.

PMID:25730767 SUPPORT In Vitro

"The addition of MG132, which is a proteosomal degradation inhibitor, resulted in the recovery of AFF4 bands."

Identifies the proteasome as the degradation route being escaped.

PMID:31058441 SUPPORT In Vitro

"both p.A255T and p.P253R mutants showed a similar resistance to degradation when co-transfected with SIAH1 as the p.T254A mutant"

Extends the same degradation-resistance mechanism to two later-identified alleles.

Accumulation of Chromatin-Associated AFF4 Protein

AFF4 protein is elevated in patient-derived skin fibroblasts while AFF4 mRNA is unchanged, confirming a post-translational cause. The excess partitions specifically to the chromatin fraction, and the other SEC components ELL2 and CDK9 are not correspondingly increased - so the complex is not simply more abundant; its scaffold is over-represented on chromatin. Deleting the mutant allele in a patient line lowers AFF4 back down, attributing the accumulation to the mutant allele rather than to a trans effect.

skin fibroblast CL:0002620

AFF4 protein stabilization GO:0050821 ↑ INCREASED

super elongation complex GO:0032783

Experimental models

CHOPS patient-derived dermal fibroblasts PRIMARY CELL CULTURE Provides the direct human measurement of AFF4 protein level and its chromatin partitioning in cells carrying the endogenous variant.

Downstream

Dysregulated SEC-Dependent Transcriptional Elongation Excess chromatin-bound AFF4 alters the genome-wide deployment of the SEC and of RNA polymerase II.

Attenuation of Enhancer Complexes and Enhancer-Promoter Looping In patient cells the enhancer landscape is degraded in parallel with the elongation defect; the step from AFF4 accumulation to enhancer-complex loss is not yet resolved mechanistically.

Show evidence (3 references)

PMID:25730767 SUPPORT In Vitro

"The amount of AFF4 protein in patient derived skin fibroblasts was elevated, supporting the suggestion that the missense mutations found in these probands results in a more stable AFF4 protein"

Establishes AFF4 protein accumulation in patient cells.

PMID:25730767 SUPPORT In Vitro

"accumulation of AFF4 mainly occurred on the chromatin fraction in the CHOPS syndrome cell lines"

Localises the excess AFF4 to chromatin, which is where it acts.

PMID:25730767 SUPPORT In Vitro

"The amount of other SEC components such as ELL2 and CDK9 did not show major alterations in the chromatin fraction of the CHOPS syndrome cell lines."

Shows the accumulation is scaffold-specific rather than a uniform increase in the whole complex - the reason this node is worth separating from SEC activity.

Dysregulated SEC-Dependent Transcriptional Elongation

The super elongation complex mobilises promoter-proximally paused RNA polymerase II, with its P-TEFb (CDK9-cyclin T1) module phosphorylating Ser2 of the RNAP2 C-terminal domain to license productive elongation. With AFF4 over-represented on chromatin, genome-wide binding of AFF4, RNAP2 and cohesin is altered and direct AFF4 target genes are de-repressed: MYC, JUN, TMEM100, ZNF711 and FAM13C are all significantly upregulated in patient fibroblasts. This is the gain-of-function read-out that names the mechanism.

skin fibroblast CL:0002620

transcription elongation by RNA polymerase II GO:0006368 ⇑ GAIN OF FUNCTION positive regulation of transcriptional elongation GO:0032968 ↑ INCREASED

Downstream

Global Transcriptional Dysregulation of Developmental Gene Programmes Altered elongation control propagates into a genome-scale change in the developmental transcriptome.

Show evidence (6 references)

PMID:25730767 SUPPORT In Vitro

"Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2)."

States the normal function of the complex whose activity is dysregulated here.

PMID:25730767 SUPPORT In Vitro

"CDK9 phosphorylates the Ser2 residue of RNAP2 in order for initiation of transcriptional elongation"

Names the molecular step by which the SEC licenses productive elongation.

PMID:25730767 SUPPORT In Vitro

"The up-regulation of 5 of these genes was statistically significant: MYC, JUN, TMEM100, ZNF711 and FAM13C. These observations further support the notion that AFF4 mutations render gain-of-function effects."

Quantitative evidence that direct AFF4 targets are de-repressed, and the authors' own basis for calling the mechanism gain of function.

+ 3 more references

Attenuation of Enhancer Complexes and Enhancer-Promoter Looping

Chromosome-architecture analysis of CHOPS and CdLS patient cell lines found cohesin, the cohesin loader NIPBL, BRD4 and H3K27ac all reduced at most enhancers, with attenuation of enhancer-promoter loops, while topologically associating domains were preserved. The lesion is therefore at the level of enhancer complex maintenance and looping, not at the level of large-scale genome compartmentalisation - and it is shared with CdLS, which is the structural basis of the two disorders' phenotypic overlap.

patient-derived skin fibroblast CL:0002620

chromatin looping GO:0140588 ↓ DECREASED

cohesin complex GO:0008278

Downstream

Global Transcriptional Dysregulation of Developmental Gene Programmes Loss of enhancer complexes and enhancer-promoter contacts changes which developmental genes are transcribed.

Show evidence (3 references)

PMID:39983729 SUPPORT In Vitro

"In both patient cells, we found a decrease in cohesin, NIPBL, BRD4, and acetylation of lysine 27 on histone H3"

Reports the loss of enhancer-complex components in CHOPS patient cells.

PMID:39983729 SUPPORT In Vitro

"By contrast, TADs were maintained in both patient cells."

Bounds the claim: the defect is enhancer/loop-level, not TAD-level.

PMID:39983729 SUPPORT In Vitro

"These findings reveal a shared molecular mechanism in these syndromes and highlight unexpected roles for cohesin, cohesin loaders, and the SEC in maintaining the enhancer complexes."

States the shared-mechanism conclusion linking CHOPS syndrome to CdLS.

Global Transcriptional Dysregulation of Developmental Gene Programmes

Expression profiling of patient fibroblasts identifies hundreds of dysregulated genes. Upregulated genes are enriched for homeobox proteins, skeletal system development and morphogenesis, anterior/posterior pattern formation, and embryonic organ development; downregulated genes are enriched for actin-binding and extracellular-matrix genes. The dysregulated set correlates positively with that of CdLS fibroblasts. This is the disorder-agnostic convergence point that CHOPS syndrome shares with the wider class of transcriptional-regulation disorders.

regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL skeletal system development GO:0001501 ⚠ ABNORMAL

Experimental models

CHOPS patient-derived dermal fibroblasts PRIMARY CELL CULTURE Supplies the expression-profiling and RNA-seq data defining the dysregulated gene set, and the comparison against CdLS fibroblasts.

Downstream

Multisystem Developmental Malformation and Growth Dysregulation Disturbed developmental transcription during embryogenesis produces structural malformation across organ systems.

Food-Seeking Behaviour and Impaired Satiety The route from transcriptional dysregulation to the appetite phenotype is not established; the link is asserted only as an unexplained consequence.

Show evidence (2 references)

PMID:25730767 SUPPORT In Vitro

"upregulated genes are enriched for Homeobox proteins, skeletal system development/morphogenesis and anterior/posterior pattern formation as well as embryonic organ development/morphogenesis, and downregulated genes are enriched for actin binding genes and extracellular matrix genes"

Characterises which developmental programmes are disturbed, connecting the molecular lesion to a skeletal and organ-morphogenesis phenotype.

PMID:27867341 SUPPORT Other

"Some genetic disorders caused by mutations in genes encoding components of the transcriptional machinery as well as proteins involved in epigenetic modification of the genome share many overlapping features, such as facial dysmorphisms, growth problems and developmental delay/intellectual disability."

Places CHOPS syndrome in the disorders-of-transcriptional-regulation class and explains why global transcriptional disturbance yields this phenotype triad.

Multisystem Developmental Malformation and Growth Dysregulation

The organism-level convergence node: craniofacial, cardiac, pulmonary, skeletal, genitourinary, ocular and neurodevelopmental structures are all affected, with linear growth failure that is not corrected by a normal growth hormone response. Phenotypes attach here.

heart development GO:0007507 ⚠ ABNORMAL lung development GO:0030324 ⚠ ABNORMAL

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"These individuals have a distinct phenotype, that is, characterized by short stature, characteristic facial features (synophrys, arched eyebrows, long eyelashes, upturned nasal tip with anteverted nares and coarse, full facies), congenital heart defects, pulmonary involvement, brachydactyly and..."

Enumerates the organ systems that converge at this node.

PMID:42273204 SUPPORT Human Clinical

"The patient exhibited significant growth failure despite an adequate growth hormone response."

Shows the growth failure is not attributable to growth hormone deficiency, which is why it is placed at the developmental-programme node rather than at a pituitary one.

Food-Seeking Behaviour and Impaired Satiety

Excessive food-seeking behaviour with impaired satiety is near-universal and is one of the features that distinguishes CHOPS syndrome from CdLS. On a food-related problems questionnaire originally designed for Prader-Willi syndrome, the impairment-of-satiety items scored highest, every respondent reported their child helping themselves to forbidden food, and most families had found it necessary to lock food away. The node is behavioural and deliberately makes no hypothalamic claim - no mechanism linking AFF4 to appetite regulation has been demonstrated.

Downstream

Multisystem Developmental Malformation and Growth Dysregulation Hyperphagia contributes the weight arm of the characteristic short-but-heavy growth pattern, in which weight percentiles sit disproportionately above height percentiles.

Show evidence (3 references)

PMID:31058441 SUPPORT Human Clinical

"Excessive food-seeking behaviors and over-affection were common in all individuals, in addition to pulmonary involvement, which are not seen in CdLS"

Establishes food-seeking behaviour as a consistent and CHOPS-discriminating feature.

PMID:31058441 SUPPORT Human Clinical

"The group of questions pertaining to impairment of satiety category had the highest average scores ranging from 3 to 4.5."

Instrumented evidence that satiety, specifically, is impaired.

PMID:41712746 SUPPORT Human Clinical

"Neurobehavioral features include disruptive and self-absorbed behaviors, communication disturbance, and food-seeking behaviors leading to obesity."

GeneReviews places food-seeking behaviour causally upstream of the obesity.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

49

Blood 1

Pulmonary Alveolar Haemorrhage OCCASIONAL Pulmonary hemorrhage HP:0040223

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Pulmonary alveolar hemorrhage occurred in Case-1 and Case-7"

Two of eleven individuals is 18%, within the OCCASIONAL band.

Cardiovascular 3

Patent Ductus Arteriosus FREQUENT HP:0001643

Onset: CONGENITAL

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Congenital heart disease was present in 8 of the 11 individuals reported here. Of these eight individuals, six had a patent ductus arteriosis (PDA)"

Six of eleven individuals is 55%, within the FREQUENT band.

Ventricular Septal Defect FREQUENT HP:0001629

Onset: CONGENITAL

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"five had a ventricular septal defect (VSD)"

Five of eleven individuals is 45%, within the FREQUENT band.

Pulmonary Arterial Hypertension OCCASIONAL HP:0002092

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Pulmonary hypertension was found in Case-1 and Case-6, and a dilated aortic root was noted in Case-6 and Case-7."

Two of eleven individuals is 18%, within the OCCASIONAL band.

Digestive 2

Feeding Difficulties Requiring Gastrostomy FREQUENT HP:0011968

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Six individuals (Case-2, 3, 6, 7, 9, 10) required G-tube insertion."

Six of eleven individuals is 55%, within the FREQUENT band.

Constipation FREQUENT HP:0002019

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Constipation was present in four individuals (Case-1, 2, 3, and 11)."

Four of eleven individuals is 36%, within the FREQUENT band.

Ear 1

Hearing Impairment FREQUENT HP:0000365

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Eight out of 11 individuals were reported to have some type of hearing loss"

Eight of eleven individuals is 73%, within the FREQUENT band.

Eye 5

Proptosis HP:0000520

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"Characteristic facial features include synophrys, highly arched eyebrows, long eyelashes, proptosis, and anteverted nares."

GeneReviews lists proptosis among the characteristic facial features.

Cataract OCCASIONAL HP:0000518

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"Other reported abnormalities included myopia (Case-2, 8, 9), strabismus (Case-5, 8), cataracts (Case-3, 9, 10), ptosis (Case-5, 6), hypothyroidism (Case-4), acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)."

Three of eleven individuals is 27%, within the OCCASIONAL band.

PMID:42273204 SUPPORT Human Clinical

"Additional features included congenital cataracts, laryngomalacia, and mild mitral insufficiency."

Independent report of congenital cataract.

Myopia OCCASIONAL HP:0000545

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"Other reported abnormalities included myopia (Case-2, 8, 9), strabismus (Case-5, 8), cataracts (Case-3, 9, 10), ptosis (Case-5, 6), hypothyroidism (Case-4), acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)."

Three of eleven individuals is 27%, within the OCCASIONAL band.

PMID:41712746 SUPPORT Human Clinical

"Assess for myopia and strabismus per ophthalmologist and at least annually; annual audiology evaluation."

GeneReviews treats myopia as expected enough to warrant annual surveillance.

Strabismus OCCASIONAL HP:0000486

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Other reported abnormalities included myopia (Case-2, 8, 9), strabismus (Case-5, 8), cataracts (Case-3, 9, 10), ptosis (Case-5, 6), hypothyroidism (Case-4), acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)."

Two of eleven individuals is 18%, within the OCCASIONAL band.

Ptosis OCCASIONAL HP:0000508

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Other reported abnormalities included myopia (Case-2, 8, 9), strabismus (Case-5, 8), cataracts (Case-3, 9, 10), ptosis (Case-5, 6), hypothyroidism (Case-4), acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)."

Two of eleven individuals is 18%, within the OCCASIONAL band.

Genitourinary 3

Cryptorchidism HP:0000028

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Genital abnormalities in males included cryptorchidism (Case-2), hypospadias (Case-5), and small genitalia (Case-5 and Case-11)."

Single-individual observation; frequency omitted since the denominator is males only and the count is one.

Hypospadias HP:0000047

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Genital abnormalities in males included cryptorchidism (Case-2), hypospadias (Case-5), and small genitalia (Case-5 and Case-11)."

Single-individual observation; frequency omitted for the same reason.

Horseshoe Kidney OCCASIONAL HP:0000085

Onset: CONGENITAL

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Other anomalies of the genitourinary system included horseshoe kidney (Case-1, 5) and vesicoureteral reflux (Case-2, 3)."

Two of eleven individuals is 18%, within the OCCASIONAL band.

Head and Neck 6

Coarse Facial Features VERY_FREQUENT HP:0000280

Course: PROGRESSIVE

Show evidence (2 references)

PMID:41712746 SUPPORT Human Clinical

"Coarse facies and round face with full cheeks become more noticeable with age."

Records both the feature and its progressive character.

PMID:31058441 SUPPORT Human Clinical

"Additional distinctive facial dysmorphia included anteverted nares, coarse facies, and facial fullness"

Cohort confirmation of coarse facies and facial fullness.

Highly Arched Eyebrows VERY_FREQUENT HP:0002553

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes."

Arched eyebrows reported in 11 of 11 individuals.

Anteverted Nares HP:0000463

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"Characteristic facial features include synophrys, highly arched eyebrows, long eyelashes, proptosis, and anteverted nares."

GeneReviews lists anteverted nares among the characteristic facial features.

Midface Retrusion HP:0011800

Show evidence (1 reference)

PMID:42178648 SUPPORT Human Clinical

"Extraoral examination revealed midface hypoplasia, thick eyebrows, broad forehead, large ears, and coarse facial appearance."

Single detailed dentofacial case description; frequency is deliberately omitted because this rests on one report.

Wormian Bones OCCASIONAL HP:0002645

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Other noted recurrent features were large anterior fontanelle (Case-1, 2, 5), and Wormian skull bones (Case-1, 5)."

Names the two individuals with Wormian skull bones; two of eleven is 18%, within the OCCASIONAL band.

Enamel Hypoplasia and Tooth Agenesis HP:0006297

Show evidence (2 references)

PMID:42178648 SUPPORT Human Clinical

"Intraoral findings included a narrow and high palatal vault, enamel hypoplasia, and multiple carious lesions."

Reports the enamel defect and palatal morphology.

PMID:42178648 SUPPORT Human Clinical

"This report highlights previously unrecognized oral and craniofacial features of CHOPS syndrome"

The authors state these are newly recognised features, which is why no frequency is asserted.

Immune 1

Recurrent Pneumonia FREQUENT HP:0006532

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Four individuals had a history of pneumonia (Case-1, 2, 7, 9)."

Four of eleven individuals is 36%, within the FREQUENT band.

Integument 1

Acanthosis Nigricans OCCASIONAL HP:0000956

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)"

Two of eleven individuals is 18%, within the OCCASIONAL band.

Limbs 2

Brachydactyly FREQUENT HP:0001156

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"Brachydactyly was present in 8 out of the 11 individuals."

Eight of eleven individuals is 73%, within the FREQUENT band.

PMID:41712746 SUPPORT Human Clinical

"Other common features include growth deficiency, respiratory issues, congenital heart defects, small hands, brachydactyly, ocular abnormalities, genitourinary abnormalities, and gastrointestinal manifestations."

GeneReviews independently lists small hands and brachydactyly as common.

Small Hands HP:0200055

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"Other common features include growth deficiency, respiratory issues, congenital heart defects, small hands, brachydactyly, ocular abnormalities, genitourinary abnormalities, and gastrointestinal manifestations."

GeneReviews lists small hands among the common features.

Musculoskeletal 1

Reduced Bone Mineral Density HP:0004349

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density."

Names low bone mineral density among the common skeletal features.

PMID:42178648 SUPPORT Human Clinical

"Panoramic radiography demonstrated reduced bone mineralization and agenesis of all second premolars and Tooth 47."

Independent radiographic observation of reduced mineralisation in the jaws.

Nervous System 6

Developmental Delay and Intellectual Disability VERY_FREQUENT HP:0001249

Onset: INFANTILE

Show evidence (2 references)

PMID:41712746 SUPPORT Human Clinical

"All individuals reported to date have mild-to-moderate developmental delay and intellectual disability without regression."

GeneReviews states both the universality and the mild-to-moderate severity, supporting the VERY_FREQUENT band.

PMID:31058441 SUPPORT Human Clinical

"All individuals with CHOPS syndrome had developmental delay, and varying degrees of intellectual disability."

Independent cohort confirmation that the feature is universal.

Global Developmental Delay VERY_FREQUENT HP:0001263

Onset: INFANTILE

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"The age at which individuals with CHOPS syndrome started rolling ranges between 9 and 15 months (average: 12 months), age to sit independently ranges between 11 months and 3 years (average: 18 months), and age to walk independently ranges between 3 and 6 years (average: 4.8 years)."

Quantifies the delay across motor milestones.

Hyperphagia and Food-Seeking Behaviour VERY_FREQUENT Polyphagia HP:0002591

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"Excessive food-seeking behaviors and over-affection were common in all individuals, in addition to pulmonary involvement, which are not seen in CdLS"

Reports the behaviour in all individuals of the cohort, supporting the VERY_FREQUENT band.

PMID:41712746 SUPPORT Human Clinical

"food-seeking behaviors leading to obesity"

GeneReviews independently records the behaviour and its consequence.

Disruptive and Self-Absorbed Behaviour Atypical behavior HP:0000708

Show evidence (2 references)

PMID:41712746 SUPPORT Human Clinical

"Neurobehavioral features include disruptive and self-absorbed behaviors, communication disturbance, and food-seeking behaviors leading to obesity."

Names the behavioural domains affected.

PMID:31058441 SUPPORT Human Clinical

"Most problematic behaviors in all individuals included disruptive, self-absorbed, and communication disturbance behaviors."

Instrumented behavioural assessment identifying the same domains.

Sleep Apnea OCCASIONAL HP:0010535

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Pulmonary alveolar hemorrhage occurred in Case-1 and Case-7, and sleep apnea was documented in Case-1, 3, 9."

Three of eleven individuals is 27%, within the OCCASIONAL band.

Cerebral Atrophy and Corpus Callosum Hypoplasia Hypoplasia of the corpus callosum HP:0002079

Show evidence (1 reference)

PMID:42273204 SUPPORT Human Clinical

"neuroimaging findings indicative of cortical atrophy and corpus callosum hypoplasia"

Single case report of these neuroimaging findings.

Growth 2

Short Stature VERY_FREQUENT HP:0004322

Course: PROGRESSIVE

Show evidence (3 references)

PMID:31058441 SUPPORT Human Clinical

"All 11 individuals had short stature and obesity."

11 of 11 individuals, supporting the VERY_FREQUENT band.

PMID:31058441 SUPPORT Human Clinical

"However, the measurements at the latest clinic visit indicated average height was around −5 SD, although HC remained around −2 SD"

Documents the progressive worsening of the height deficit.

PMID:42273204 SUPPORT Human Clinical

"The patient exhibited significant growth failure despite an adequate growth hormone response."

Shows growth failure is not explained by growth hormone deficiency.

Obesity VERY_FREQUENT HP:0001513

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"All 11 individuals had short stature and obesity."

11 of 11 individuals, supporting the VERY_FREQUENT band.

PMID:31058441 SUPPORT Human Clinical

"Obesity, pulmonary involvement, skeletal findings, and distinct craniofacial features are the most notable features distinguishing CHOPS syndrome from CdLS."

Establishes obesity as a discriminating feature against the main differential.

Other 15

Temper Tantrums Abnormal temper tantrums HP:0025160

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Common disruptive behaviors included excessive food seeking behaviors, throwing off clothes, and temper tantrums."

Names temper tantrums as a recurrent behaviour. No denominator is given, so no frequency band is asserted.

Synophrys VERY_FREQUENT HP:0000664

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes."

Reports synophrys in 11 of 11 individuals, supporting VERY_FREQUENT.

Long Eyelashes VERY_FREQUENT HP:0000527

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes."

Long eyelashes reported in 11 of 11 individuals.

Wide Anterior Fontanel OCCASIONAL HP:0000260

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Other noted recurrent features were large anterior fontanelle (Case-1, 2, 5), and Wormian skull bones (Case-1, 5)."

Names the three individuals with a large anterior fontanelle; three of eleven is 27%, within the OCCASIONAL band.

Patent Foramen Ovale OCCASIONAL HP:0001655

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"and three had a patent foramen ovale (PFO)"

Three of eleven individuals is 27%, within the OCCASIONAL band.

Dilated Aortic Root OCCASIONAL Abnormal aortic morphology HP:0001679

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Pulmonary hypertension was found in Case-1 and Case-6, and a dilated aortic root was noted in Case-6 and Case-7."

Names the two individuals with a dilated aortic root; two of eleven is 18%, within the OCCASIONAL band.

Chronic Lung Disease FREQUENT HP:0006528

Temporal: CHRONIC

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"Pulmonary and respiratory tract involvement was found in 8 of the 11 individuals. Chronic lung disease was noted in six individuals."

Six of eleven individuals is 55%, within the FREQUENT band.

PMID:31058441 SUPPORT Human Clinical

"Pulmonary issues most commonly manifested as chronic lung disease, of as yet undetermined etiology"

Records explicitly that the mechanism of the lung disease is unknown.

Laryngomalacia OCCASIONAL HP:0001601

Onset: CONGENITAL

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"three subjects (Case-2, 3, 9) required a tracheostomy, with two of these having laryngomalacia (Case-2, 3)."

Two of eleven individuals is 18%, within the OCCASIONAL band.

PMID:42273204 SUPPORT Human Clinical

"Additional features included congenital cataracts, laryngomalacia, and mild mitral insufficiency."

Independent case report of laryngomalacia in CHOPS syndrome.

Subglottic Stenosis OCCASIONAL HP:0001607

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Structurally, two cases (Case-2, 6, 7) had subglottic stenosis, and Case-3 had a congenital narrow oropharynx."

Structural airway narrowing in the cohort. Note the source's own case list is internally inconsistent (it says "two cases" but names three); the OCCASIONAL band covers either reading.

Abnormal Vertebral Body Morphology FREQUENT Abnormal form of the vertebral bodies HP:0003312

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density."

Reports abnormal vertebral body shape as a common skeletal finding.

PMID:31058441 SUPPORT Human Clinical

"An abnormal shape of the vertebral bodies with decreased height, pronounced from T8 to L1, was noted in Case-1"

Radiographic detail of the vertebral involvement.

Hypoplastic Long Bones Aplasia/hypoplasia involving bones of the extremities HP:0045060

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density."

Lists hypoplastic long bones among the common skeletal features. The sentence gives no denominator, which is why frequency is omitted.

PMID:31058441 SUPPORT Human Clinical

"Hypoplasia of the proximal radii bilaterally, hypoplasia of the fibula bilaterally was noted in Case-3"

Radiographic detail naming the specific long bones affected.

Small Genitalia Hypoplastic male external genitalia HP:0000050

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Genital abnormalities in males included cryptorchidism (Case-2), hypospadias (Case-5), and small genitalia (Case-5 and Case-11)."

Names the two individuals with small genitalia. Frequency is omitted because the denominator is males only and is not stated.

Vesicoureteral Reflux OCCASIONAL HP:0000076

Show evidence (1 reference)

PMID:31058441 SUPPORT Human Clinical

"Other anomalies of the genitourinary system included horseshoe kidney (Case-1, 5) and vesicoureteral reflux (Case-2, 3)."

Two of eleven individuals is 18%, within the OCCASIONAL band.

Moyamoya Phenomenon and Systemic Vasculopathy HP:0011834

Show evidence (3 references)

PMID:33248856 SUPPORT Human Clinical

"She was also diagnosed with Moyamoya disease at 6 years of age and had undergone synangiosis surgery thrice. Her renal arteries and infrarenal aorta were diffusely narrowed."

Documents the vasculopathy in an individual with a confirmed AFF4 variant, but only in a single case.

PMID:33248856 SUPPORT Human Clinical

"No additional candidate variants for her vascular manifestation were found except a susceptibility variant, c.14429G > A (p.Arg4810Lys) in RNF213, inherited from asymptomatic mother."

Names the competing explanation - an RNF213 moyamoya susceptibility allele - which is why this is curated as PARTIAL rather than SUPPORT.

PMID:33248856 SUPPORT Human Clinical

"More clinical observations and functional studies are required to clarify this association."

The authors decline to assert the association, and this entry follows them.

🧬

Genetic Associations

1

AFF4 (De novo heterozygous missense variants in the ALF homology domain)

Gene: AFF4 hgnc:17869 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (4 references)

PMID:25730767 SUPPORT Human Clinical

"we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome"

Establishes AFF4 as the causative gene and names the disorder.

PMID:31058441 SUPPORT Human Clinical

"The p. R258W mutation represents the most common recurrent mutation, and this mutation accounted for 55% of CHOPS syndrome cases."

Quantifies the recurrent allele's contribution.

PMID:40904637 SUPPORT Human Clinical

"Genetic analyses identified a de novo heterozygous c.778A>G (p.Met260Val) variant in AFF4 in the proband, absent in parents and little sister"

Independent replication in an unrelated family, extending the allelic spectrum with trio confirmation of de novo status.

+ 1 more reference

💊

Medical Actions

9

Developmental and Educational Support

Action: rehabilitation Ontology label: Rehabilitation NCIT:C15315

Early intervention, special education and behavioural support for the mild-to-moderate intellectual disability and the disruptive/food-seeking behavioural profile. There is no disease-modifying therapy for CHOPS syndrome; management is entirely supportive and organ-directed.

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"Treatment of manifestations: Developmental and educational support; feeding therapy; gastrostomy tube placement as needed; nutritional management for obesity"

GeneReviews management recommendation.

Nutritional Management of Obesity

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Dietary management directed at the obesity, which is driven by impaired satiety and food-seeking behaviour rather than by a metabolic defect; families commonly need to restrict access to food.

Mechanism Target:

MODULATES Food-Seeking Behaviour and Impaired Satiety — Environmental food restriction manages the consequences of impaired satiety; it does not correct the underlying behaviour.

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"gastrostomy tube placement as needed; nutritional management for obesity; standard treatments for chronic lung disease and sleep apnea"

GeneReviews recommends nutritional management specifically for the obesity.

Feeding Therapy and Gastrostomy Tube Placement

Action: gastrostomy tube placement Ontology label: Gastrostomy Tube Procedure NCIT:C157864

Feeding therapy with gastrostomy placement where oral intake is unsafe or inadequate; six of eleven individuals in the largest series required a G-tube.

Show evidence (2 references)

PMID:41712746 SUPPORT Human Clinical

"Developmental and educational support; feeding therapy; gastrostomy tube placement as needed"

GeneReviews management recommendation.

PMID:31058441 SUPPORT Human Clinical

"Six individuals (Case-2, 3, 6, 7, 9, 10) required G-tube insertion."

Quantifies how frequently gastrostomy is actually needed.

Management of Chronic Lung Disease and Sleep Apnea

Action: respiratory therapy Ontology label: Respiratory Therapy NCIT:C15322

Standard respiratory management, with tracheostomy where laryngomalacia or subglottic stenosis compromises the airway; three of eleven individuals in the largest series were tracheostomised. Because the chronic lung disease has no identified aetiology, treatment is symptomatic rather than mechanism-directed.

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"standard treatments for chronic lung disease and sleep apnea; standard vaccinations; tracheostomy as needed for laryngomalacia"

GeneReviews management recommendation covering both the chronic lung disease and the airway.

Surgical Repair of Congenital Heart Defects

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Standard cardiac surgical and medical management of the PDA, VSD and other lesions, and of vertebral anomalies.

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"standard treatment for congenital heart defects and vertebral anomalies"

GeneReviews management recommendation.

Cataract Surgery

Action: cataract surgery Ontology label: Cataract Surgery NCIT:C157809

Subspecialist surgical management of the cataracts, which include congenital cataract.

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"treatment of cataract per ophthalmic subspecialist"

GeneReviews routes cataract specifically to an ophthalmic subspecialist.

Ophthalmological Management

Action: therapeutic procedure Ontology label: Therapeutic Procedure NCIT:C49236

Correction of refractive errors and strabismus, with at least annual ophthalmological assessment. The generic procedure term is kept deliberately: this entry spans refraction, spectacle correction and strabismus management, which no single more specific NCIT clinical-action term covers.

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"treatment of refractive errors and strabismus per ophthalmologist; treatment of cataract per ophthalmic subspecialist"

GeneReviews management recommendation.

Hearing Aids for Hearing Loss

Amplification as needed for the hearing loss seen in the majority of affected individuals, with annual audiology evaluation. NCIT has no clinical-action term for hearing aid fitting - the former MAXO "hearing aid usage" concept had no NCIT equivalent and was dropped - so `term:` is deliberately omitted rather than bound to a generic procedure term that would misdescribe a device intervention.

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"hearing aids as needed for hearing loss; standard treatment of genitourinary anomalies and bowel dysfunction"

GeneReviews management recommendation.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling covering the de novo autosomal dominant mechanism, the roughly 1% sib recurrence risk from possible parental gonadal mosaicism, and the availability of prenatal and preimplantation testing.

Show evidence (1 reference)

PMID:41712746 SUPPORT Human Clinical

"Given this risk, prenatal and preimplantation genetic testing may be considered."

GeneReviews genetic counseling recommendation following from the mosaicism recurrence risk.

🔬

Diagnosis

2

Molecular Genetic Testing for a Heterozygous AFF4 Variant (Positive in affected individuals)

Diagnosis rests on identifying a heterozygous pathogenic AFF4 variant in an individual with suggestive clinical findings. Because pathogenic variation is confined to a 14-amino-acid stretch of one domain, targeted AFF4 sequencing is a practical alternative to exome sequencing once the gestalt is recognised - two of eight newly diagnosed individuals in the largest series were found this way.

molecular genetic testing for AFF4 NCIT:C15709

Show evidence (2 references)

PMID:41712746 SUPPORT Human Clinical

"The diagnosis of AFF4-related CHOPS syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in AFF4 identified by molecular genetic testing."

States the diagnostic criterion.

PMID:31058441 SUPPORT Human Clinical

"In fact, two out of eight of our newly identified patients were found to have AFF4 mutations by targeted AFF4 mutational analysis rather than exome sequencing."

Shows targeted single-gene testing is a viable route once the phenotype is recognised clinically.

Clinical Differentiation from Cornelia de Lange Syndrome (Discriminating clinical assessment)

CHOPS syndrome is most often mistaken for CdLS. The discriminating features are obesity (CdLS is growth-restricted in weight as well as height), pulmonary involvement, skeletal findings, and the coarse full round face that emerges with age - as against the shared synophrys, arched eyebrows, long eyelashes and upturned nose seen in both.

Show evidence (2 references)

PMID:31058441 SUPPORT Human Clinical

"Obesity, pulmonary involvement, skeletal findings, and distinct craniofacial features are the most notable features distinguishing CHOPS syndrome from CdLS."

Names the four discriminating feature classes.

PMID:31058441 SUPPORT Human Clinical

"Pulmonary issues are not typically observed in CdLS and the pulmonary involvement for children with CHOPS syndrome can be significant with chronic lung disease present in the majority of patients"

Elaborates the pulmonary discriminator specifically.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Described as extremely rare; no incidence or prevalence rate has been published, so no numeric rate is asserted here. The largest series describes eleven individuals and subsequent reports have been single cases. Ascertainment is likely incomplete because affected children are frequently referred first as suspected Cornelia de Lange syndrome.

Show evidence (2 references)

PMID:40904637 SUPPORT Human Clinical

"CHOPS (cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia) syndrome is an extremely rare disorder with multiple congenital anomalies caused by missense variants in the ALF transcription elongation factor 4 gene (AFF4)."

Characterises the disorder as extremely rare.

PMID:31058441 SUPPORT Human Clinical

"Here, we provide clinical descriptions of an additional eight individuals with CHOPS syndrome, as well as neurocognitive analysis of three individuals."

Establishes the size of the largest published cohort, which is the basis for the case-count claim.

🧫

Experimental Models

2

CHOPS patient-derived dermal fibroblasts PRIMARY_CELL_CULTURE

Primary skin fibroblast lines from individuals carrying p.Thr254Ala, p.Thr254Ser and p.Arg258Trp, with hTERT-immortalised derivatives, compared against age- and sex-matched controls and against NIPBL-mutant CdLS fibroblasts. This is the system in which every human-cell observation of the CHOPS mechanism was made.

Publication

PMID:25730767

Pathograph links

Accumulation of Chromatin-Associated AFF4 Protein measures fidelity: moderate Provides the direct human measurement of AFF4 protein level and its chromatin partitioning in cells carrying the endogenous variant.

Limitations: Dermal fibroblasts are not the affected lineage for any CHOPS phenotype - not lung, not cartilage, not neurons - so the magnitude and gene-selectivity of AFF4 accumulation in the tissues that actually malform is inferred, not measured. Few patient lines were available and controls were correspondingly few.

Readouts

Chromatin-fraction AFF4 protein abundance by western blot

Direction: INCREASED

Interpretation: The variant protein accumulates specifically on chromatin.

Show evidence (1 reference)

PMID:25730767 SUPPORT In Vitro

"accumulation of AFF4 mainly occurred on the chromatin fraction in the CHOPS syndrome cell lines"

Reports the fractionation result behind this readout.

Show evidence (1 reference)

PMID:25730767 SUPPORT In Vitro

"The amount of AFF4 protein in patient derived skin fibroblasts was elevated, supporting the suggestion that the missense mutations found in these probands results in a more stable AFF4 protein"

Justifies the patient fibroblast line as informative for the protein-stability mechanism.

Global Transcriptional Dysregulation of Developmental Gene Programmes measures fidelity: low Supplies the expression-profiling and RNA-seq data defining the dysregulated gene set, and the comparison against CdLS fibroblasts.

Limitations: A fibroblast transcriptome cannot report the developmental programmes of the tissues that malform, so the reported enrichment for homeobox and skeletal-development genes is suggestive of, not equivalent to, the in vivo lesion. Only two patient lines were profiled on the microarray, at an FDR cutoff of 0.2.

Readouts

Differentially expressed gene count in patient fibroblasts

Direction: ALTERED

Interpretation: Hundreds of genes change expression in either direction.

Show evidence (1 reference)

PMID:25730767 SUPPORT In Vitro

"Using an FDR cutoff of 0.2, 288 genes were downregulated in patient skin fibroblasts, and 445 genes were upregulated in patient samples"

Reports the differential-expression counts behind this readout.

Show evidence (1 reference)

PMID:25730767 SUPPORT In Vitro

"we performed genome-wide expression profiling using Affymetrix U133plus2 chips on patient derived skin fibroblast cell lines"

Establishes that the transcriptomic claims rest on this cell system.

HEK293T AFF4/SIAH1 co-overexpression assay CELL_LINE

Transient co-transfection of tagged wild-type or CHOPS-variant AFF4 with SIAH1 in HEK293T cells, read out by western blot, with MG132 used to confirm the proteasomal route. This is the assay that established gain of function and that was reused to validate each newly reported allele.

Publication

PMID:25730767

Pathograph links

Loss of SIAH1-Mediated Degradation of AFF4 perturbs fidelity: low Directly tests whether each variant escapes SIAH1-driven degradation, and is the standard functional-validation step for a candidate CHOPS allele.

Limitations: Both proteins are supraphysiologically overexpressed from cDNA in a kidney-derived immortalised line, so the assay establishes that the variant can escape SIAH1 but says nothing about the size of the effect at endogenous stoichiometry, in a relevant tissue, or during development.

Readouts

AFF4 protein level under SIAH1 co-expression

Direction: UNCHANGED

Interpretation: Variant AFF4 is not depleted by SIAH1 co-expression, whereas wild-type AFF4 is - the definition of degradation resistance in this assay.

Show evidence (1 reference)

PMID:31058441 SUPPORT In Vitro

"both p.A255T and p.P253R mutants showed a similar resistance to degradation when co-transfected with SIAH1 as the p.T254A mutant, while WT AFF4 experienced a significant decrease when co-transfected with SIAH1"

Reports the comparative band intensities behind this readout.

Show evidence (1 reference)

PMID:25730767 SUPPORT In Vitro

"we created an AFF4 and SIAH1 overexpression model using HEK293T cells"

Establishes the assay system used for the degradation-resistance claim.

🐁

Animal Models

1

robotic mouse (ENU Aff1 ALF-homology-domain missense)

An ENU-mutagenesis ataxia mouse carrying a missense change in the ALF homology domain of Aff1, the AFF4 paralogue. Its mechanism - gain of function through reduced SIAH1-mediated clearance - is the precedent that led the CHOPS discovery team to test the same hypothesis for AFF4. It is a mechanistic analogy, not a CHOPS disease model.

Species

Mouse

Genotype

Aff1 (Af4) ALF homology domain missense, ENU-induced

Publication

PMID:25730767

Pathograph links

Loss of SIAH1-Mediated Degradation of AFF4 partially recapitulates fidelity: low Demonstrates in a whole organism that a missense change in this domain of an ALF-family protein produces gain of function via escape from SIAH1-mediated degradation.

Limitations: The mutated gene is Aff1, not Aff4, and the phenotype is ataxia - not the craniofacial, cardiac, pulmonary, skeletal or obesity features of CHOPS syndrome. No mouse carrying a CHOPS Aff4 allele has been reported, so there is currently no animal model of the disorder itself; this model supports only the degradation-escape step.

Show evidence (2 references)

PMID:25730767 SUPPORT Model Organism

"A missense mutation in the ALF homology domain of Aff1 (Af4) was reported in the robotic mouse, an ataxia mouse model created by ENU mutagenesis"

Establishes the existence and nature of the model. Curated as PARTIAL because the gene is the paralogue and the phenotype is not CHOPS syndrome.

+ 1 more reference

{ }

Source YAML

click to show

name: CHOPS Syndrome
creation_date: "2026-08-19T00:00:00Z"
category: Mendelian
synonyms:
- CHOPS
- AFF4-related CHOPS syndrome
- cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement
  - short stature - skeletal dysplasia syndrome
description: >-
  CHOPS syndrome is an ultra-rare autosomal dominant multiple congenital anomaly /
  intellectual disability disorder caused by de novo missense variants in AFF4, the
  scaffold subunit of the super elongation complex (SEC). The acronym, coined in the
  founding report, records the constellation of Cognitive impairment and Coarse
  facies, Heart defects, Obesity, Pulmonary involvement, and Short stature with
  Skeletal dysplasia. Every pathogenic variant reported to date falls in a highly
  conserved 14-amino-acid stretch of the AFF4 ALF homology domain, which carries the
  degron recognised by the SIAH1 ubiquitin E3 ligase. The variants do not abolish
  AFF4 function; they make the protein resistant to proteasomal clearance, so
  chromatin-associated AFF4 accumulates and SEC-dependent transcription is
  dysregulated - a gain-of-function mechanism. Because the SEC physically engages
  cohesin and RNA polymerase II, CHOPS syndrome shares a transcriptional-elongation
  and enhancer-attenuation pathology with Cornelia de Lange syndrome (CdLS), which
  is why affected children are frequently referred first as suspected CdLS. Obesity
  driven by food-seeking behaviour, chronic lung disease, and skeletal involvement
  are the features that most reliably separate CHOPS syndrome from CdLS.
disease_term:
  preferred_term: CHOPS syndrome
  term:
    id: MONDO:0014609
    label: cognitive impairment - coarse facies - heart defects - obesity - pulmonary
      involvement - short stature - skeletal dysplasia syndrome
parents:
- Genetic Disease
- Multiple congenital anomalies-intellectual disability syndrome
- Skeletal Dysplasia
- Disorder of Transcriptional Regulation

classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A de novo single-gene multiple congenital anomaly / intellectual disability
      syndrome; the clinical burden is distributed across cardiac, pulmonary,
      skeletal, endocrine and neurodevelopmental systems rather than concentrated
      in one organ.
    evidence:
    - reference: PMID:31058441
      reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CHOPS syndrome is a multisystem disorder caused by missense mutations in AFF4."
      explanation: >-
        Confirms the multisystem, genetically determined character that places this
        entry in the genetics Part rather than an organ-system Part.

references:
- reference: PMID:41712746
  title: "AFF4-Related CHOPS Syndrome."
  tags:
  - GeneReviews

inheritance:
- name: Autosomal dominant, de novo
  description: >-
    CHOPS syndrome is autosomal dominant. Every reported proband whose parents were
    tested carries a de novo AFF4 variant; no vertically transmitted family has been
    described, and sib recurrence risk is quoted at roughly 1% on the basis of
    possible parental gonadal mosaicism.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AFF4-related CHOPS syndrome is an autosomal dominant disorder."
    explanation: >-
      GeneReviews states the mode of inheritance directly.
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All probands reported to date with AFF4-related CHOPS syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant."
    explanation: >-
      Establishes that the disorder arises de novo rather than being inherited.
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is, however, a recurrence risk (~1%) to sibs based on the possibility of parental gonadal mosaicism."
    explanation: >-
      Quantifies the residual sib recurrence risk that follows from gonadal
      mosaicism, which is what makes prenatal testing a discussable option.

pathophysiology:
- name: De Novo AFF4 ALF-Homology-Domain Missense Variant
  biological_scale: MOLECULAR
  description: >-
    A single heterozygous de novo missense variant in AFF4 (chromosome 5q31.1). The
    reported alleles cluster in a 14-amino-acid stretch (residues ~251-263) of the
    ALF (AF4/LAF4/FMR2) homology domain: p.Pro253Arg, p.Pro253Leu, p.Thr254Ala,
    p.Thr254Ser, p.Ala255Thr, p.Ala255Val, p.Arg258Trp, p.Met260Thr and
    p.Met260Val. p.Arg258Trp is the recurrent allele. This node records the genomic
    lesion only; no truncating or whole-gene-deletion allele has been implicated,
    which is itself an argument against haploinsufficiency.
  genetic_context:
    gene:
      preferred_term: AFF4
      term:
        id: hgnc:17869
        label: AFF4
    allele_type: missense
    variant_origin: DE_NOVO
    allelic_events:
    - MISSENSE_VARIANT
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      A single de novo heterozygous missense allele in the AFF4 ALF homology domain.
      The consequence is gain of function - escape from SIAH1-mediated degradation -
      not haploinsufficiency; no truncating allele has been implicated.
  evidence:
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the missense mutations found in AFF4 (c.760A>G (p.Thr254Ala), c.761C>G (p.Thr254Ser) and c.772C>T (p.Arg258Trp)) were de novo"
    explanation: >-
      Reports the three founding alleles and their de novo status.
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 3 missense mutations were located within the ALF (AF4/LAF4/FMR2) homology domain of AFF4, and these missense mutations altered highly evolutionarily conserved amino acids"
    explanation: >-
      Localises the lesion to the ALF homology domain and notes the conservation of
      the affected residues.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the mutations identified in CHOPS syndrome were de novo, and those clustered in the ALF homology domain"
    explanation: >-
      Confirms clustering and de novo origin across an eleven-individual cohort.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p. R258W mutation represents the most common recurrent mutation, and this mutation accounted for 55% of CHOPS syndrome cases."
    explanation: >-
      Identifies the recurrent allele and its share of reported cases.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there are no missense variants reported in this region in ExAC"
    explanation: >-
      Population-database constraint on the affected 14-amino-acid stretch, which is
      why variants there are interpretable as pathogenic.
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, all CHOPS-related pathogenic variants are located in the AFF4 ALF homology domain."
    explanation: >-
      GeneReviews restates the domain restriction as a diagnostic rule.
  downstream:
  - target: Loss of SIAH1-Mediated Degradation of AFF4
    causal_link_type: DIRECT
    description: >-
      The substituted residues sit in the degron that SIAH1 must recognise, so the
      variant protein is no longer efficiently ubiquitinated and degraded.
    evidence:
    - reference: PMID:25730767
      reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the missense mutations found in the three CHOPS syndrome probands caused a decreased clearance of mutated AFF4 protein due to the acquired resistance to SIAH1-mediated proteasomal degradation"
      explanation: >-
        States the causal step from the missense variant to loss of SIAH1-mediated
        clearance.

- name: Loss of SIAH1-Mediated Degradation of AFF4
  biological_scale: MOLECULAR
  description: >-
    Wild-type AFF4 is cleared by the SIAH1 ubiquitin E3 ligase through the
    proteasome. Co-expression experiments in HEK293T cells show that each CHOPS
    allele resists SIAH1-driven degradation, and proteasome inhibition with MG132
    restores wild-type AFF4 levels - confirming the route being escaped is
    proteasomal. The same escape was demonstrated independently for the later
    alleles p.Ala255Thr and p.Pro253Arg. This is a protein-turnover defect, distinct
    from the abundance change it produces.
  molecular_functions:
  - preferred_term: SIAH1 ubiquitin ligase binding
    term:
      id: GO:0031625
      label: ubiquitin protein ligase binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: proteasomal degradation of AFF4
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the AFF4 constructs containing the missense mutations found in the three CHOPS syndrome probands hindered the degradation of AFF4 with SIAH1 overexpression"
    explanation: >-
      Direct demonstration that the CHOPS alleles escape SIAH1-mediated degradation.
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The addition of MG132, which is a proteosomal degradation inhibitor, resulted in the recovery of AFF4 bands."
    explanation: >-
      Identifies the proteasome as the degradation route being escaped.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "both p.A255T and p.P253R mutants showed a similar resistance to degradation when co-transfected with SIAH1 as the p.T254A mutant"
    explanation: >-
      Extends the same degradation-resistance mechanism to two later-identified
      alleles.
  downstream:
  - target: Accumulation of Chromatin-Associated AFF4 Protein
    causal_link_type: DIRECT
    description: >-
      Reduced clearance raises the steady-state amount of AFF4 protein.
    evidence:
    - reference: PMID:25730767
      reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The amount of AFF4 protein in patient derived skin fibroblasts was elevated, supporting the suggestion that the missense mutations found in these probands results in a more stable AFF4 protein"
      explanation: >-
        Links reduced clearance to the measured rise in AFF4 protein in patient cells.

- name: Accumulation of Chromatin-Associated AFF4 Protein
  biological_scale: MOLECULAR
  description: >-
    AFF4 protein is elevated in patient-derived skin fibroblasts while AFF4 mRNA is
    unchanged, confirming a post-translational cause. The excess partitions
    specifically to the chromatin fraction, and the other SEC components ELL2 and
    CDK9 are not correspondingly increased - so the complex is not simply more
    abundant; its scaffold is over-represented on chromatin. Deleting the mutant
    allele in a patient line lowers AFF4 back down, attributing the accumulation to
    the mutant allele rather than to a trans effect.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  cellular_components:
  - preferred_term: super elongation complex
    term:
      id: GO:0032783
      label: super elongation complex
  biological_processes:
  - preferred_term: AFF4 protein stabilization
    term:
      id: GO:0050821
      label: protein stabilization
    modifier: INCREASED
  evidence:
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The amount of AFF4 protein in patient derived skin fibroblasts was elevated, supporting the suggestion that the missense mutations found in these probands results in a more stable AFF4 protein"
    explanation: >-
      Establishes AFF4 protein accumulation in patient cells.
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "accumulation of AFF4 mainly occurred on the chromatin fraction in the CHOPS syndrome cell lines"
    explanation: >-
      Localises the excess AFF4 to chromatin, which is where it acts.
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The amount of other SEC components such as ELL2 and CDK9 did not show major alterations in the chromatin fraction of the CHOPS syndrome cell lines."
    explanation: >-
      Shows the accumulation is scaffold-specific rather than a uniform increase in
      the whole complex - the reason this node is worth separating from SEC activity.
  downstream:
  - target: Dysregulated SEC-Dependent Transcriptional Elongation
    causal_link_type: DIRECT
    description: >-
      Excess chromatin-bound AFF4 alters the genome-wide deployment of the SEC and
      of RNA polymerase II.
    evidence:
    - reference: PMID:25730767
      reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome."
      explanation: >-
        Measures the altered genome-wide deployment that this edge asserts.
  - target: Attenuation of Enhancer Complexes and Enhancer-Promoter Looping
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In patient cells the enhancer landscape is degraded in parallel with the
      elongation defect; the step from AFF4 accumulation to enhancer-complex loss is
      not yet resolved mechanistically.

- name: Dysregulated SEC-Dependent Transcriptional Elongation
  biological_scale: MOLECULAR
  description: >-
    The super elongation complex mobilises promoter-proximally paused RNA polymerase
    II, with its P-TEFb (CDK9-cyclin T1) module phosphorylating Ser2 of the RNAP2
    C-terminal domain to license productive elongation. With AFF4 over-represented on
    chromatin, genome-wide binding of AFF4, RNAP2 and cohesin is altered and direct
    AFF4 target genes are de-repressed: MYC, JUN, TMEM100, ZNF711 and FAM13C are all
    significantly upregulated in patient fibroblasts. This is the gain-of-function
    read-out that names the mechanism.
  biological_processes:
  - preferred_term: transcription elongation by RNA polymerase II
    term:
      id: GO:0006368
      label: transcription elongation by RNA polymerase II
    modifier: GAIN_OF_FUNCTION
  - preferred_term: positive regulation of transcriptional elongation
    term:
      id: GO:0032968
      label: positive regulation of transcription elongation by RNA polymerase II
    modifier: INCREASED
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  evidence:
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2)."
    explanation: >-
      States the normal function of the complex whose activity is dysregulated here.
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CDK9 phosphorylates the Ser2 residue of RNAP2 in order for initiation of transcriptional elongation"
    explanation: >-
      Names the molecular step by which the SEC licenses productive elongation.
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The up-regulation of 5 of these genes was statistically significant: MYC, JUN, TMEM100, ZNF711 and FAM13C. These observations further support the notion that AFF4 mutations render gain-of-function effects."
    explanation: >-
      Quantitative evidence that direct AFF4 targets are de-repressed, and the
      authors' own basis for calling the mechanism gain of function.
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome."
    explanation: >-
      Genome-wide evidence that AFF4, cohesin and RNAP2 deployment is altered.
  - reference: PMID:37528066
    reference_title: "Distinct roles of two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA polymerase II transcription elongation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "AFF1 mainly binds upstream of the TSS, while AFF4 is enriched downstream of the TSS."
    explanation: >-
      Establishes that AFF4 specifically occupies the post-initiation region where
      elongation is controlled, which is why an excess of chromatin-bound AFF4 is
      expected to act on elongation rather than on initiation. This is general cell
      biology in non-CHOPS cells, not a patient-derived observation.
  - reference: PMID:37528066
    reference_title: "Distinct roles of two SEC scaffold proteins, AFF1 and AFF4, in regulating RNA polymerase II transcription elongation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "disruption of AFF4 results in slow elongation and early termination in a subset of AFF4-bound active genes, whereas AFF1 deletion leads to fast elongation and transcriptional readthrough in the same subset of genes"
    explanation: >-
      Shows AFF4 dosage on chromatin sets elongation rate and termination in a
      gene-selective way. It is curated as PARTIAL because the experiment is AFF4
      loss, the opposite direction from the CHOPS gain of function, so it constrains
      the mechanism without directly evidencing it.
  downstream:
  - target: Global Transcriptional Dysregulation of Developmental Gene Programmes
    causal_link_type: DIRECT
    description: >-
      Altered elongation control propagates into a genome-scale change in the
      developmental transcriptome.
    evidence:
    - reference: PMID:25730767
      reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Using an FDR cutoff of 0.2, 288 genes were downregulated in patient skin fibroblasts, and 445 genes were upregulated in patient samples"
      explanation: >-
        Quantifies the genome-scale transcriptional change in patient cells.

- name: Attenuation of Enhancer Complexes and Enhancer-Promoter Looping
  biological_scale: MOLECULAR
  description: >-
    Chromosome-architecture analysis of CHOPS and CdLS patient cell lines found
    cohesin, the cohesin loader NIPBL, BRD4 and H3K27ac all reduced at most
    enhancers, with attenuation of enhancer-promoter loops, while topologically
    associating domains were preserved. The lesion is therefore at the level of
    enhancer complex maintenance and looping, not at the level of large-scale genome
    compartmentalisation - and it is shared with CdLS, which is the structural basis
    of the two disorders' phenotypic overlap.
  biological_processes:
  - preferred_term: chromatin looping
    term:
      id: GO:0140588
      label: chromatin looping
    modifier: DECREASED
  cellular_components:
  - preferred_term: cohesin complex
    term:
      id: GO:0008278
      label: cohesin complex
  cell_types:
  - preferred_term: patient-derived skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  evidence:
  - reference: PMID:39983729
    reference_title: "A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In both patient cells, we found a decrease in cohesin, NIPBL, BRD4, and acetylation of lysine 27 on histone H3"
    explanation: >-
      Reports the loss of enhancer-complex components in CHOPS patient cells.
  - reference: PMID:39983729
    reference_title: "A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By contrast, TADs were maintained in both patient cells."
    explanation: >-
      Bounds the claim: the defect is enhancer/loop-level, not TAD-level.
  - reference: PMID:39983729
    reference_title: "A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings reveal a shared molecular mechanism in these syndromes and highlight unexpected roles for cohesin, cohesin loaders, and the SEC in maintaining the enhancer complexes."
    explanation: >-
      States the shared-mechanism conclusion linking CHOPS syndrome to CdLS.
  downstream:
  - target: Global Transcriptional Dysregulation of Developmental Gene Programmes
    causal_link_type: DIRECT
    description: >-
      Loss of enhancer complexes and enhancer-promoter contacts changes which
      developmental genes are transcribed.
    evidence:
    - reference: PMID:39983729
      reference_title: "A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These complexes are crucial for recruiting transcriptional regulators, sustaining active histone modifications, and facilitating enhancer-promoter looping."
      explanation: >-
        States that the enhancer complexes whose loss is measured are what recruit
        transcriptional regulators, which is the step this edge asserts.

- name: Global Transcriptional Dysregulation of Developmental Gene Programmes
  biological_scale: CELLULAR
  description: >-
    Expression profiling of patient fibroblasts identifies hundreds of dysregulated
    genes. Upregulated genes are enriched for homeobox proteins, skeletal system
    development and morphogenesis, anterior/posterior pattern formation, and
    embryonic organ development; downregulated genes are enriched for actin-binding
    and extracellular-matrix genes. The dysregulated set correlates positively with
    that of CdLS fibroblasts. This is the disorder-agnostic convergence point that
    CHOPS syndrome shares with the wider class of transcriptional-regulation
    disorders.
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  - preferred_term: skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "upregulated genes are enriched for Homeobox proteins, skeletal system development/morphogenesis and anterior/posterior pattern formation as well as embryonic organ development/morphogenesis, and downregulated genes are enriched for actin binding genes and extracellular matrix genes"
    explanation: >-
      Characterises which developmental programmes are disturbed, connecting the
      molecular lesion to a skeletal and organ-morphogenesis phenotype.
  - reference: PMID:27867341
    reference_title: "Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Some genetic disorders caused by mutations in genes encoding components of the transcriptional machinery as well as proteins involved in epigenetic modification of the genome share many overlapping features, such as facial dysmorphisms, growth problems and developmental delay/intellectual disability."
    explanation: >-
      Places CHOPS syndrome in the disorders-of-transcriptional-regulation class and
      explains why global transcriptional disturbance yields this phenotype triad.
  downstream:
  - target: Multisystem Developmental Malformation and Growth Dysregulation
    causal_link_type: DIRECT
    description: >-
      Disturbed developmental transcription during embryogenesis produces structural
      malformation across organ systems.
  - target: Food-Seeking Behaviour and Impaired Satiety
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The route from transcriptional dysregulation to the appetite phenotype is not
      established; the link is asserted only as an unexplained consequence.

- name: Multisystem Developmental Malformation and Growth Dysregulation
  biological_scale: ORGANISM
  description: >-
    The organism-level convergence node: craniofacial, cardiac, pulmonary, skeletal,
    genitourinary, ocular and neurodevelopmental structures are all affected, with
    linear growth failure that is not corrected by a normal growth hormone response.
    Phenotypes attach here.
  biological_processes:
  - preferred_term: heart development
    term:
      id: GO:0007507
      label: heart development
    modifier: ABNORMAL
  - preferred_term: lung development
    term:
      id: GO:0030324
      label: lung development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These individuals have a distinct phenotype, that is, characterized by short stature, characteristic facial features (synophrys, arched eyebrows, long eyelashes, upturned nasal tip with anteverted nares and coarse, full facies), congenital heart defects, pulmonary involvement, brachydactyly and other skeletal involvement, genitourinary issues, and developmental delay/intellectual disability."
    explanation: >-
      Enumerates the organ systems that converge at this node.
  - reference: PMID:42273204
    reference_title: "CHOPS Syndrome: A Rare Malformation Syndrome with de novo AFF4 Gene Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient exhibited significant growth failure despite an adequate growth hormone response."
    explanation: >-
      Shows the growth failure is not attributable to growth hormone deficiency,
      which is why it is placed at the developmental-programme node rather than at a
      pituitary one.

- name: Food-Seeking Behaviour and Impaired Satiety
  biological_scale: ORGANISM
  description: >-
    Excessive food-seeking behaviour with impaired satiety is near-universal and is
    one of the features that distinguishes CHOPS syndrome from CdLS. On a
    food-related problems questionnaire originally designed for Prader-Willi
    syndrome, the impairment-of-satiety items scored highest, every respondent
    reported their child helping themselves to forbidden food, and most families had
    found it necessary to lock food away. The node is behavioural and deliberately
    makes no hypothalamic claim - no mechanism linking AFF4 to appetite regulation
    has been demonstrated.
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive food-seeking behaviors and over-affection were common in all individuals, in addition to pulmonary involvement, which are not seen in CdLS"
    explanation: >-
      Establishes food-seeking behaviour as a consistent and CHOPS-discriminating
      feature.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The group of questions pertaining to impairment of satiety category had the highest average scores ranging from 3 to 4.5."
    explanation: >-
      Instrumented evidence that satiety, specifically, is impaired.
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurobehavioral features include disruptive and self-absorbed behaviors, communication disturbance, and food-seeking behaviors leading to obesity."
    explanation: >-
      GeneReviews places food-seeking behaviour causally upstream of the obesity.
  downstream:
  - target: Multisystem Developmental Malformation and Growth Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hyperphagia contributes the weight arm of the characteristic
      short-but-heavy growth pattern, in which weight percentiles sit
      disproportionately above height percentiles.

phenotypes:
- category: Neurological
  name: Developmental Delay and Intellectual Disability
  description: >-
    Every individual reported has developmental delay with mild-to-moderate
    intellectual disability, and importantly without regression. Motor milestones are
    substantially delayed - independent walking at an average of 4.8 years in the
    eleven-individual cohort.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals reported to date have mild-to-moderate developmental delay and intellectual disability without regression."
    explanation: >-
      GeneReviews states both the universality and the mild-to-moderate severity,
      supporting the VERY_FREQUENT band.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All individuals with CHOPS syndrome had developmental delay, and varying degrees of intellectual disability."
    explanation: >-
      Independent cohort confirmation that the feature is universal.
- category: Neurological
  name: Global Developmental Delay
  description: >-
    Delay across motor and communication domains from infancy; rolling at an average
    of 12 months, sitting at 18 months, and independent walking between 3 and 6
    years.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The age at which individuals with CHOPS syndrome started rolling ranges between 9 and 15 months (average: 12 months), age to sit independently ranges between 11 months and 3 years (average: 18 months), and age to walk independently ranges between 3 and 6 years (average: 4.8 years)."
    explanation: >-
      Quantifies the delay across motor milestones.
- category: Behavioral
  name: Hyperphagia and Food-Seeking Behaviour
  description: >-
    Preoccupation with food and impaired satiety, requiring food to be locked away in
    most families. This is the behavioural driver of the obesity and one of the
    features distinguishing CHOPS syndrome from Cornelia de Lange syndrome.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Polyphagia
    term:
      id: HP:0002591
      label: Polyphagia
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive food-seeking behaviors and over-affection were common in all individuals, in addition to pulmonary involvement, which are not seen in CdLS"
    explanation: >-
      Reports the behaviour in all individuals of the cohort, supporting the
      VERY_FREQUENT band.
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "food-seeking behaviors leading to obesity"
    explanation: >-
      GeneReviews independently records the behaviour and its consequence.
- category: Behavioral
  name: Disruptive and Self-Absorbed Behaviour
  description: >-
    Behavioural profile on the Developmental Behaviour Checklist is dominated by
    disruptive, self-absorbed and communication-disturbance behaviours, including
    temper tantrums and disrobing. Notably, significant autistic behaviour was not
    observed in the reported cohort.
  phenotype_term:
    preferred_term: Disruptive and self-absorbed behaviour
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurobehavioral features include disruptive and self-absorbed behaviors, communication disturbance, and food-seeking behaviors leading to obesity."
    explanation: >-
      Names the behavioural domains affected.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most problematic behaviors in all individuals included disruptive, self-absorbed, and communication disturbance behaviors."
    explanation: >-
      Instrumented behavioural assessment identifying the same domains.
- category: Behavioral
  name: Temper Tantrums
  description: >-
    Temper tantrums are named among the recurrent disruptive behaviours, alongside
    food-seeking and disrobing.
  phenotype_term:
    preferred_term: Temper tantrums
    term:
      id: HP:0025160
      label: Abnormal temper tantrums
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common disruptive behaviors included excessive food seeking behaviors, throwing off clothes, and temper tantrums."
    explanation: >-
      Names temper tantrums as a recurrent behaviour. No denominator is given, so no
      frequency band is asserted.
- category: Behavioral
  name: Over-Affectionate Social Behaviour
  description: >-
    Indiscriminate over-affection was reported in all individuals of the cohort and,
    like the food-seeking behaviour, is one of the features not seen in Cornelia de
    Lange syndrome.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Over-affectionate behaviour
    term:
      id: HP:0012433
      label: Abnormal social behavior
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive food-seeking behaviors and over-affection were common in all individuals, in addition to pulmonary involvement, which are not seen in CdLS"
    explanation: >-
      Reports over-affection in all individuals of the cohort, supporting the
      VERY_FREQUENT band, and marks it as a CHOPS-discriminating feature.
- category: Craniofacial
  name: Coarse Facial Features
  description: >-
    Coarse facies with a round face and full cheeks, becoming progressively more
    recognisable with age. This evolution is one of the features that eventually
    separates the CHOPS gestalt from the CdLS gestalt, which the younger face
    resembles.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coarse facies and round face with full cheeks become more noticeable with age."
    explanation: >-
      Records both the feature and its progressive character.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional distinctive facial dysmorphia included anteverted nares, coarse facies, and facial fullness"
    explanation: >-
      Cohort confirmation of coarse facies and facial fullness.
- category: Craniofacial
  name: Synophrys
  description: Confluent eyebrows, present in all eleven individuals of the reported cohort.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes."
    explanation: >-
      Reports synophrys in 11 of 11 individuals, supporting VERY_FREQUENT.
- category: Craniofacial
  name: Highly Arched Eyebrows
  description: Arched, thick eyebrows, part of the CdLS-like facial gestalt.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes."
    explanation: >-
      Arched eyebrows reported in 11 of 11 individuals.
- category: Craniofacial
  name: Long Eyelashes
  description: Trichomegaly of the eyelashes, a shared feature with CdLS.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Long eyelashes
    term:
      id: HP:0000527
      label: Long eyelashes
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes."
    explanation: >-
      Long eyelashes reported in 11 of 11 individuals.
- category: Craniofacial
  name: Anteverted Nares
  description: Upturned nasal tip with anteverted nares.
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic facial features include synophrys, highly arched eyebrows, long eyelashes, proptosis, and anteverted nares."
    explanation: >-
      GeneReviews lists anteverted nares among the characteristic facial features.
- category: Craniofacial
  name: Proptosis
  description: Prominent, protruding globes contributing to the facial gestalt.
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic facial features include synophrys, highly arched eyebrows, long eyelashes, proptosis, and anteverted nares."
    explanation: >-
      GeneReviews lists proptosis among the characteristic facial features.
- category: Craniofacial
  name: Wide Anterior Fontanel
  description: >-
    A large anterior fontanelle was a recurrent finding in three of the eleven
    individuals of the cohort.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Wide anterior fontanel
    term:
      id: HP:0000260
      label: Wide anterior fontanel
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other noted recurrent features were large anterior fontanelle (Case-1, 2, 5), and Wormian skull bones (Case-1, 5)."
    explanation: >-
      Names the three individuals with a large anterior fontanelle; three of eleven
      is 27%, within the OCCASIONAL band.
- category: Craniofacial
  name: Midface Retrusion
  description: >-
    Midface hypoplasia noted on extraoral examination in a detailed dentofacial
    assessment, alongside a broad forehead and large ears.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:42178648
    reference_title: "Dental and Dentofacial Findings in a Child With CHOPS Syndrome Managed Under General Anesthesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extraoral examination revealed midface hypoplasia, thick eyebrows, broad forehead, large ears, and coarse facial appearance."
    explanation: >-
      Single detailed dentofacial case description; frequency is deliberately
      omitted because this rests on one report.
- category: Growth
  name: Short Stature
  description: >-
    Short stature is universal and progressive: birth length averages -2 to -3 SD but
    height at latest follow-up averages around -5 SD, while head circumference stays
    near -2 SD. Growth failure persists despite an adequate growth hormone response.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 11 individuals had short stature and obesity."
    explanation: >-
      11 of 11 individuals, supporting the VERY_FREQUENT band.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the measurements at the latest clinic visit indicated average height was around −5 SD, although HC remained around −2 SD"
    explanation: >-
      Documents the progressive worsening of the height deficit.
  - reference: PMID:42273204
    reference_title: "CHOPS Syndrome: A Rare Malformation Syndrome with de novo AFF4 Gene Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient exhibited significant growth failure despite an adequate growth hormone response."
    explanation: >-
      Shows growth failure is not explained by growth hormone deficiency.
- category: Growth
  name: Obesity
  description: >-
    Obesity with weight percentiles disproportionately higher than height
    percentiles. Together with pulmonary involvement and skeletal findings, obesity
    is one of the features most reliably distinguishing CHOPS syndrome from CdLS,
    where growth restriction affects weight as well as height.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 11 individuals had short stature and obesity."
    explanation: >-
      11 of 11 individuals, supporting the VERY_FREQUENT band.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Obesity, pulmonary involvement, skeletal findings, and distinct craniofacial features are the most notable features distinguishing CHOPS syndrome from CdLS."
    explanation: >-
      Establishes obesity as a discriminating feature against the main differential.
- category: Cardiovascular
  name: Patent Ductus Arteriosus
  description: >-
    The most common congenital heart defect in CHOPS syndrome, present in six of the
    eight individuals with congenital heart disease in the eleven-individual cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital heart disease was present in 8 of the 11 individuals reported here. Of these eight individuals, six had a patent ductus arteriosis (PDA)"
    explanation: >-
      Six of eleven individuals is 55%, within the FREQUENT band.
- category: Cardiovascular
  name: Ventricular Septal Defect
  description: >-
    The second most common cardiac lesion, in five of the eleven individuals of the
    reported cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "five had a ventricular septal defect (VSD)"
    explanation: >-
      Five of eleven individuals is 45%, within the FREQUENT band.
- category: Cardiovascular
  name: Patent Foramen Ovale
  description: Present in three of the eleven individuals of the reported cohort.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Patent foramen ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and three had a patent foramen ovale (PFO)"
    explanation: >-
      Three of eleven individuals is 27%, within the OCCASIONAL band.
- category: Cardiovascular
  name: Pulmonary Arterial Hypertension
  description: >-
    Reported in two of the eleven individuals of the cohort, and clinically important
    because it compounds the chronic lung disease.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary hypertension was found in Case-1 and Case-6, and a dilated aortic root was noted in Case-6 and Case-7."
    explanation: >-
      Two of eleven individuals is 18%, within the OCCASIONAL band.
- category: Cardiovascular
  name: Dilated Aortic Root
  description: >-
    Aortic root dilatation in two of the eleven individuals of the cohort, in the
    same sentence that records the pulmonary hypertension. HPO has no live term for
    aortic root dilatation - HP:0002616 is aortic root *aneurysm*, a different and
    stronger claim, and the two dilatation terms (HP:0001724, HP:0002622) are
    obsolete - so this is bound to the accurate broader parent rather than to the
    aneurysm term. A term request for aortic root dilatation would let this be
    curated at the granularity the source actually reports.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dilated aortic root
    term:
      id: HP:0001679
      label: Abnormal aortic morphology
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary hypertension was found in Case-1 and Case-6, and a dilated aortic root was noted in Case-6 and Case-7."
    explanation: >-
      Names the two individuals with a dilated aortic root; two of eleven is 18%,
      within the OCCASIONAL band.
- category: Respiratory
  name: Chronic Lung Disease
  description: >-
    Chronic lung disease affects the majority of individuals and its aetiology is
    explicitly undetermined - it is not attributed to prematurity, aspiration or the
    cardiac lesions. Pulmonary involvement overall was present in 8 of 11 individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chronic lung disease
    term:
      id: HP:0006528
      label: Chronic lung disease
    temporality: CHRONIC
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary and respiratory tract involvement was found in 8 of the 11 individuals. Chronic lung disease was noted in six individuals."
    explanation: >-
      Six of eleven individuals is 55%, within the FREQUENT band.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary issues most commonly manifested as chronic lung disease, of as yet undetermined etiology"
    explanation: >-
      Records explicitly that the mechanism of the lung disease is unknown.
- category: Respiratory
  name: Laryngomalacia
  description: >-
    Upper-airway collapse contributing to the respiratory burden; two of the three
    tracheostomised individuals in the cohort had laryngomalacia, and it is also
    described in an independent case report.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Laryngomalacia
    term:
      id: HP:0001601
      label: Laryngomalacia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three subjects (Case-2, 3, 9) required a tracheostomy, with two of these having laryngomalacia (Case-2, 3)."
    explanation: >-
      Two of eleven individuals is 18%, within the OCCASIONAL band.
  - reference: PMID:42273204
    reference_title: "CHOPS Syndrome: A Rare Malformation Syndrome with de novo AFF4 Gene Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features included congenital cataracts, laryngomalacia, and mild mitral insufficiency."
    explanation: >-
      Independent case report of laryngomalacia in CHOPS syndrome.
- category: Respiratory
  name: Subglottic Stenosis
  description: >-
    Fixed structural narrowing of the airway below the vocal cords, distinct from the
    dynamic collapse of laryngomalacia and a separate reason for tracheostomy.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Subglottic stenosis
    term:
      id: HP:0001607
      label: Subglottic stenosis
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Structurally, two cases (Case-2, 6, 7) had subglottic stenosis, and Case-3 had a congenital narrow oropharynx."
    explanation: >-
      Structural airway narrowing in the cohort. Note the source's own case list is
      internally inconsistent (it says "two cases" but names three); the OCCASIONAL
      band covers either reading.
- category: Respiratory
  name: Recurrent Pneumonia
  description: Four of the eleven individuals had a history of pneumonia.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four individuals had a history of pneumonia (Case-1, 2, 7, 9)."
    explanation: >-
      Four of eleven individuals is 36%, within the FREQUENT band.
- category: Respiratory
  name: Sleep Apnea
  description: >-
    Documented in three of the eleven individuals; a recognised surveillance target
    given the combination of obesity and upper-airway anomaly.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sleep apnea
    term:
      id: HP:0010535
      label: Sleep apnea
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary alveolar hemorrhage occurred in Case-1 and Case-7, and sleep apnea was documented in Case-1, 3, 9."
    explanation: >-
      Three of eleven individuals is 27%, within the OCCASIONAL band.
- category: Respiratory
  name: Pulmonary Alveolar Haemorrhage
  description: Alveolar haemorrhage in two of the eleven individuals of the cohort.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pulmonary hemorrhage
    term:
      id: HP:0040223
      label: Pulmonary hemorrhage
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary alveolar hemorrhage occurred in Case-1 and Case-7"
    explanation: >-
      Two of eleven individuals is 18%, within the OCCASIONAL band.
- category: Skeletal
  name: Brachydactyly
  description: >-
    Short digits with small hands, present in eight of eleven individuals; the most
    consistent skeletal finding.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly was present in 8 out of the 11 individuals."
    explanation: >-
      Eight of eleven individuals is 73%, within the FREQUENT band.
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other common features include growth deficiency, respiratory issues, congenital heart defects, small hands, brachydactyly, ocular abnormalities, genitourinary abnormalities, and gastrointestinal manifestations."
    explanation: >-
      GeneReviews independently lists small hands and brachydactyly as common.
- category: Skeletal
  name: Abnormal Vertebral Body Morphology
  description: >-
    Vertebral bodies of abnormal shape with decreased height, anterior beaking,
    congenital vertebral fusion and narrowed intervertebral disc spaces are reported
    across the cohort - the "skeletal dysplasia" of the acronym.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal form of the vertebral bodies
    term:
      id: HP:0003312
      label: Abnormal form of the vertebral bodies
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density."
    explanation: >-
      Reports abnormal vertebral body shape as a common skeletal finding.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An abnormal shape of the vertebral bodies with decreased height, pronounced from T8 to L1, was noted in Case-1"
    explanation: >-
      Radiographic detail of the vertebral involvement.
- category: Skeletal
  name: Reduced Bone Mineral Density
  description: >-
    Low bone mineral density is reported as a common skeletal finding, and reduced
    bone mineralisation was independently noted on panoramic radiography in a
    dentofacial case study.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density."
    explanation: >-
      Names low bone mineral density among the common skeletal features.
  - reference: PMID:42178648
    reference_title: "Dental and Dentofacial Findings in a Child With CHOPS Syndrome Managed Under General Anesthesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Panoramic radiography demonstrated reduced bone mineralization and agenesis of all second premolars and Tooth 47."
    explanation: >-
      Independent radiographic observation of reduced mineralisation in the jaws.
- category: Skeletal
  name: Wormian Bones
  description: >-
    Accessory sutural bones in the cranial sutures, reported in two of the eleven
    individuals. Wormian bones and the wide anterior fontanel together indicate
    delayed or abnormal cranial ossification, consistent with the reduced bone
    mineral density recorded separately.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Wormian bones
    term:
      id: HP:0002645
      label: Wormian bones
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other noted recurrent features were large anterior fontanelle (Case-1, 2, 5), and Wormian skull bones (Case-1, 5)."
    explanation: >-
      Names the two individuals with Wormian skull bones; two of eleven is 18%,
      within the OCCASIONAL band.
- category: Skeletal
  name: Hypoplastic Long Bones
  description: >-
    Long-bone hypoplasia is listed among the common skeletal findings, with
    bilateral hypoplasia of the proximal radii and of the fibulae documented
    radiographically in one individual, and shortening of the proximal humeri and
    metacarpals with hypoplastic distal phalanges in another. No frequency is
    asserted because the summary sentence gives no count.
  phenotype_term:
    preferred_term: Hypoplastic long bones
    term:
      id: HP:0045060
      label: Aplasia/hypoplasia involving bones of the extremities
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density."
    explanation: >-
      Lists hypoplastic long bones among the common skeletal features. The sentence
      gives no denominator, which is why frequency is omitted.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoplasia of the proximal radii bilaterally, hypoplasia of the fibula bilaterally was noted in Case-3"
    explanation: >-
      Radiographic detail naming the specific long bones affected.
- category: Skeletal
  name: Small Hands
  description: Small hands accompanying the brachydactyly.
  phenotype_term:
    preferred_term: Small hand
    term:
      id: HP:0200055
      label: Small hand
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other common features include growth deficiency, respiratory issues, congenital heart defects, small hands, brachydactyly, ocular abnormalities, genitourinary abnormalities, and gastrointestinal manifestations."
    explanation: >-
      GeneReviews lists small hands among the common features.
- category: Ophthalmological
  name: Cataract
  description: >-
    Cataracts, including congenital cataracts, in three of the eleven individuals of
    the cohort and in an independent case report; GeneReviews recommends
    subspecialist treatment.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported abnormalities included myopia (Case-2, 8, 9), strabismus (Case-5, 8), cataracts (Case-3, 9, 10), ptosis (Case-5, 6), hypothyroidism (Case-4), acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)."
    explanation: >-
      Three of eleven individuals is 27%, within the OCCASIONAL band.
  - reference: PMID:42273204
    reference_title: "CHOPS Syndrome: A Rare Malformation Syndrome with de novo AFF4 Gene Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features included congenital cataracts, laryngomalacia, and mild mitral insufficiency."
    explanation: >-
      Independent report of congenital cataract.
- category: Ophthalmological
  name: Myopia
  description: >-
    Refractive error in three of eleven individuals; GeneReviews makes annual
    ophthalmological assessment for myopia and strabismus a surveillance
    recommendation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported abnormalities included myopia (Case-2, 8, 9), strabismus (Case-5, 8), cataracts (Case-3, 9, 10), ptosis (Case-5, 6), hypothyroidism (Case-4), acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)."
    explanation: >-
      Three of eleven individuals is 27%, within the OCCASIONAL band.
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Assess for myopia and strabismus per ophthalmologist and at least annually; annual audiology evaluation."
    explanation: >-
      GeneReviews treats myopia as expected enough to warrant annual surveillance.
- category: Ophthalmological
  name: Strabismus
  description: Ocular misalignment, reported in two of eleven individuals.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported abnormalities included myopia (Case-2, 8, 9), strabismus (Case-5, 8), cataracts (Case-3, 9, 10), ptosis (Case-5, 6), hypothyroidism (Case-4), acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)."
    explanation: >-
      Two of eleven individuals is 18%, within the OCCASIONAL band.
- category: Ophthalmological
  name: Ptosis
  description: Drooping eyelids, reported in two of eleven individuals.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other reported abnormalities included myopia (Case-2, 8, 9), strabismus (Case-5, 8), cataracts (Case-3, 9, 10), ptosis (Case-5, 6), hypothyroidism (Case-4), acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)."
    explanation: >-
      Two of eleven individuals is 18%, within the OCCASIONAL band.
- category: Auditory
  name: Hearing Impairment
  description: >-
    Some form of hearing loss in eight of eleven individuals; annual audiology
    evaluation is a GeneReviews surveillance recommendation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight out of 11 individuals were reported to have some type of hearing loss"
    explanation: >-
      Eight of eleven individuals is 73%, within the FREQUENT band.
- category: Gastrointestinal
  name: Feeding Difficulties Requiring Gastrostomy
  description: >-
    Six of the eleven individuals required gastrostomy tube placement, and feeding
    therapy plus G-tube placement as needed is a GeneReviews management
    recommendation. Note this coexists with hyperphagia later in life - the feeding
    problem is one of safe oral intake, not of appetite.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six individuals (Case-2, 3, 6, 7, 9, 10) required G-tube insertion."
    explanation: >-
      Six of eleven individuals is 55%, within the FREQUENT band.
- category: Gastrointestinal
  name: Constipation
  description: Constipation in four of the eleven individuals of the cohort.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Constipation was present in four individuals (Case-1, 2, 3, and 11)."
    explanation: >-
      Four of eleven individuals is 36%, within the FREQUENT band.
- category: Genitourinary
  name: Cryptorchidism
  description: Undescended testes, reported in a male in the cohort.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genital abnormalities in males included cryptorchidism (Case-2), hypospadias (Case-5), and small genitalia (Case-5 and Case-11)."
    explanation: >-
      Single-individual observation; frequency omitted since the denominator is
      males only and the count is one.
- category: Genitourinary
  name: Hypospadias
  description: Reported in a male in the cohort, alongside small genitalia.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genital abnormalities in males included cryptorchidism (Case-2), hypospadias (Case-5), and small genitalia (Case-5 and Case-11)."
    explanation: >-
      Single-individual observation; frequency omitted for the same reason.
- category: Genitourinary
  name: Small Genitalia
  description: >-
    Hypoplastic external genitalia in two of the male individuals in the cohort,
    reported in the same sentence as the cryptorchidism and hypospadias. No genital
    abnormality was reported in any female.
  phenotype_term:
    preferred_term: Small genitalia
    term:
      id: HP:0000050
      label: Hypoplastic male external genitalia
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genital abnormalities in males included cryptorchidism (Case-2), hypospadias (Case-5), and small genitalia (Case-5 and Case-11)."
    explanation: >-
      Names the two individuals with small genitalia. Frequency is omitted because
      the denominator is males only and is not stated.
- category: Genitourinary
  name: Horseshoe Kidney
  description: Renal fusion anomaly in two of the eleven individuals of the cohort.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Horseshoe kidney
    term:
      id: HP:0000085
      label: Horseshoe kidney
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other anomalies of the genitourinary system included horseshoe kidney (Case-1, 5) and vesicoureteral reflux (Case-2, 3)."
    explanation: >-
      Two of eleven individuals is 18%, within the OCCASIONAL band.
- category: Genitourinary
  name: Vesicoureteral Reflux
  description: Reported in two of the eleven individuals of the cohort.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Vesicoureteral reflux
    term:
      id: HP:0000076
      label: Vesicoureteral reflux
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other anomalies of the genitourinary system included horseshoe kidney (Case-1, 5) and vesicoureteral reflux (Case-2, 3)."
    explanation: >-
      Two of eleven individuals is 18%, within the OCCASIONAL band.
- category: Endocrine
  name: Acanthosis Nigricans
  description: >-
    Velvety hyperpigmented skin thickening, a marker of insulin resistance,
    consistent with the obesity phenotype; reported in two of eleven individuals.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Acanthosis nigricans
    term:
      id: HP:0000956
      label: Acanthosis nigricans
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "acanthosis nigricans and skin changes (Case-5, 8), and gynecomastia (Case-5)"
    explanation: >-
      Two of eleven individuals is 18%, within the OCCASIONAL band.
- category: Dental
  name: Enamel Hypoplasia and Tooth Agenesis
  description: >-
    A single detailed dentofacial assessment found a narrow high palatal vault,
    enamel hypoplasia, extensive caries, and agenesis of all second premolars plus
    one molar. These oral features had not previously been reported in CHOPS
    syndrome, so they are curated without a frequency band.
  phenotype_term:
    preferred_term: Enamel hypoplasia
    term:
      id: HP:0006297
      label: Enamel hypoplasia
  evidence:
  - reference: PMID:42178648
    reference_title: "Dental and Dentofacial Findings in a Child With CHOPS Syndrome Managed Under General Anesthesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intraoral findings included a narrow and high palatal vault, enamel hypoplasia, and multiple carious lesions."
    explanation: >-
      Reports the enamel defect and palatal morphology.
  - reference: PMID:42178648
    reference_title: "Dental and Dentofacial Findings in a Child With CHOPS Syndrome Managed Under General Anesthesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report highlights previously unrecognized oral and craniofacial features of CHOPS syndrome"
    explanation: >-
      The authors state these are newly recognised features, which is why no
      frequency is asserted.
- category: Neurological
  name: Cerebral Atrophy and Corpus Callosum Hypoplasia
  description: >-
    Neuroimaging abnormalities reported in a single individual; structural brain
    involvement is not an established core feature of CHOPS syndrome and is curated
    here without a frequency band.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:42273204
    reference_title: "CHOPS Syndrome: A Rare Malformation Syndrome with de novo AFF4 Gene Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neuroimaging findings indicative of cortical atrophy and corpus callosum hypoplasia"
    explanation: >-
      Single case report of these neuroimaging findings.
- category: Vascular
  name: Moyamoya Phenomenon and Systemic Vasculopathy
  description: >-
    A single individual with a p.Pro253Leu variant developed moyamoya disease
    requiring three synangiosis procedures, with diffuse narrowing of the renal
    arteries and infrarenal aorta. The association is not established: the same
    individual carried the RNF213 p.Arg4810Lys moyamoya susceptibility allele
    inherited from an asymptomatic mother, and the authors themselves called for more
    observation before accepting a link.
  phenotype_term:
    preferred_term: Moyamoya phenomenon
    term:
      id: HP:0011834
      label: Moyamoya phenomenon
  evidence:
  - reference: PMID:33248856
    reference_title: "A case of CHOPS syndrome accompanied with moyamoya disease and systemic vasculopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was also diagnosed with Moyamoya disease at 6 years of age and had undergone synangiosis surgery thrice. Her renal arteries and infrarenal aorta were diffusely narrowed."
    explanation: >-
      Documents the vasculopathy in an individual with a confirmed AFF4 variant, but
      only in a single case.
  - reference: PMID:33248856
    reference_title: "A case of CHOPS syndrome accompanied with moyamoya disease and systemic vasculopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No additional candidate variants for her vascular manifestation were found except a susceptibility variant, c.14429G > A (p.Arg4810Lys) in RNF213, inherited from asymptomatic mother."
    explanation: >-
      Names the competing explanation - an RNF213 moyamoya susceptibility allele -
      which is why this is curated as PARTIAL rather than SUPPORT.
  - reference: PMID:33248856
    reference_title: "A case of CHOPS syndrome accompanied with moyamoya disease and systemic vasculopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More clinical observations and functional studies are required to clarify this association."
    explanation: >-
      The authors decline to assert the association, and this entry follows them.

genetic:
- name: AFF4
  association: De novo heterozygous missense variants in the ALF homology domain
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    AFF4 (chromosome 5q31.1) encodes the scaffold subunit of the super elongation
    complex. Every CHOPS allele is a missense change within a highly conserved
    14-amino-acid stretch of the ALF homology domain (approximately residues
    251-263), which carries the SIAH1 degron. p.Arg258Trp is recurrent and accounted
    for 55% of cases in the largest published series; p.Pro253Arg, p.Pro253Leu,
    p.Thr254Ala, p.Thr254Ser, p.Ala255Thr, p.Ala255Val, p.Met260Thr and p.Met260Val
    are also reported. The mechanism is gain of function through escape from
    proteasomal degradation, not haploinsufficiency - no truncating allele has been
    implicated, and the restriction of pathogenic variation to this one small domain
    is what makes targeted AFF4 sequencing a viable diagnostic route.
  gene_term:
    preferred_term: AFF4
    term:
      id: hgnc:17869
      label: AFF4
  evidence:
  - reference: PMID:25730767
    reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome"
    explanation: >-
      Establishes AFF4 as the causative gene and names the disorder.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p. R258W mutation represents the most common recurrent mutation, and this mutation accounted for 55% of CHOPS syndrome cases."
    explanation: >-
      Quantifies the recurrent allele's contribution.
  - reference: PMID:40904637
    reference_title: "Identification of a novel de novo AFF4 variant (c.778A>G) associated with CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analyses identified a de novo heterozygous c.778A>G (p.Met260Val) variant in AFF4 in the proband, absent in parents and little sister"
    explanation: >-
      Independent replication in an unrelated family, extending the allelic
      spectrum with trio confirmation of de novo status.
  - reference: PMID:37815186
    reference_title: "The Biological Significance of AFF4: Promoting Transcription Elongation, Osteogenic Differentiation and Tumor Progression."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "As a member of the AF4/FMR2 (AFF) family, AFF4 is a scaffold protein in the superelongation complex (SEC)."
    explanation: >-
      Establishes the normal molecular role of the gene product.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Described as extremely rare; no incidence or prevalence rate has been
    published, so no numeric rate is asserted here. The largest series describes
    eleven individuals and subsequent reports have been single cases. Ascertainment
    is likely incomplete because affected children are frequently referred first as
    suspected Cornelia de Lange syndrome.
  evidence:
  - reference: PMID:40904637
    reference_title: "Identification of a novel de novo AFF4 variant (c.778A>G) associated with CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CHOPS (cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia) syndrome is an extremely rare disorder with multiple congenital anomalies caused by missense variants in the ALF transcription elongation factor 4 gene (AFF4)."
    explanation: >-
      Characterises the disorder as extremely rare.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we provide clinical descriptions of an additional eight individuals with CHOPS syndrome, as well as neurocognitive analysis of three individuals."
    explanation: >-
      Establishes the size of the largest published cohort, which is the basis for
      the case-count claim.

diagnosis:
- name: Molecular Genetic Testing for a Heterozygous AFF4 Variant
  description: >-
    Diagnosis rests on identifying a heterozygous pathogenic AFF4 variant in an
    individual with suggestive clinical findings. Because pathogenic variation is
    confined to a 14-amino-acid stretch of one domain, targeted AFF4 sequencing is a
    practical alternative to exome sequencing once the gestalt is recognised - two of
    eight newly diagnosed individuals in the largest series were found this way.
  diagnosis_term:
    preferred_term: molecular genetic testing for AFF4
    term:
      id: NCIT:C15709
      label: Genetic Testing
  presence: Positive in affected individuals
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of AFF4-related CHOPS syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in AFF4 identified by molecular genetic testing."
    explanation: >-
      States the diagnostic criterion.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In fact, two out of eight of our newly identified patients were found to have AFF4 mutations by targeted AFF4 mutational analysis rather than exome sequencing."
    explanation: >-
      Shows targeted single-gene testing is a viable route once the phenotype is
      recognised clinically.
- name: Clinical Differentiation from Cornelia de Lange Syndrome
  description: >-
    CHOPS syndrome is most often mistaken for CdLS. The discriminating features are
    obesity (CdLS is growth-restricted in weight as well as height), pulmonary
    involvement, skeletal findings, and the coarse full round face that emerges with
    age - as against the shared synophrys, arched eyebrows, long eyelashes and
    upturned nose seen in both.
  presence: Discriminating clinical assessment
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Obesity, pulmonary involvement, skeletal findings, and distinct craniofacial features are the most notable features distinguishing CHOPS syndrome from CdLS."
    explanation: >-
      Names the four discriminating feature classes.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary issues are not typically observed in CdLS and the pulmonary involvement for children with CHOPS syndrome can be significant with chronic lung disease present in the majority of patients"
    explanation: >-
      Elaborates the pulmonary discriminator specifically.

treatments:
- name: Developmental and Educational Support
  description: >-
    Early intervention, special education and behavioural support for the
    mild-to-moderate intellectual disability and the disruptive/food-seeking
    behavioural profile. There is no disease-modifying therapy for CHOPS syndrome;
    management is entirely supportive and organ-directed.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Developmental and educational support; feeding therapy; gastrostomy tube placement as needed; nutritional management for obesity"
    explanation: >-
      GeneReviews management recommendation.
- name: Nutritional Management of Obesity
  description: >-
    Dietary management directed at the obesity, which is driven by impaired satiety
    and food-seeking behaviour rather than by a metabolic defect; families commonly
    need to restrict access to food.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "gastrostomy tube placement as needed; nutritional management for obesity; standard treatments for chronic lung disease and sleep apnea"
    explanation: >-
      GeneReviews recommends nutritional management specifically for the obesity.
  target_mechanisms:
  - target: Food-Seeking Behaviour and Impaired Satiety
    treatment_effect: MODULATES
    description: >-
      Environmental food restriction manages the consequences of impaired satiety;
      it does not correct the underlying behaviour.
- name: Feeding Therapy and Gastrostomy Tube Placement
  description: >-
    Feeding therapy with gastrostomy placement where oral intake is unsafe or
    inadequate; six of eleven individuals in the largest series required a G-tube.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy tube placement
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental and educational support; feeding therapy; gastrostomy tube placement as needed"
    explanation: >-
      GeneReviews management recommendation.
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six individuals (Case-2, 3, 6, 7, 9, 10) required G-tube insertion."
    explanation: >-
      Quantifies how frequently gastrostomy is actually needed.
- name: Management of Chronic Lung Disease and Sleep Apnea
  description: >-
    Standard respiratory management, with tracheostomy where laryngomalacia or
    subglottic stenosis compromises the airway; three of eleven individuals in the
    largest series were tracheostomised. Because the chronic lung disease has no
    identified aetiology, treatment is symptomatic rather than mechanism-directed.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: respiratory therapy
    term:
      id: NCIT:C15322
      label: Respiratory Therapy
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatments for chronic lung disease and sleep apnea; standard vaccinations; tracheostomy as needed for laryngomalacia"
    explanation: >-
      GeneReviews management recommendation covering both the chronic lung disease
      and the airway.
- name: Surgical Repair of Congenital Heart Defects
  description: >-
    Standard cardiac surgical and medical management of the PDA, VSD and other
    lesions, and of vertebral anomalies.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatment for congenital heart defects and vertebral anomalies"
    explanation: >-
      GeneReviews management recommendation.
- name: Cataract Surgery
  description: >-
    Subspecialist surgical management of the cataracts, which include congenital
    cataract.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cataract surgery
    term:
      id: NCIT:C157809
      label: Cataract Surgery
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment of cataract per ophthalmic subspecialist"
    explanation: >-
      GeneReviews routes cataract specifically to an ophthalmic subspecialist.
- name: Ophthalmological Management
  description: >-
    Correction of refractive errors and strabismus, with at least annual
    ophthalmological assessment. The generic procedure term is kept deliberately:
    this entry spans refraction, spectacle correction and strabismus management,
    which no single more specific NCIT clinical-action term covers.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "treatment of refractive errors and strabismus per ophthalmologist; treatment of cataract per ophthalmic subspecialist"
    explanation: >-
      GeneReviews management recommendation.
- name: Hearing Aids for Hearing Loss
  description: >-
    Amplification as needed for the hearing loss seen in the majority of affected
    individuals, with annual audiology evaluation. NCIT has no clinical-action term
    for hearing aid fitting - the former MAXO "hearing aid usage" concept had no
    NCIT equivalent and was dropped - so `term:` is deliberately omitted rather
    than bound to a generic procedure term that would misdescribe a device
    intervention.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid fitting
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hearing aids as needed for hearing loss; standard treatment of genitourinary anomalies and bowel dysfunction"
    explanation: >-
      GeneReviews management recommendation.
- name: Genetic Counseling
  description: >-
    Counseling covering the de novo autosomal dominant mechanism, the roughly 1% sib
    recurrence risk from possible parental gonadal mosaicism, and the availability of
    prenatal and preimplantation testing.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41712746
    reference_title: "AFF4-Related CHOPS Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given this risk, prenatal and preimplantation genetic testing may be considered."
    explanation: >-
      GeneReviews genetic counseling recommendation following from the mosaicism
      recurrence risk.

discussions:
- discussion_id: gap_pulmonary_mechanism_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism does AFF4 gain of function produce chronic lung disease?
  attaches_to:
  - pathophysiology#Multisystem Developmental Malformation and Growth Dysregulation
  rationale: >-
    Pulmonary involvement is one of the two features that most reliably separate
    CHOPS syndrome from CdLS, and it carries much of the morbidity - a third of the
    largest cohort required tracheostomy. Yet the largest clinical series states
    plainly that the aetiology of the chronic lung disease is undetermined, and it is
    not attributed to the cardiac lesions, prematurity, or aspiration. Nothing in the
    published transcriptomic work identifies a lung-specific programme downstream of
    excess AFF4. The pathograph therefore stops at the organism-level malformation
    node rather than inventing a pulmonary mechanism.
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary issues most commonly manifested as chronic lung disease, of as yet undetermined etiology"
    explanation: >-
      The source states the gap in its own words.
  proposed_experiments:
  - experiment_id: exp_lung_lineage_aff4_transcriptomics
    name: Airway and alveolar transcriptomics in AFF4 gain-of-function models
    description: >-
      Profile AFF4 occupancy and transcription in lung epithelial and mesenchymal
      lineages carrying a knock-in CHOPS allele (for example p.Arg258Trp), to test
      whether excess chromatin-bound AFF4 dysregulates a lung developmental or
      airway-remodelling programme rather than acting through a systemic route.
- discussion_id: gap_appetite_mechanism_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How does a transcriptional-elongation defect produce hyperphagia and impaired
    satiety?
  attaches_to:
  - pathophysiology#Food-Seeking Behaviour and Impaired Satiety
  rationale: >-
    The obesity of CHOPS syndrome is behaviourally driven: satiety items score
    highest on a Prader-Willi-derived questionnaire, and families lock food away. But
    no hypothalamic, leptin-melanocortin, or other appetite-pathway link to AFF4 has
    been demonstrated, and the phenotypic resemblance to Prader-Willi syndrome is not
    evidence of a shared mechanism. The causal edge into this node is therefore
    curated as INDIRECT and the node makes no anatomical claim.
  evidence:
  - reference: PMID:31058441
    reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The group of questions pertaining to impairment of satiety category had the highest average scores ranging from 3 to 4.5."
    explanation: >-
      Establishes that the phenotype is one of impaired satiety, which is what a
      mechanism would need to explain.
  proposed_experiments:
  - experiment_id: exp_hypothalamic_appetite_circuit_knockin
    name: Hypothalamic appetite-circuit assessment in a CHOPS knock-in model
    description: >-
      Measure food intake, satiety responses, and AFF4-dependent transcription in
      hypothalamic arcuate neurons of a mouse carrying a CHOPS AFF4 allele, to test
      whether the appetite phenotype has a central origin at all.
- discussion_id: gap_vasculopathy_association_unconfirmed
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is systemic vasculopathy, including moyamoya, part of the CHOPS syndrome
    phenotype?
  attaches_to:
  - phenotypes#Moyamoya Phenomenon and Systemic Vasculopathy
  rationale: >-
    One individual with a p.Pro253Leu AFF4 variant developed moyamoya disease and
    diffuse narrowing of the renal arteries and infrarenal aorta. The observation is
    confounded: the same individual carried the RNF213 p.Arg4810Lys moyamoya
    susceptibility allele inherited from an unaffected mother. With n=1 and a
    competing explanation in the same genome, this cannot be curated as a CHOPS
    feature; the report's own authors ask for more observation. The phenotype is
    recorded with PARTIAL evidence so that a second case would be recognised as
    confirmatory rather than novel.
  evidence:
  - reference: PMID:33248856
    reference_title: "A case of CHOPS syndrome accompanied with moyamoya disease and systemic vasculopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More clinical observations and functional studies are required to clarify this association."
    explanation: >-
      The authors explicitly decline to assert the association.
  proposed_experiments:
  - experiment_id: exp_cohort_vascular_imaging_rnf213
    name: Systematic vascular imaging in a CHOPS syndrome cohort
    description: >-
      Cerebral and abdominal vascular imaging across an unselected CHOPS syndrome
      cohort, with RNF213 genotyping, to establish whether vasculopathy occurs above
      background in AFF4 variant carriers independently of known susceptibility
      alleles.
- discussion_id: gap_shared_vs_specific_arm_partition
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which of the CHOPS phenotypes are driven by enhancer-complex loss shared with
    CdLS, and which by the CHOPS-specific elongation gain of function?
  attaches_to:
  - pathophysiology#Attenuation of Enhancer Complexes and Enhancer-Promoter Looping
  rationale: >-
    CHOPS and CdLS patient cells converge on the same enhancer and looping defect,
    which plausibly accounts for the shared features - synophrys, arched eyebrows,
    long eyelashes, developmental delay, heart defects, hearing loss. But obesity,
    pulmonary involvement and skeletal dysplasia are CHOPS-specific and would have to
    arise from something the shared mechanism does not explain, presumably the
    elongation-side gain of function. No study has yet partitioned the phenotype
    between the two arms, so the pathograph runs both into a single convergence node
    rather than assigning phenotypes to one arm or the other.
  evidence:
  - reference: PMID:39983729
    reference_title: "A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings reveal a shared molecular mechanism in these syndromes and highlight unexpected roles for cohesin, cohesin loaders, and the SEC in maintaining the enhancer complexes."
    explanation: >-
      Establishes the shared arm whose phenotypic scope is the open question.
  proposed_experiments:
  - experiment_id: exp_isogenic_lineage_enhancer_comparison
    name: Allele-resolved comparison of CHOPS and CdLS transcriptomes by lineage
    description: >-
      Differentiate isogenic CHOPS-allele and NIPBL-haploinsufficient iPSC lines into
      lung, cartilage and hypothalamic lineages and compare enhancer occupancy and
      transcription, to identify which programmes diverge between the two disorders
      and therefore which phenotypes belong to the CHOPS-specific arm.

experimental_models:
- name: CHOPS patient-derived dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary skin fibroblast lines from individuals carrying p.Thr254Ala, p.Thr254Ser
    and p.Arg258Trp, with hTERT-immortalised derivatives, compared against
    age- and sex-matched controls and against NIPBL-mutant CdLS fibroblasts. This is
    the system in which every human-cell observation of the CHOPS mechanism was made.
  publication: PMID:25730767
  modeled_mechanisms:
  - target: Accumulation of Chromatin-Associated AFF4 Protein
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides the direct human measurement of AFF4 protein level and its chromatin
      partitioning in cells carrying the endogenous variant.
    limitations: >-
      Dermal fibroblasts are not the affected lineage for any CHOPS phenotype - not
      lung, not cartilage, not neurons - so the magnitude and gene-selectivity of
      AFF4 accumulation in the tissues that actually malform is inferred, not
      measured. Few patient lines were available and controls were correspondingly few.
    readouts:
    - name: Chromatin-fraction AFF4 protein abundance by western blot
      target: Accumulation of Chromatin-Associated AFF4 Protein
      direction: INCREASED
      interpretation: >-
        The variant protein accumulates specifically on chromatin.
      evidence:
      - reference: PMID:25730767
        reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "accumulation of AFF4 mainly occurred on the chromatin fraction in the CHOPS syndrome cell lines"
        explanation: >-
          Reports the fractionation result behind this readout.
    evidence:
    - reference: PMID:25730767
      reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The amount of AFF4 protein in patient derived skin fibroblasts was elevated, supporting the suggestion that the missense mutations found in these probands results in a more stable AFF4 protein"
      explanation: >-
        Justifies the patient fibroblast line as informative for the protein-stability
        mechanism.
  - target: Global Transcriptional Dysregulation of Developmental Gene Programmes
    relationship: MEASURES
    fidelity: LOW
    description: >-
      Supplies the expression-profiling and RNA-seq data defining the dysregulated
      gene set, and the comparison against CdLS fibroblasts.
    limitations: >-
      A fibroblast transcriptome cannot report the developmental programmes of the
      tissues that malform, so the reported enrichment for homeobox and
      skeletal-development genes is suggestive of, not equivalent to, the in vivo
      lesion. Only two patient lines were profiled on the microarray, at an FDR
      cutoff of 0.2.
    readouts:
    - name: Differentially expressed gene count in patient fibroblasts
      target: Global Transcriptional Dysregulation of Developmental Gene Programmes
      direction: ALTERED
      interpretation: >-
        Hundreds of genes change expression in either direction.
      evidence:
      - reference: PMID:25730767
        reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Using an FDR cutoff of 0.2, 288 genes were downregulated in patient skin fibroblasts, and 445 genes were upregulated in patient samples"
        explanation: >-
          Reports the differential-expression counts behind this readout.
    evidence:
    - reference: PMID:25730767
      reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we performed genome-wide expression profiling using Affymetrix U133plus2 chips on patient derived skin fibroblast cell lines"
      explanation: >-
        Establishes that the transcriptomic claims rest on this cell system.
- name: HEK293T AFF4/SIAH1 co-overexpression assay
  experimental_model_type: CELL_LINE
  description: >-
    Transient co-transfection of tagged wild-type or CHOPS-variant AFF4 with SIAH1 in
    HEK293T cells, read out by western blot, with MG132 used to confirm the
    proteasomal route. This is the assay that established gain of function and that
    was reused to validate each newly reported allele.
  publication: PMID:25730767
  modeled_mechanisms:
  - target: Loss of SIAH1-Mediated Degradation of AFF4
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Directly tests whether each variant escapes SIAH1-driven degradation, and is
      the standard functional-validation step for a candidate CHOPS allele.
    limitations: >-
      Both proteins are supraphysiologically overexpressed from cDNA in a
      kidney-derived immortalised line, so the assay establishes that the variant can
      escape SIAH1 but says nothing about the size of the effect at endogenous
      stoichiometry, in a relevant tissue, or during development.
    readouts:
    - name: AFF4 protein level under SIAH1 co-expression
      target: Loss of SIAH1-Mediated Degradation of AFF4
      direction: UNCHANGED
      interpretation: >-
        Variant AFF4 is not depleted by SIAH1 co-expression, whereas wild-type AFF4
        is - the definition of degradation resistance in this assay.
      evidence:
      - reference: PMID:31058441
        reference_title: "Clinical and molecular spectrum of CHOPS syndrome."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "both p.A255T and p.P253R mutants showed a similar resistance to degradation when co-transfected with SIAH1 as the p.T254A mutant, while WT AFF4 experienced a significant decrease when co-transfected with SIAH1"
        explanation: >-
          Reports the comparative band intensities behind this readout.
    evidence:
    - reference: PMID:25730767
      reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we created an AFF4 and SIAH1 overexpression model using HEK293T cells"
      explanation: >-
        Establishes the assay system used for the degradation-resistance claim.

animal_models:
- name: robotic mouse (ENU Aff1 ALF-homology-domain missense)
  species: Mouse
  genotype: Aff1 (Af4) ALF homology domain missense, ENU-induced
  publication: PMID:25730767
  description: >-
    An ENU-mutagenesis ataxia mouse carrying a missense change in the ALF homology
    domain of Aff1, the AFF4 paralogue. Its mechanism - gain of function through
    reduced SIAH1-mediated clearance - is the precedent that led the CHOPS discovery
    team to test the same hypothesis for AFF4. It is a mechanistic analogy, not a
    CHOPS disease model.
  modeled_mechanisms:
  - target: Loss of SIAH1-Mediated Degradation of AFF4
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Demonstrates in a whole organism that a missense change in this domain of an
      ALF-family protein produces gain of function via escape from SIAH1-mediated
      degradation.
    limitations: >-
      The mutated gene is Aff1, not Aff4, and the phenotype is ataxia - not the
      craniofacial, cardiac, pulmonary, skeletal or obesity features of CHOPS
      syndrome. No mouse carrying a CHOPS Aff4 allele has been reported, so there is
      currently no animal model of the disorder itself; this model supports only the
      degradation-escape step.
    evidence:
    - reference: PMID:25730767
      reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A missense mutation in the ALF homology domain of Aff1 (Af4) was reported in the robotic mouse, an ataxia mouse model created by ENU mutagenesis"
      explanation: >-
        Establishes the existence and nature of the model. Curated as PARTIAL because
        the gene is the paralogue and the phenotype is not CHOPS syndrome.
    - reference: PMID:25730767
      reference_title: "Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The pathogenetic mechanism of this missense mutation is a gain-of-function effect due to decreased clearance of the protein by SIAH1 ubiquitin E3 ligase"
      explanation: >-
        States the shared mechanism - degradation escape - that makes this model
        informative for the AFF4 node despite the gene and phenotype mismatch.

datasets: []

📚

References & Deep Research

References

1

PMID:41712746

AFF4-Related CHOPS Syndrome.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

CHOPS Syndrome: Comprehensive Disease-Characteristics Report

Edison Scientific Literature 30 citations 2026-08-19T09:16:41.477218

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.

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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 1-3)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, OpenTargets Search: CHOPS syndrome-AFF4)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 4-6, izumi2015germlinegainoffunctionmutations pages 10-11, izumi2015germlinegainoffunctionmutations pages 11-13)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 1-3)	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 (izumi2015germlinegainoffunctionmutations pages 3-4)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 15-18)	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 (izumi2015germlinegainoffunctionmutations pages 4-6, izumi2015germlinegainoffunctionmutations pages 6-8, izumi2015germlinegainoffunctionmutations pages 3-4)	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 (izumi2015germlinegainoffunctionmutations pages 4-6, izumi2015germlinegainoffunctionmutations pages 8-10, izumi2015germlinegainoffunctionmutations pages 6-8, izumi2016disordersoftranscriptional pages 9-10, tei2024cohesinregulatespromoterproximal pages 1-3)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 15-18)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 15-18)	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 (izumi2015germlinegainoffunctionmutations pages 15-18)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 15-18, izumi2015germlinegainoffunctionmutations pages 8-10)	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 (izumi2015germlinegainoffunctionmutations pages 15-18, izumi2015germlinegainoffunctionmutations pages 8-10)	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 (izumi2015germlinegainoffunctionmutations pages 15-18)	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 (izumi2015germlinegainoffunctionmutations pages 15-18, piche2019theexpandingphenotypes pages 7-9)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 15-18)	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 (izumi2015germlinegainoffunctionmutations pages 15-18, izumi2015germlinegainoffunctionmutations pages 10-11, izumi2015germlinegainoffunctionmutations pages 11-13)	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%) (izumi2015germlinegainoffunctionmutations pages 4-6, izumi2015germlinegainoffunctionmutations pages 11-13)	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 (izumi2015germlinegainoffunctionmutations pages 8-10, izumi2015germlinegainoffunctionmutations pages 18-22, izumi2016disordersoftranscriptional pages 9-10)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 1-3, tei2024cohesinregulatespromoterproximal pages 1-3)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 15-18)	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 (piche2019theexpandingphenotypes pages 7-9)	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 (izumi2015germlinegainoffunctionmutations pages 3-4)	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 (izumi2015germlinegainoffunctionmutations pages 3-4)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, izumi2015germlinegainoffunctionmutations pages 15-18)	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 (izumi2015germlinegainoffunctionmutations pages 3-4)	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 (izumi2015germlinegainoffunctionmutations pages 6-8, izumi2015germlinegainoffunctionmutations pages 3-4)	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 (che2023distinctrolesof pages 2-3, che2023distinctrolesof pages 1-2, tei2024cohesinregulatespromoterproximal pages 1-3)	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 (izumi2015germlinegainoffunctionmutations pages 3-4, tei2024cohesinregulatespromoterproximal pages 1-3)	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.

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

A missense change alters the AFF4 degron/ALF-homology region.
Mutant AFF4 interacts inadequately with the SIAH1 degradation machinery and becomes resistant to ubiquitin-dependent proteasomal clearance.
Stabilized AFF4 accumulates on chromatin as part of the SEC, whose other components include ELL/ELL2 and P-TEFb (CDK9–cyclin T1).
Excess SEC perturbs promoter-proximal Pol II pause release and productive elongation, including altered Ser2-phosphorylated Pol II distribution.
Genome-wide AFF4, cohesin/RAD21, SPT5, and Pol II occupancy changes produce developmental transcriptional dysregulation.
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:

Trio whole-exome or genome sequencing with phenotype-driven analysis of AFF4, including careful review of missense variants near residues Thr254–Arg258.
Confirm by an orthogonal method and test both parents to establish de novo status.
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.
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

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)
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)
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)
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)
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

(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.

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References weighed for topical relevance	5
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Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

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CHOPS Syndrome: Comprehensive Disease-Characteristics Report

Executive summary

1. Disease information

Definition and identifiers

2. Etiology, risk, and protective factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Recent mechanistic developments

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment and current applications

13. Prevention

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15. Model organisms and experimental systems

Evidence assessment and research priorities

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