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MONDO

MONDO:0032572 cardiac, facial, and digital anomalies with developmental delay

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Inheritance

1

Autosomal dominant inheritance HP:0000006

Autosomal dominant, usually de novo. Established familial transmission includes an affected mother and affected dizygotic twins, and a mosaic affected mother transmitting her variant to a non-mosaic affected son. Variable expressivity in these families is distinct from the disputed isolated-CHD variants inherited from apparently unaffected parents. Parental and proband mosaicism can complicate testing and recurrence counseling.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:29961569 SUPPORT Human Clinical

"The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals."

Establishes de novo occurrence and the recurrent p.Arg655Gln allele in the discovery series.

PMID:32376980 SUPPORT Human Clinical

"The cohort includes 36 sporadic cases in which the TRAF7 variant was de novo, one patient with low level maternal mosaicism for the TRAF7 variant, five cases with unknown inheritance and one familial case (patients 24-26) in which affected dizygotic twins inherited a TRAF7 variant from their..."

Includes confirmed familial transmission and low-level maternal mosaicism.

PMID:37067385 SUPPORT Human Clinical

"She was identified to harbor this likely pathogenic variant in a mosaic (33.89%) state in leukocytes."

A clinically affected mother carried the variant in a mosaic state.

+ 1 more reference

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Discussions and Knowledge Gaps

3

Do inherited TRAF7 variants transmitted from unaffected parents cause isolated congenital heart disease, or are the three reported alleles (p.Val142Met, p.Val442Met, c.1998+2T>G) not pathogenic?

CONTROVERSY OPEN controversy_traf7_inherited_variants_and_chd

Attached to

pathophysiology#Heterozygous TRAF7 missense variant phenotypes#Congenital cardiovascular malformation

The PNAS report interpreted three variants found in an isolated-CHD cohort as causal despite transmission from apparently unaffected parents. A published letter challenged their pathogenicity based on population variation, inheritance and absence of the characteristic syndrome; the authors defended functional and computational results. This dispute concerns those alleles and does not negate affected-parent transmission established in syndrome families. Population loss-of-function tolerance alone also does not settle every allele-specific mechanism.

Show evidence (4 references)

PMID:37043537 SUPPORT Human Clinical

"While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects."

The claim under dispute, stated by the authors who made it.

PMID:38466850 REFUTE Human Clinical

"All were inherited from healthy parents, while non-penetrance of TRAF7 variants has not been previously reported in the MCA-IDS."

The letter challenges these three variants on the basis of unaffected transmitting parents; this is distinct from affected-parent transmission in established families.

PMID:38466850 REFUTE Human Clinical

"However, the gnomAD probability of being loss-of-function intolerant of TRAF7 is 0.02, suggesting good tolerance to heterozygous loss-of-function variants in the general population, and arguing against c.1998+2T>G causing a CHD."

The population-genetic argument against the splice allele specifically, which is the one that would establish haploinsufficiency.

+ 1 more reference

TRAF7 sits upstream of the shear-responsive MEKK3-MEK5-ERK5-KLF2 endothelial pathway. Does that branch contribute to the congenital cardiovascular malformations of this syndrome, or only to the vascular-integrity failure seen when Traf7 is deleted outright?

EMERGING HYPOTHESIS OPEN hypothesis_traf7_endothelial_mekk3_erk5_klf2_branch

Attached to

pathophysiology#Heterozygous TRAF7 missense variant phenotypes#Congenital cardiovascular malformation

Global and endothelial Traf7 deletion impairs vascular integrity and Klf2 expression in mice. TRAF7 depletion also reduces shear-induced ERK5 phosphorylation in cultured endothelial cells. These experiments establish normal TRAF7 function, but the contribution of this pathway to human missense-variant disease remains unproven. The clinical predominance of patent ductus arteriosus makes vessel-wall mechanisms worth testing alongside neural crest and ciliary hypotheses.

Show evidence (2 references)

PMID:37583551 SUPPORT Model Organism

"They displayed significantly lower expression of transcription factor Klf2, an essential regulator of vascular hemodynamic forces downstream of the MEKK3-MEK-ERK5 signaling pathway."

Places TRAF7 upstream of the KLF2 axis in the mouse, which is the observation this hypothesis rests on and the limit of what is shown.

PMID:37583551 SUPPORT In Vitro

"Downregulation of TRAF7 as well as SCRIB inhibited fluid shear stress-induced phosphorylation of ERK5 in cultured endothelial cells."

Supports the endothelial signaling branch in cell experiments, without demonstrating a patient-variant effect.

How do allele identity, mosaic distribution and tissue context distinguish developmental TRAF7 disease from tumor-associated TRAF7 alterations, and is tumor incidence increased in constitutional carriers?

KNOWLEDGE GAP OPEN gap_traf7_germline_somatic_overlap_and_tumor_risk

Attached to

pathophysiology#Heterozygous TRAF7 missense variant treatments#Supportive multidisciplinary care

Germline and somatic variant spectra are largely distinct, but absolute mutual exclusivity is inaccurate. The 2020 cohort noted p.Arg524Trp in both syndrome patients and a meningioma carrying an activating SMO variant, leaving the TRAF7 contribution to that tumor uncertain. The 2024 p.Arg653Leu syndrome variant affects the same residue as other tumor substitutions. A mosaic p.Arg641Cys case combines developmental anomalies and meningiomatosis. These observations do not quantify tumor risk for constitutional heterozygotes. Proposed oncological follow-up is based on sparse observations; one reported endometrioid carcinoma occurred in a carrier of a coiled-coil variant of uncertain significance.

Proposed experiments

Side-by-side interactome comparison of germline-type and somatic-type TRAF7 alleles

exp_traf7_allele_matched_interactome

Express matched sets of recurrent germline (p.Arg655Gln, p.Arg524Trp, p.Phe617Leu) and somatic meningioma TRAF7 alleles in one cell background and compare their interactomes by affinity purification mass spectrometry, focusing on IFT57, CYLD, MEKK3 and NEMO, together with ubiquitin ligase activity and cilium assembly readouts.

Decision criterion

Compare prespecified interaction and ciliary readouts across alleles, with expression matching and independent replication; interpret negative results within assay sensitivity.

Would support

discussions#gap_traf7_germline_somatic_overlap_and_tumor_risk

Supporting outcome

Reproducible allele-dependent differences would support distinct molecular effects in the tested system.

Refuting outcome

No detectable difference would weaken that particular assay-level hypothesis without establishing biological equivalence or predicting tumor risk.

Longitudinal tumour-incidence study in a germline TRAF7 cohort

exp_traf7_tumour_incidence_cohort

Follow an international registry cohort of individuals with confirmed germline TRAF7 variants with a defined imaging and clinical protocol, reporting age-specific incidence of meningioma, mesothelioma and other tumours against population expectation.

Decision criterion

Estimate age-specific risk with confidence intervals and adequate follow-up, separating constitutional and mosaic carriers; failure to detect an increase does not establish absence of risk.

Supporting outcome

Excess age-specific incidence would support increased tumor susceptibility; surveillance benefit would still require separate assessment.

Refuting outcome

Sufficiently precise incidence estimates near population expectation would constrain the magnitude of possible excess risk.

Show evidence (3 references)

PMID:32376980 SUPPORT Human Clinical

"To the best of our knowledge, there is only one syndromic variant, p.(Arg524Trp) (de novo or maternal mosaic in four unrelated cases here) that has also been reported in a tumor sample."

Explicit exception to the broad non-overlap claim; the following text notes a co-occurring activating SMO variant.

PMID:35733823 SUPPORT Human Clinical

"This case involved a 15-year-old girl with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis, and syndromic features, including craniosynostosis, brain anomalies, syndactyly, brachydactyly, epicanthus, and patent ductus arteriosus."

Mosaic developmental and neoplastic overlap in one patient, not a constitutional-carrier risk estimate.

PMID:38569228 SUPPORT Human Clinical

"A novel missense variant, p.(Arg653Leu), further underscores the complex relationship between germline TRAF7 variants and somatic changes linked to meningiomas."

Different amino-acid substitutions can affect the same residue.

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Pathophysiology

7

Heterozygous TRAF7 missense variant

The developmental syndrome is associated predominantly with recurrent heterozygous missense variants in the WD40 repeats, with some coiled-coil variants also established. The variant spectrum favors allele-specific altered function over simple haploinsufficiency, but does not establish a single biochemical mechanism for every allele. Constitutional and postzygotic mosaic presentations are reported.

TRAF7 hgnc:20456

Genetic context allele_type: SNV variant_origin: GERMLINE zygosity: HETEROZYGOUS

This node describes constitutional heterozygous missense variants, predominantly de novo. A dominant-negative effect is a proposed mechanism rather than an established property of all syndrome alleles; mosaic presentations are described separately in genetics and inheritance.

ubiquitin protein ligase activity GO:0061630

Downstream

Reduced TRAF7-IFT57 binding Binding was reduced for tested variants including syndrome-associated p.Thr601Ala; extrapolation to other syndrome variants remains untested.

Reduced ERK1/2 phosphorylation in overexpression assays Variant-dependent ERK1/2 changes were measured in an overexpression system.

Destabilization of the TRAF7 coiled-coil trimer This effect was measured for p.Lys346Glu, not every coiled-coil variant.

Dysregulation of developmental gene expression Patient fibroblasts carrying WD40 missense variants have altered transcriptomes; the intervening signaling events remain unresolved.

Global developmental delay Human cohorts establish the genotype-phenotype association; the mechanism of developmental delay is unresolved.

Abnormal digit morphology Human cohorts establish digital anomalies, without demonstrating a neural-crest mechanism for the limb phenotype.

Show evidence (3 references)

PMID:41372821 SUPPORT Other

"TRAF7 syndrome is caused by several pathogenic TRAF7 mutations, most of which are located within the WD40 repeat protein domain, and the most recurrent of these mutations are p.Arg655Gln, p.Arg524Trp, and p.Phe617Leu"

Names the domain and the recurrent alleles this node records. Evidence source is OTHER because this is a review.

PMID:38466850 SUPPORT Human Clinical

"Variants are predominantly within the WD40 repeats and recurrent, suggesting specific alterations to the protein as the pathomechanism, as opposed to haploinsufficiency."

States the argument against haploinsufficiency directly. Notable because this letter disputes other claims by the group whose dominant-negative model is cited on the next node, so the two sides agree on this point.

PMID:32376980 SUPPORT Human Clinical

"The finding of recurrent missense variants largely restricted to the WD40 repeats suggests a disease mechanism involving specific functional changes to the mutant TRAF7 protein, rather than haploinsufficiency."

Primary cohort supports altered function without proving one direction of effect for every variant.

Destabilization of the TRAF7 coiled-coil trimer

Purified TRAF7 coiled-coil fragments form trimers. p.Lys346Glu reduces the apparent molecular weight and stability of this assembly, whereas p.Arg371Gly showed no significant molecular-weight change. Both variants failed to rescue Traf7 knockdown in zebrafish; the shared rescue failure does not demonstrate a shared trimer defect or dominant-negative mechanism.

Show evidence (1 reference)

PMID:38178633 SUPPORT In Vitro

"MALS assays revealed that K346E exhibited a lower molecular weight compared to the wild-type TRAF7 CC, while R371G did not present a significant difference in molecular weight (Figure 5B), suggesting a weakened stability of the TRAF7 homotrimer caused by the K346E mutation."

Direct biophysical comparison distinguishes the two syndrome-associated coiled-coil alleles.

Reduced TRAF7-IFT57 binding

Coimmunoprecipitation in HEK293 cells showed reduced IFT57 binding for p.Thr601Ala, the disputed CHD-associated p.Val442Met, and somatic tumor-associated p.Gly536Ser. The p.Thr601Ala experiment supplies a direct connection to the established developmental syndrome. These selected alleles do not establish a universal effect of all germline variants.

Experimental models

HEK293 TRAF7-IFT57 binding assay CELL LINE

Downstream

Reduced cilium maintenance Reduced IFT57 binding and impaired ciliation support the proposed interaction-to-cilium mechanism, although allele-specific rescue is still needed.

Show evidence (1 reference)

PMID:37043537 SUPPORT In Vitro

"Meningioma and CHD- and craniofacial defect-associated TRAF7 mutants (G536S, V442M, and T601A, respectively) show reduced interaction with IFT57."

Figure 6 identifies the specific tested variants; the following sentence specifies HEK293 coimmunoprecipitation.

Reduced cilium maintenance

Expression of p.Thr601Ala or p.Val442Met reduced primary cilia in O9 neural crest cells. In frog and fish depletion models, ciliary transport, cilium number and motility were impaired. These findings support a ciliary mechanism for selected alleles; patient-wide ciliary dysfunction has not been demonstrated.

cilium assembly GO:0060271 ↓ DECREASED

Animal models

Traf7-depleted zebrafish Zebrafish perturbs

Traf7-depleted and mutant-overexpressing Xenopus Xenopus tropicalis perturbs

Downstream

Perturbed neural crest development Loss of cilia and altered neural crest markers coexist in developmental models; mediation of the human syndrome remains a hypothesis.

Show evidence (2 references)

PMID:37043537 SUPPORT In Vitro

"transfection of CHD-associated mutant TRAF7 (V442M, T601A), but not WT-TRAF7, into O9 primary neural crest cells abrogates primary cilia (SI Appendix, Fig. S7 A–D)."

The experiment includes p.Thr601Ala from the original syndrome cohort as well as disputed p.Val442Met.

PMID:37043537 SUPPORT Model Organism

"Both anterograde and retrograde transport were severely abrogated in the TRAF7 morphant embryos as compared to controls"

Frog depletion experiments directly measured intraflagellar transport.

Reduced ERK1/2 phosphorylation in overexpression assays

The discovery study measured reduced ERK1/2 phosphorylation in cells overexpressing syndrome-associated variants. Effects differ by allele: the coiled-coil variants had no or smaller effects than the WD40 variants. These are overexpression results, not measurements in patient-derived fibroblasts. Their relationship to the fibroblast transcriptome and to specific clinical findings is unresolved.

ERK1 and ERK2 cascade GO:0070371 ↓ DECREASED

Show evidence (2 references)

PMID:29961569 SUPPORT In Vitro

"In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation."

The measurement this node records, from the syndrome's discovery series.

PMID:32376980 SUPPORT BACKGROUND In Vitro

"Tokita et al reported two TRAF7 syndrome patients with variants in the coiled-coil domain (p.(Lys346Glu) and p.(Arg371Gly)), although these had no or less negative effect on ERK1/2 phosphorylation compared to the two WD40 repeat variants they identified (p.(Thr601Ala) and p.(Arg655Gln))."

The later cohort paper summarizes allele dependence in the original overexpression assays.

Dysregulation of developmental gene expression

RNA sequencing compared skin fibroblasts from three patients with p.Leu402Val, p.Leu519Phe or p.Arg655Gln against six controls, with and without TNF stimulation. There were 76 differentially expressed genes at baseline and 90 after TNF under the stringent differential-expression threshold. Pathway enrichment used a separate, less stringent set of 726 baseline genes and suggested axon-guidance, Wnt/calcium and NFAT-related pathways. A fourth patient was included in selected qPCR validation; these exploratory findings do not prove that a particular pathway causes the clinical abnormalities.

fibroblast CL:0000057

Experimental models

TRAF7 syndrome patient fibroblasts PRIMARY CELL CULTURE

Show evidence (3 references)

PMID:32376980 SUPPORT In Vitro

"We identified 76 DEGs in basal conditions (51.31% up-regulated and 48.68% down-regulated) and 90 DEGs after TNFα treatment (40% up-regulated and 60% down-regulated)"

Measured differential expression in patient-derived fibroblasts.

PMID:32376980 SUPPORT Computational

"To explore the different pathways and biological functions that might be affected, we performed IPA on the 726 DEGs identified under basal conditions using less stringent criteria than the preceding analyses"

Pathway enrichment is computational and uses a different threshold from the 76-gene result.

PMID:32376980 SUPPORT In Vitro

"Results for seven out of the 12 were confirmatory (ANGPT1, CASK, KIF26B, WNT5A, CFD, GPC6, KAZALD1)"

Selected qPCR follow-up supports part of the transcriptomic signal.

Perturbed neural crest development

Traf7 depletion in fish and frog alters neural crest markers and pharyngeal arches. Overexpression of selected developmental variants also perturbs neural crest markers in Xenopus. This is a proposed route to craniofacial and cardiac abnormalities, supported by experimental embryology rather than by lineage tracing in patients. It does not establish a neural-crest origin for developmental delay or digital anomalies.

neural crest cell CL:0011012

neural crest cell development GO:0014032 ⚠ ABNORMAL

Downstream

Congenital cardiovascular malformation Model-derived hypothesis connecting neural crest defects to cardiac malformation; the precise route to the common patent ductus arteriosus phenotype is unresolved.

Abnormal facial shape Craniofacial defects in the model systems motivate this proposed human disease link.

Show evidence (1 reference)

PMID:37043537 SUPPORT Model Organism

"Furthermore, TRAF7 knockdown by unilateral injection of morpholinos at the 2-cell stage disrupted the expression of neural crest markers Sox10 and Twist on the injected side (Fig. 2 O and Q)."

Direct neural crest marker perturbation in Xenopus depletion experiments.

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Pathograph

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

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Phenotypes

66

Breast 1

Inverted nipples HP:0003186

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Infrequent phenotypes included a range of kidney anomalies (n=10), cryptorchidism (n=7), hernias (n=11), inverted nipples (n=6) and lower limb edema (n=3)."

Reported clinical finding in the source cohort.

Cardiovascular 6

Congenital cardiovascular malformation Abnormal heart morphology HP:0001627

Show evidence (2 references)

PMID:38466850 SUPPORT Human Clinical

"Patent ductus arteriosus (PDA; not found in Mishra-Gorur et al.’s patients) is the most frequent feature, followed by septal and valvular defects."

The ordering of cardiac lesion types, from the group that assembled the largest phenotype series.

PMID:38569228 SUPPORT Human Clinical

"Cardiac defects, frequently severe, pose early-life complications."

Supports the clinical weight this phenotype carries.

Patent ductus arteriosus HP:0001643

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Congenital cardiac defects were also frequent: 24 patients had patent ductus arteriosus (many of which required surgical repair), nine had atrial and six had ventricular septal defects and 10 had anomalies of valves."

Reported clinical finding in the source cohort.

Atrial septal defect HP:0001631

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Congenital cardiac defects were also frequent: 24 patients had patent ductus arteriosus (many of which required surgical repair), nine had atrial and six had ventricular septal defects and 10 had anomalies of valves."

Reported clinical finding in the source cohort.

Ventricular septal defect HP:0001629

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Congenital cardiac defects were also frequent: 24 patients had patent ductus arteriosus (many of which required surgical repair), nine had atrial and six had ventricular septal defects and 10 had anomalies of valves."

Reported clinical finding in the source cohort.

Bicuspid aortic valve HP:0001647

Show evidence (2 references)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"bicuspid aortic valve (3/ 11), atrioventricular canal and atrial septal defect (1/11)."

Reported clinical finding in the source cohort.

PMID:38612512 SUPPORT Human Clinical

"Transesophageal and transthoracic echocardiography unveiled right ventricular dilatation without significant pulmonary hypertension, bicuspid aortic valve with aortic root aneurysm, and aortic regurgitation in the proband."

Directly supports bicuspid aortic valve in the adult case mentioned in the description.

Coarctation of aorta HP:0001680

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"Other cardiac defects included aortic coarctation (4/11) and valvular or septal defects (ventricular septal defect; 4/11)"

Reported clinical finding in the source cohort.

Digestive 3

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Many patients presented with feeding difficulties (n=24), often requiring tube feeding in infancy."

Reported clinical finding in the source cohort.

Gastroesophageal reflux HP:0002020

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"gastroesophageal reflux and dysphagia (three patients needed feeding through a nasogastric tube or a gastrostomy)."

Reported clinical finding in the source cohort.

Dysphagia HP:0002015

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"gastroesophageal reflux and dysphagia (three patients needed feeding through a nasogastric tube or a gastrostomy)."

Reported clinical finding in the source cohort.

Ear 4

Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Conductive and/or sensorineural hearing loss occurred in 21 cases."

Reported clinical finding in the source cohort.

Low-set ears HP:0000369

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Ear anomalies (n=27) most frequently consisted of low-set, posteriorly rotated and/or protruding ears."

Reported clinical finding in the source cohort.

Posteriorly rotated ears HP:0000358

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Ear anomalies (n=27) most frequently consisted of low-set, posteriorly rotated and/or protruding ears."

Reported clinical finding in the source cohort.

Protruding ears HP:0000411

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Ear anomalies (n=27) most frequently consisted of low-set, posteriorly rotated and/or protruding ears."

Reported clinical finding in the source cohort.

Eye 6

Optic atrophy HP:0000648

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"including strabismus in most patients (8/11), myopia (3/11) and optic nerve atrophy (2/11)."

Earlier version of the 2024 cohort; optic atrophy was reported in two patients and confirmed in the accepted manuscript.

Ptosis HP:0000508

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Almost all patients presented with anomalies of the palpebral fissures; most frequently blepharophimosis (n=33), along with epicanthus (n=20), telecanthus (n=14), ptosis (n=19) and up- or downslanting palpebral fissures (n=11)"

Reported clinical finding in the source cohort.

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Hypertelorism was reported in 17 cases."

Reported clinical finding in the source cohort.

Strabismus HP:0000486

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Anomalies of the eyes included refractive errors (n=10) and strabismus (n=10)."

Reported clinical finding in the source cohort.

Refractive error Abnormality of refraction HP:0000539

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Anomalies of the eyes included refractive errors (n=10) and strabismus (n=10)."

Reported clinical finding in the source cohort.

Myopia HP:0000545

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"myopia (3/11) and optic nerve atrophy (2/11)."

Reported clinical finding in the source cohort.

Genitourinary 3

Renal anomalies Abnormality of the kidney HP:0000077

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Infrequent phenotypes included a range of kidney anomalies (n=10), cryptorchidism (n=7), hernias (n=11), inverted nipples (n=6) and lower limb edema (n=3)."

Reported clinical finding in the source cohort.

Cryptorchidism HP:0000028

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Infrequent phenotypes included a range of kidney anomalies (n=10), cryptorchidism (n=7), hernias (n=11), inverted nipples (n=6) and lower limb edema (n=3)."

Reported clinical finding in the source cohort.

Hypospadias HP:0000047

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"hypospadias in half of the male cases (4/8)."

Reported clinical finding in the source cohort.

Head and Neck 14

Abnormal facial shape HP:0001999

Show evidence (2 references)

PMID:32376980 SUPPORT Human Clinical

"Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus."

Establishes the recognizable gestalt and names blepharophimosis as its leading element.

PMID:38569228 SUPPORT Human Clinical

"Facial features, including arched eyebrows, contribute to the distinct gestalt."

Adds arched eyebrows to the gestalt from the most recent series.

Blepharophimosis HP:0000581

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Almost all patients presented with anomalies of the palpebral fissures; most frequently blepharophimosis (n=33), along with epicanthus (n=20), telecanthus (n=14), ptosis (n=19) and up- or downslanting palpebral fissures (n=11)"

Reported clinical finding in the source cohort.

Short neck HP:0000470

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Anomalies of the axial skeleton were frequent: short neck (n=24), pectus carinatum (n=17) and other chest shape anomalies (n=10, including barrel-shaped or narrow chest), rib anomalies (n=5), deviations of the vertebral column (n=7) and vertebral anomalies (n=14)."

Reported clinical finding in the source cohort.

Craniosynostosis HP:0001363

Show evidence (2 references)

PMID:32459067 SUPPORT Human Clinical

"In addition to the typical hallmarks of the TRAF7-related disorder, both subjects presented with a recognizable "pear-shaped" skull due to multiple craniosynostosis, sinus pericranii, skull base/cranio-cervical junction anomalies, dysgyria, and inferior cerebellar vermis hypoplasia."

Describes the cranial subgroup this phenotype records, in two patients.

PMID:34247275 SUPPORT Human Clinical

"Here, we report a child who presented with multi-suture craniosynostosis and had the uncommon c.1570C>T (p.Arg524Trp) variant of TRAF7."

An independent case linking multi-suture craniosynostosis to one of the recurrent TRAF7 alleles, which is why the cranial subgroup is recorded as a real but minority feature rather than a one-family finding.

Epicanthus HP:0000286

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Almost all patients presented with anomalies of the palpebral fissures; most frequently blepharophimosis (n=33), along with epicanthus (n=20), telecanthus (n=14), ptosis (n=19) and up- or downslanting palpebral fissures (n=11)"

Reported clinical finding in the source cohort.

Telecanthus HP:0000506

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Almost all patients presented with anomalies of the palpebral fissures; most frequently blepharophimosis (n=33), along with epicanthus (n=20), telecanthus (n=14), ptosis (n=19) and up- or downslanting palpebral fissures (n=11)"

Reported clinical finding in the source cohort.

Bulbous nose HP:0000414

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Other frequent facial features include a bulbous nasal tip (n=17), wide or flat nasal bridge (n=11), micro- or retrognathia, albeit typically mild (n=13) and a high or prominent forehead (n=11)."

Reported clinical finding in the source cohort.

Micrognathia HP:0000347

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"micro- or retrognathia, albeit typically mild (n=13)"

Reported clinical finding in the source cohort.

Retrognathia HP:0000278

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"micro- or retrognathia, albeit typically mild (n=13)"

Reported clinical finding in the source cohort.

Submucous cleft palate HP:5201016

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Palatal anomalies (n=15) included submucous cleft and velopharyngeal insufficiency."

Reported clinical finding in the source cohort.

Velopharyngeal insufficiency HP:0000220

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Palatal anomalies (n=15) included submucous cleft and velopharyngeal insufficiency."

Reported clinical finding in the source cohort.

High forehead HP:0000348

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Other frequent facial features include a bulbous nasal tip (n=17), wide or flat nasal bridge (n=11), micro- or retrognathia, albeit typically mild (n=13) and a high or prominent forehead (n=11)."

Reported clinical finding in the source cohort.

Wide nasal bridge HP:0000431

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Other frequent facial features include a bulbous nasal tip (n=17), wide or flat nasal bridge (n=11), micro- or retrognathia, albeit typically mild (n=13) and a high or prominent forehead (n=11)."

Reported clinical finding in the source cohort.

Depressed nasal bridge HP:0005280

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Other frequent facial features include a bulbous nasal tip (n=17), wide or flat nasal bridge (n=11), micro- or retrognathia, albeit typically mild (n=13) and a high or prominent forehead (n=11)."

Reported clinical finding in the source cohort.

Limbs 7

Abnormal digit morphology HP:0011297

Show evidence (1 reference)

PMID:29961569 SUPPORT Human Clinical

"The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features."

Establishes limb and digital anomalies as a unifying feature.

Brachydactyly HP:0001156

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10), varus or valgus abnormalities (n=10) and sandal gap (n=5)."

Reported clinical finding in the source cohort.

Syndactyly HP:0001159

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10), varus or valgus abnormalities (n=10) and sandal gap (n=5)."

Reported clinical finding in the source cohort.

Overlapping toes HP:0001845

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10), varus or valgus abnormalities (n=10) and sandal gap (n=5)."

Reported clinical finding in the source cohort.

Pes planus HP:0001763

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10), varus or valgus abnormalities (n=10) and sandal gap (n=5)."

Reported clinical finding in the source cohort.

Sandal gap HP:0001852

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10), varus or valgus abnormalities (n=10) and sandal gap (n=5)."

Reported clinical finding in the source cohort.

Clinodactyly HP:0030084

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"Clinodactyly was present in five cases (5/11) and brachydactyly in four cases."

Reported clinical finding in the source cohort.

Musculoskeletal 9

Pectus carinatum HP:0000768

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Anomalies of the axial skeleton were frequent: short neck (n=24), pectus carinatum (n=17) and other chest shape anomalies (n=10, including barrel-shaped or narrow chest), rib anomalies (n=5), deviations of the vertebral column (n=7) and vertebral anomalies (n=14)."

Reported clinical finding in the source cohort.

Hypotonia HP:0001252

Show evidence (2 references)

PMID:32376980 SUPPORT Human Clinical

"Hypotonia was noted in 17 patients."

Reported clinical finding in the source cohort.

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"At birth, all patients showed hypotonia (11/11) with poor sucking (7/11), some of them requiring a feeding tube."

Earlier version of the 2024 series; neonatal hypotonia and poor sucking counts agree with the accepted manuscript.

Camptodactyly HP:0012385

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10), varus or valgus abnormalities (n=10) and sandal gap (n=5)."

Reported clinical finding in the source cohort.

Cervical spinal stenosis Cervical spinal canal stenosis HP:0008445

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Regarding the latter, cervical stenosis or spinal cord compression was of clinical concern in several cases."

Reported clinical finding in the source cohort.

Hernia HP:0100790

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Infrequent phenotypes included a range of kidney anomalies (n=10), cryptorchidism (n=7), hernias (n=11), inverted nipples (n=6) and lower limb edema (n=3)."

Reported clinical finding in the source cohort.

Scoliosis HP:0002650

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"Scoliosis (6/11) and kyphosis (4/11) were also present in a range of patients."

Reported clinical finding in the source cohort.

Kyphosis HP:0002808

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"Scoliosis (6/11) and kyphosis (4/11) were also present in a range of patients."

Reported clinical finding in the source cohort.

Joint hypermobility HP:0001382

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"Joint hypermobility (4/10) or joint contractures (3/10) were also present in some cases."

Reported clinical finding in the source cohort.

Joint contracture HP:0034392

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"Joint hypermobility (4/10) or joint contractures (3/10) were also present in some cases."

Reported clinical finding in the source cohort.

Nervous System 10

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:29961569 SUPPORT Human Clinical

"The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features."

Establishes developmental delay as one of the four unifying features of the syndrome.

PMID:38569228 SUPPORT Human Clinical

"In this enlarged collection, novelties include a wider range of cognitive dysfunction, with some individuals exhibiting normal development despite early psychomotor delay."

The basis for the description's warning that developmental delay is frequent rather than obligate.

Sleep disturbance HP:0002360

Show evidence (2 references)

PMID:38569228 SUPPORT Human Clinical

"Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency."

Same sentence, recording sleep disturbance as a highlighted feature.

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"As in other neurodevelopmental conditions, some kind of sleep disorder was reported for most of the patients (7/10) as assessed by SDSC scale."

Reported screening result in the earlier version of the 2024 cohort.

Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:38569228 SUPPORT Human Clinical

"Autistic traits, notably rigidity, are observed in the cohort."

The source for autistic traits, at the strength the source states.

Delayed speech and language development HP:0000750

Show evidence (2 references)

PMID:38569228 SUPPORT Human Clinical

"Communication challenges, particularly in expressive language, are prevalent, necessitating alternative communication methods."

Establishes the expressive-language emphasis and its functional consequence.

PMID:32376980 SUPPORT Human Clinical

"All patients had some form of developmental delay; intellectual disability (n=23) and/or speech delay (n=29) occurred in all but a small minority, while motor delay occurred in the majority (n=30)."

Reported clinical finding in the source cohort.

Seizure HP:0001250

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Autism spectrum disorder was observed in six cases and epilepsy in seven."

Reported clinical finding in the source cohort.

Brain imaging abnormality HP:0410263

Coarse binding: variable spectrum

Show evidence (2 references)

PMID:32459067 SUPPORT Human Clinical

"In addition to the typical hallmarks of the TRAF7-related disorder, both subjects presented with a recognizable "pear-shaped" skull due to multiple craniosynostosis, sinus pericranii, skull base/cranio-cervical junction anomalies, dysgyria, and inferior cerebellar vermis hypoplasia."

Records dysgyria and cerebellar vermis hypoplasia. Same sentence used for craniosynostosis, so the evidence_source is unchanged.

PMID:38612512 SUPPORT Human Clinical

"Brain magnetic resonance imaging indicated diffuse cerebral atrophy, and cervical computed tomography scan revealed disc bulging with spondylosis"

A different structural finding in an adult patient, which is the basis for describing the imaging abnormalities as heterogeneous rather than stereotyped.

Obstructive sleep apnea HP:0002870

Show evidence (1 reference)

PMID:38612512 SUPPORT Human Clinical

"The underlying cause of his symptoms was attributed to OSA, likely exacerbated by the vertebral anomaly and short neck associated with CAFDADD syndrome."

Links the apnoea to the syndrome's own skeletal features rather than treating it as a coincidental comorbidity.

Motor delay HP:0001270

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"All patients had some form of developmental delay; intellectual disability (n=23) and/or speech delay (n=29) occurred in all but a small minority, while motor delay occurred in the majority (n=30)."

Reported clinical finding in the source cohort.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"All patients had some form of developmental delay; intellectual disability (n=23) and/or speech delay (n=29) occurred in all but a small minority, while motor delay occurred in the majority (n=30)."

Reported clinical finding in the source cohort.

Ventriculomegaly HP:0002119

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"There was a range of nonspecific anomalies on brain MRI (most frequently, enlarged ventricles)."

Reported clinical finding in the source cohort.

Growth 3

Growth delay HP:0001510

Show evidence (1 reference)

PMID:38569228 SUPPORT Human Clinical

"Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency."

Same sentence, recording growth deficiency.

Short stature HP:0004322

Show evidence (2 references)

PMID:32376980 SUPPORT Human Clinical

"Short stature was noted in 12 cases, low weight in five and microcephaly or macrocephaly in a total of 10."

Reported clinical finding in the source cohort.

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"most patients presented values of height below -2SD (8/11) (Figure 1), despite presenting normal IGF-1 and IGFBP-3 hormonal levels when they were analyzed."

Cohort-specific growth and hormone observations from the preprint, also present in the accepted manuscript.

Low body weight Decreased body weight HP:0004325

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Short stature was noted in 12 cases, low weight in five and microcephaly or macrocephaly in a total of 10."

Reported clinical finding in the source cohort.

🧬

Genetic Associations

2

TRAF7 (Germline missense, WD40-repeat clustered)

Gene: TRAF7 hgnc:20456 variant_origin: GERMLINE

Show evidence (2 references)

PMID:29961569 SUPPORT Human Clinical

"Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance."

The statistical argument for causality in the discovery series, rather than a bare assertion of association.

PMID:32376980 SUPPORT Human Clinical

"Almost all variants occur in the WD40 repeats and most are recurrent."

Establishes the domain clustering and recurrence in the largest cohort.

TRAF7 mosaicism (Postzygotic mosaic multisystem presentation)

Gene: TRAF7 hgnc:20456

Show evidence (1 reference)

PMID:35733823 SUPPORT Human Clinical

"Additional testing of unaffected tissues identified the same variant at lower allele frequencies, consistent with postzygotic somatic mosaicism."

Multi-tissue testing distinguishes constitutional mosaicism from a tumor-only mutation.

🗃️

External Assertions

2

OMIM cardiac, facial, and digital anomalies with developmental delay

OMIM disease record OMIM:618164

The OMIM phenotype entry for this syndrome, cross-referenced by MONDO:0032572.

Orphanet TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome

Orphanet disease record ORPHA:592570

The Orphanet entry, cross-referenced by MONDO:0032572. Its label names motor and speech delay explicitly, which is the emphasis the 2024 series also reports.

💊

Medical Actions

6

Supportive multidisciplinary care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Care is directed at the manifestations present, with cardiology, developmental, hearing, ophthalmologic, orthopedic and growth assessment. The 2024 cohort authors proposed a management schedule; this is an expert proposal from a small series rather than a validated consensus guideline. Disease-modifying treatment is not established in the reviewed literature.

Show evidence (1 reference)

PMID:38569228 SUPPORT Human Clinical

"Our comprehensive analysis expands the phenotypic spectrum, emphasizing the need for oncological evaluations and proposing an evidence-based schedule for clinical management."

The source of the proposed management schedule. Note it also calls for oncological evaluation, which is treated as an open question below rather than as an established surveillance recommendation here.

Assisted learning and augmentative communication

Platform: Behavioral / lifestyle

Developmental support includes assisted learning and alternative or augmentative communication tailored to expressive-language impairment.

Show evidence (2 references)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"the use of alternative or augmentative communication methods is recommended for TRAF7 syndrome."

Earlier version of the published clinical series; the recommendation also appears in the accepted manuscript.

PMID:32376980 SUPPORT Human Clinical

"TRAF7 syndrome patients typically require assisted learning and may be at risk of cervical stenosis."

Primary cohort supports assisted learning.

Enteral feeding support

Tube feeding may be needed for significant infant feeding problems; the approach is individualized to clinical need.

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Many patients presented with feeding difficulties (n=24), often requiring tube feeding in infancy."

Directly documents feeding support in the cohort.

Cardiac surgery for structural lesions

Action: cardiac surgical repair Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Surgical repair is used for appropriate cardiac lesions, including patent ductus arteriosus; an adult with progressive aortic root aneurysm underwent aortic root and valve replacement.

Show evidence (2 references)

PMID:32376980 SUPPORT Human Clinical

"Congenital cardiac defects were also frequent: 24 patients had patent ductus arteriosus (many of which required surgical repair), nine had atrial and six had ventricular septal defects and 10 had anomalies of valves."

Documents surgical treatment of PDA in the primary cohort.

PMID:38612512 SUPPORT Human Clinical

"Subsequently, aortic root replacement using the Bentall procedure was performed."

Documents the operation in the adult case.

Hearing assessment and rehabilitation

Periodic hearing assessment can guide tympanic drainage or audiological devices as appropriate for the type of hearing loss.

Show evidence (1 reference)

DOI:10.1101/2023.12.13.23299272 Preprint · not peer-reviewed SUPPORT Human Clinical

"an early detection may facilitate therapeutic approaches such as tympanic drainages or the use of audiology devices"

Clinical series recommendation, cross-checked against the accepted manuscript.

Continuous positive airway pressure

Platform: Device

CPAP alleviated symptoms of severe obstructive sleep apnea in a reported adult with TRAF7 syndrome. This is treatment of documented apnea, not a syndrome-wide intervention.

Show evidence (1 reference)

PMID:38612512 SUPPORT Human Clinical

"Upon re-evaluating OSA with polysomnography, it was discovered that continuous positive airway pressure support alleviated his symptoms."

Direct case-level treatment response.

🔬

Diagnosis

3

TRAF7 sequencing and segregation analysis

Exome sequencing, targeted panels or directed TRAF7 testing can identify a causative variant. A negative karyotype or chromosomal microarray does not exclude a sequence variant. Parental segregation testing helps establish de novo occurrence or familial transmission, and suspected mosaic cases may require sensitive testing of multiple tissues. Published cohorts predominantly contain missense variants; variant classification requires clinical and molecular context.

exome sequencing NCIT:C101295

Show evidence (4 references)

PMID:38612512 SUPPORT Human Clinical

"The initial tests included conventional karyotyping and chromosomal microarray analysis, but unfortunately, no pathogenic alterations were identified."

Records that karyotype and array were uninformative in a confirmed case, which is the point about a prior negative array.

PMID:38612512 SUPPORT Human Clinical

"Sanger sequencing confirmed the segregation of the TRAF7 c.1964G>A; p.Arg655Gln variant with the phenotype and established the de novo autosomal dominant status of the heterozygous variant in the patient, but not in his parents and sibling."

The parental-segregation step that establishes de novo status.

PMID:38612512 SUPPORT Human Clinical

"This variant was classified as pathogenic according to ACMG guidelines, considering the following criteria: PS2, PM1, PM2, PP1, PP2, and PP3."

A worked ACMG classification for the recurrent p.Arg655Gln allele, showing which criteria the evidence supports.

+ 1 more reference

Baseline cardiac assessment

Cardiac assessment is central because congenital defects, especially patent ductus arteriosus, septal and valvular lesions, are common. Continued cardiology follow-up is tailored to the findings. An adult case with bicuspid aortic valve developed a progressive aortic root aneurysm requiring surgery.

Show evidence (2 references)

PMID:38466850 SUPPORT Human Clinical

"Patent ductus arteriosus (PDA; not found in Mishra-Gorur et al.’s patients) is the most frequent feature, followed by septal and valvular defects."

The lesion ordering that a baseline echocardiogram is looking for. Same sentence as the cardiovascular phenotype, so the evidence_source is unchanged.

PMID:38612512 SUPPORT Human Clinical

"Transesophageal and transthoracic echocardiography unveiled right ventricular dilatation without significant pulmonary hypertension, bicuspid aortic valve with aortic root aneurysm, and aortic regurgitation in the proband."

The adult cardiac findings that argue for continued rather than one-off cardiac surveillance.

Assessment for cervical stenosis

Clinical follow-up should consider cervical stenosis or cord compression when relevant symptoms or vertebral abnormalities are present; these were clinically important in the core cohort.

Show evidence (1 reference)

PMID:32376980 SUPPORT Human Clinical

"Regarding the latter, cervical stenosis or spinal cord compression was of clinical concern in several cases."

Supports attention to this potentially consequential manifestation; no fixed screening interval is inferred.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Published cohorts establish an ultra-rare disorder, but do not provide a population prevalence. The 2020 study recruited 45 individuals and analyzed a core group of 42 after excluding three uncertain coiled-coil variants. Later cohorts and follow-up reports overlap, so their sample sizes are not summed into a current count of unique affected individuals.

Show evidence (2 references)

PMID:32376980 SUPPORT Human Clinical

"We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients."

Documents the size of this published cohort or literature review; not a population prevalence or a deduplicated current case total.

PMID:38569228 SUPPORT Human Clinical

"Phenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac defects."

Documents the size of this published cohort or literature review; not a population prevalence or a deduplicated current case total.

📊

Related Datasets

1

TRAF7 is an essential regulator of vascular integrity geo:GSE229698

RNA sequencing of developing mouse embryos after global or endothelial Traf7 deletion, used to assess altered gene expression and the vascular-integrity hypothesis. This is model-organism transcriptomics, not the human syndrome fibroblast dataset.

mouse BULK RNA SEQ

PMID:37583551

Show evidence (1 reference)

GEO:GSE229698 SUPPORT Model Organism

"Objective: to present first in vivo experimental evidence of TRAF7 function by using global and endothelium-specific TRAF7 knockout mice and comparing transcriptomes of developing embryos."

Fetched GEO summary confirms the study identity and experimental context.

🧫

Experimental Models

2

TRAF7 syndrome patient fibroblasts PRIMARY_CELL_CULTURE

Patient fibroblasts were assessed by targeted qPCR and RNA sequencing with and without TNF stimulation. Three patients and six controls entered RNA sequencing, and a fourth patient contributed to selected validation.

Cell source

Skin biopsies from patients and controls

Publication

PMID:32376980

Pathograph links

Dysregulation of developmental gene expression measures fidelity: moderate

Limitations: Skin fibroblasts are not embryonic cardiac or neural crest tissues; the sample is small and restricted to selected WD40 alleles.

Show evidence (1 reference)

PMID:32376980 SUPPORT In Vitro

"We used samples from the three patients and the six controls, with and without TNFα treatment."

Describes the transcriptomic comparison.

HEK293 TRAF7-IFT57 binding assay CELL_LINE

Coimmunoprecipitation compares binding to IFT57 for wild-type TRAF7 and selected tumor or developmental variants.

Cell source

HEK293 cells expressing wild-type or selected TRAF7 variants

Publication

PMID:37043537

Pathograph links

Reduced TRAF7-IFT57 binding measures fidelity: moderate

Limitations: Heterologous overexpression and selected alleles limit generalization to the entire syndrome.

Show evidence (1 reference)

PMID:37043537 SUPPORT In Vitro

"We observed substantially diminished interactions of IFT57 with tumor- as well as CHD-associated TRAF7 mutants (Fig. 6C) upon overexpression in HEK293 cells."

Measured interaction in the named cell system.

🐁

Animal Models

4

Traf7 knockout mouse

Global and endothelial Traf7 deletion caused midgestational lethality and impaired endothelial integrity, with reduced Klf2 expression. Postnatal endothelial deletion caused cerebral hemorrhage. These loss-of-function experiments inform the endothelial hypothesis discussed in this entry but are not heterozygous knock-ins of human syndrome alleles; they do not establish or disprove a common human dominant-negative mechanism.

Species

Mouse

Genotype

Traf7 germline and endothelial conditional knockout

Publication

PMID:37583551

Show evidence (1 reference)

PMID:37583551 SUPPORT Model Organism

"Targeted deletion of TRAF7 revealed that it is a crucial part of shear stress-responsive MEKK3-MEK5-ERK5 signaling pathway induced in endothelial cells by blood flow."

Establishes what the model does show, which is the wild-type pathway rather than the disease mechanism.

Traf7-depleted zebrafish

Traf7 depletion produced altered heart looping, pharyngeal arches and neural crest markers, as well as impaired cilia. The anatomy and perturbation differ from human heterozygous missense disease.

Species

Zebrafish

Genotype

Traf7 depletion; selected human-variant expression experiments

Publication

PMID:37043537

Pathograph links

Reduced cilium maintenance perturbs fidelity: moderate

Limitations: Depletion and overexpression do not reproduce endogenous patient-allele dosage. Cross-species ciliary phenotypes do not establish the frequency or severity of ciliary dysfunction in patients.

Show evidence (1 reference)

PMID:37043537 SUPPORT Model Organism

"TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish"

Experimental developmental abnormalities in the two model organisms.

Traf7-depleted and mutant-overexpressing Xenopus

Developmental perturbation experiments produced cardiac, craniofacial and ciliary abnormalities. The frog experiments also tested overexpression of p.Thr601Ala and p.Val442Met; these are distinct from endogenous heterozygous patient-variant models.

Species

Xenopus tropicalis

Genotype

Traf7 depletion; selected human-variant expression experiments

Publication

PMID:37043537

Pathograph links

Reduced cilium maintenance perturbs fidelity: moderate

Limitations: Depletion and overexpression do not reproduce endogenous patient-allele dosage. Cross-species ciliary phenotypes do not establish the frequency or severity of ciliary dysfunction in patients.

Show evidence (1 reference)

PMID:37043537 SUPPORT Model Organism

"TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish"

Experimental developmental abnormalities in the two model organisms.

Zebrafish rescue with coiled-coil TRAF7 variants

Wild-type human or zebrafish TRAF7 rescued developmental abnormalities after knockdown; p.Lys346Glu, p.Arg371Gly and the coiled-coil deletion did not. Separate biochemical assays showed a trimer-stability defect for p.Lys346Glu but not p.Arg371Gly. Rescue failure alone does not prove dominant-negative action.

Species

Zebrafish

Genotype

traf7 ATG-morpholino with wild-type or mutant human TRAF7 mRNA

Publication

PMID:38178633

Show evidence (1 reference)

PMID:38178633 SUPPORT Model Organism

"the abnormal phenotypes due to Traf7 knockdown were largely rescued by wild-type zTraf7 or hTRAF7 mRNA but not by hTRAF7-CCD, hTRAF7-K346E, or hTRAF7-R371G mRNA."

Direct variant-specific rescue comparison.

{ }

Source YAML

click to show

name: Cardiac, Facial, and Digital Anomalies with Developmental Delay
creation_date: "2026-09-03T23:59:00Z"
category: Mendelian
description: >-
  A multisystem congenital-anomaly and neurodevelopmental syndrome associated with heterozygous TRAF7 missense variants,
  usually de novo and clustered in the C-terminal WD40 repeats. Familial transmission and postzygotic mosaic presentations
  also occur. Characteristic findings include blepharophimosis, congenital cardiovascular malformations, digital
  and vertebral anomalies, short neck, pectus carinatum, hearing loss and variable developmental impairment. TRAF7
  is an E3 ubiquitin ligase and signaling adaptor. Allele-specific disruption of protein interactions, cilia and
  developmental signaling is under investigation. Somatic TRAF7-associated tumors are a distinct clinical context,
  with limited variant overlap and unresolved tumor risk in constitutional carriers.
disease_term:
  preferred_term: cardiac, facial, and digital anomalies with developmental delay
  term:
    id: MONDO:0032572
    label: "cardiac, facial, and digital anomalies with developmental delay"
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0032572
      label: "cardiac, facial, and digital anomalies with developmental delay"
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
external_assertions:
- name: OMIM cardiac, facial, and digital anomalies with developmental delay
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:618164
  description: >-
    The OMIM phenotype entry for this syndrome, cross-referenced by
    MONDO:0032572.
- name: Orphanet TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome
  source: Orphanet
  assertion_type: disease_record
  external_id: ORPHA:592570
  description: >-
    The Orphanet entry, cross-referenced by MONDO:0032572. Its label names motor
    and speech delay explicitly, which is the emphasis the 2024 series also
    reports.
synonyms:
- CAFDADD
- TRAF7 syndrome
- TRAF7-related neurodevelopmental disorder
- TRAF7-related multiple congenital anomalies-intellectual disability syndrome
parents:
- syndromic disease
- hereditary disease
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Published cohorts establish an ultra-rare disorder, but do not provide a population prevalence. The 2020 study
    recruited 45 individuals and analyzed a core group of 42 after excluding three uncertain coiled-coil variants.
    Later cohorts and follow-up reports overlap, so their sample sizes are not summed into a current count of unique
    affected individuals.
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome
      in 45 patients.
    explanation: >-
      Documents the size of this published cohort or literature review; not a population prevalence or a deduplicated
      current case total.
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical
      presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac
      defects.
    explanation: >-
      Documents the size of this published cohort or literature review; not a population prevalence or a deduplicated
      current case total.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant, usually de novo. Established familial transmission includes an affected mother and affected
    dizygotic twins, and a mosaic affected mother transmitting her variant to a non-mosaic affected son. Variable
    expressivity in these families is distinct from the disputed isolated-CHD variants inherited from apparently
    unaffected parents. Parental and proband mosaicism can complicate testing and recurrence counseling.
  evidence:
  - reference: PMID:29961569
    reference_title: "De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identified variants are de novo in six individuals and comprise four distinct missense changes, including
      a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals.
    explanation: >-
      Establishes de novo occurrence and the recurrent p.Arg655Gln allele in the
      discovery series.
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cohort includes 36 sporadic cases in which the TRAF7 variant was de novo, one patient with low level maternal
      mosaicism for the TRAF7 variant, five cases with unknown inheritance and one familial case (patients 24-26)
      in which affected dizygotic twins inherited a TRAF7 variant from their affected mother, in whom the variant
      arose de novo (Figure S1).
    explanation: >-
      Includes confirmed familial transmission and low-level maternal mosaicism.
  - reference: PMID:37067385
    reference_title: Novel mosaic TRAF7 likely pathogenic variant in an African American family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was identified to harbor this likely pathogenic variant in a mosaic (33.89%) state in leukocytes.
    explanation: >-
      A clinically affected mother carried the variant in a mosaic state.
  - reference: PMID:37067385
    reference_title: Novel mosaic TRAF7 likely pathogenic variant in an African American family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He has the same variant in a non-mosaic state.
    explanation: >-
      Her affected son demonstrates transmission from a mosaic parent.
pathophysiology:
- name: Heterozygous TRAF7 missense variant
  biological_scale: MOLECULAR
  description: >-
    The developmental syndrome is associated predominantly with recurrent heterozygous missense variants in the
    WD40 repeats, with some coiled-coil variants also established. The variant spectrum favors allele-specific altered
    function over simple haploinsufficiency, but does not establish a single biochemical mechanism for every allele.
    Constitutional and postzygotic mosaic presentations are reported.
  genes:
  - preferred_term: TRAF7
    term:
      id: hgnc:20456
      label: TRAF7
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: SNV
    description: >-
      This node describes constitutional heterozygous missense variants, predominantly de novo. A dominant-negative
      effect is a proposed mechanism rather than an established property of all syndrome alleles; mosaic presentations
      are described separately in genetics and inheritance.
  molecular_functions:
  - preferred_term: ubiquitin protein ligase activity
    term:
      id: GO:0061630
      label: ubiquitin protein ligase activity
  evidence:
  - reference: PMID:41372821
    reference_title: "TRAF7 in signaling and disease: emerging mechanisms and clinical implications."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TRAF7 syndrome is caused by several pathogenic TRAF7 mutations, most of which are located within the WD40
      repeat protein domain, and the most recurrent of these mutations are p.Arg655Gln, p.Arg524Trp, and p.Phe617Leu
    explanation: >-
      Names the domain and the recurrent alleles this node records. Evidence
      source is OTHER because this is a review.
  - reference: PMID:38466850
    reference_title: The spectrum of heart defects in the TRAF7-related multiple congenital anomalies-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variants are predominantly within the WD40 repeats and recurrent, suggesting specific alterations to the protein
      as the pathomechanism, as opposed to haploinsufficiency.
    explanation: >-
      States the argument against haploinsufficiency directly. Notable because
      this letter disputes other claims by the group whose dominant-negative
      model is cited on the next node, so the two sides agree on this point.
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The finding of recurrent missense variants largely restricted to the WD40 repeats suggests a disease mechanism
      involving specific functional changes to the mutant TRAF7 protein, rather than haploinsufficiency.
    explanation: >-
      Primary cohort supports altered function without proving one direction of effect for every variant.
  downstream:
  - target: Reduced TRAF7-IFT57 binding
    description: >-
      Binding was reduced for tested variants including syndrome-associated p.Thr601Ala; extrapolation to other
      syndrome variants remains untested.
    causal_link_type: DIRECT
  - target: Reduced ERK1/2 phosphorylation in overexpression assays
    description: >-
      Variant-dependent ERK1/2 changes were measured in an overexpression system.
    causal_link_type: DIRECT
  - target: Destabilization of the TRAF7 coiled-coil trimer
    description: >-
      This effect was measured for p.Lys346Glu, not every coiled-coil variant.
    causal_link_type: DIRECT
  - target: Dysregulation of developmental gene expression
    description: >-
      Patient fibroblasts carrying WD40 missense variants have altered transcriptomes; the intervening signaling
      events remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Global developmental delay
    description: >-
      Human cohorts establish the genotype-phenotype association; the mechanism of developmental delay is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal digit morphology
    description: >-
      Human cohorts establish digital anomalies, without demonstrating a neural-crest mechanism for the limb phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Destabilization of the TRAF7 coiled-coil trimer
  biological_scale: MOLECULAR
  description: >-
    Purified TRAF7 coiled-coil fragments form trimers. p.Lys346Glu reduces the apparent molecular weight and stability
    of this assembly, whereas p.Arg371Gly showed no significant molecular-weight change. Both variants failed to
    rescue Traf7 knockdown in zebrafish; the shared rescue failure does not demonstrate a shared trimer defect or
    dominant-negative mechanism.
  evidence:
  - reference: PMID:38178633
    reference_title: The structure of TRAF7 coiled-coil trimer provides insight into its function in zebrafish embryonic development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MALS assays revealed that K346E exhibited a lower molecular weight compared to the wild-type TRAF7 CC, while
      R371G did not present a significant difference in molecular weight (Figure 5B), suggesting a weakened stability
      of the TRAF7 homotrimer caused by the K346E mutation.
    explanation: >-
      Direct biophysical comparison distinguishes the two syndrome-associated coiled-coil alleles.
- name: Reduced TRAF7-IFT57 binding
  biological_scale: MOLECULAR
  description: >-
    Coimmunoprecipitation in HEK293 cells showed reduced IFT57 binding for p.Thr601Ala, the disputed CHD-associated
    p.Val442Met, and somatic tumor-associated p.Gly536Ser. The p.Thr601Ala experiment supplies a direct connection
    to the established developmental syndrome. These selected alleles do not establish a universal effect of all
    germline variants.
  evidence:
  - reference: PMID:37043537
    reference_title: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Meningioma and CHD- and craniofacial defect-associated TRAF7 mutants (G536S, V442M, and T601A, respectively)
      show reduced interaction with IFT57.
    explanation: >-
      Figure 6 identifies the specific tested variants; the following sentence specifies HEK293 coimmunoprecipitation.
  downstream:
  - target: Reduced cilium maintenance
    description: >-
      Reduced IFT57 binding and impaired ciliation support the proposed interaction-to-cilium mechanism, although
      allele-specific rescue is still needed.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced cilium maintenance
  biological_scale: CELLULAR
  description: >-
    Expression of p.Thr601Ala or p.Val442Met reduced primary cilia in O9 neural crest cells. In frog and fish depletion
    models, ciliary transport, cilium number and motility were impaired. These findings support a ciliary mechanism
    for selected alleles; patient-wide ciliary dysfunction has not been demonstrated.
  evidence:
  - reference: PMID:37043537
    reference_title: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      transfection of CHD-associated mutant TRAF7 (V442M, T601A), but not WT-TRAF7, into O9 primary neural crest
      cells abrogates primary cilia (SI Appendix, Fig. S7 A–D).
    explanation: >-
      The experiment includes p.Thr601Ala from the original syndrome cohort as well as disputed p.Val442Met.
  - reference: PMID:37043537
    reference_title: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Both anterograde and retrograde transport were severely abrogated in the TRAF7 morphant embryos as compared
      to controls
    explanation: >-
      Frog depletion experiments directly measured intraflagellar transport.
  biological_processes:
  - preferred_term: cilium assembly
    modifier: DECREASED
    term:
      id: GO:0060271
      label: cilium assembly
  downstream:
  - target: Perturbed neural crest development
    description: >-
      Loss of cilia and altered neural crest markers coexist in developmental models; mediation of the human syndrome
      remains a hypothesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Reduced ERK1/2 phosphorylation in overexpression assays
  biological_scale: MOLECULAR
  description: >-
    The discovery study measured reduced ERK1/2 phosphorylation in cells overexpressing syndrome-associated variants.
    Effects differ by allele: the coiled-coil variants had no or smaller effects than the WD40 variants. These are
    overexpression results, not measurements in patient-derived fibroblasts. Their relationship to the fibroblast
    transcriptome and to specific clinical findings is unresolved.
  biological_processes:
  - preferred_term: ERK1 and ERK2 cascade
    modifier: DECREASED
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  evidence:
  - reference: PMID:29961569
    reference_title: "De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation.
    explanation: >-
      The measurement this node records, from the syndrome's discovery series.
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Tokita et al reported two TRAF7 syndrome patients with variants in the coiled-coil domain (p.(Lys346Glu) and
      p.(Arg371Gly)), although these had no or less negative effect on ERK1/2 phosphorylation compared to the two
      WD40 repeat variants they identified (p.(Thr601Ala) and p.(Arg655Gln)).
    explanation: >-
      The later cohort paper summarizes allele dependence in the original overexpression assays.
    quote_role: BACKGROUND
- name: Dysregulation of developmental gene expression
  biological_scale: CELLULAR
  description: >-
    RNA sequencing compared skin fibroblasts from three patients with p.Leu402Val, p.Leu519Phe or p.Arg655Gln against
    six controls, with and without TNF stimulation. There were 76 differentially expressed genes at baseline and
    90 after TNF under the stringent differential-expression threshold. Pathway enrichment used a separate, less
    stringent set of 726 baseline genes and suggested axon-guidance, Wnt/calcium and NFAT-related pathways. A fourth
    patient was included in selected qPCR validation; these exploratory findings do not prove that a particular
    pathway causes the clinical abnormalities.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We identified 76 DEGs in basal conditions (51.31% up-regulated and 48.68% down-regulated) and 90 DEGs after
      TNFα treatment (40% up-regulated and 60% down-regulated)
    explanation: >-
      Measured differential expression in patient-derived fibroblasts.
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      To explore the different pathways and biological functions that might be affected, we performed IPA on the
      726 DEGs identified under basal conditions using less stringent criteria than the preceding analyses
    explanation: >-
      Pathway enrichment is computational and uses a different threshold from the 76-gene result.
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Results for seven out of the 12 were confirmatory (ANGPT1, CASK, KIF26B, WNT5A, CFD, GPC6, KAZALD1)
    explanation: >-
      Selected qPCR follow-up supports part of the transcriptomic signal.
- name: Perturbed neural crest development
  biological_scale: TISSUE
  description: >-
    Traf7 depletion in fish and frog alters neural crest markers and pharyngeal arches. Overexpression of selected
    developmental variants also perturbs neural crest markers in Xenopus. This is a proposed route to craniofacial
    and cardiac abnormalities, supported by experimental embryology rather than by lineage tracing in patients.
    It does not establish a neural-crest origin for developmental delay or digital anomalies.
  cell_types:
  - preferred_term: neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: neural crest cell development
    modifier: ABNORMAL
    term:
      id: GO:0014032
      label: neural crest cell development
  evidence:
  - reference: PMID:37043537
    reference_title: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Furthermore, TRAF7 knockdown by unilateral injection of morpholinos at the 2-cell stage disrupted the expression
      of neural crest markers Sox10 and Twist on the injected side (Fig. 2 O and Q).
    explanation: >-
      Direct neural crest marker perturbation in Xenopus depletion experiments.
  downstream:
  - target: Congenital cardiovascular malformation
    description: >-
      Model-derived hypothesis connecting neural crest defects to cardiac malformation; the precise route to the
      common patent ductus arteriosus phenotype is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal facial shape
    description: >-
      Craniofacial defects in the model systems motivate this proposed human disease link.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Global developmental delay
  category: Neurologic
  description: >-
    Developmental delay, particularly of motor and expressive-language
    milestones, is the most consistent feature. Severity varies widely, and the
    2024 series reported individuals whose early psychomotor delay resolved into
    normal development, so delay should not be treated as an obligate criterion
    despite appearing in the disease name.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:29961569
    reference_title: "De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects,
      limb and digital anomalies, and dysmorphic features emerging as key unifying features.
    explanation: >-
      Establishes developmental delay as one of the four unifying features of the
      syndrome.
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this enlarged collection, novelties include a wider range of cognitive dysfunction, with some individuals
      exhibiting normal development despite early psychomotor delay.
    explanation: >-
      The basis for the description's warning that developmental delay is
      frequent rather than obligate.
- name: Congenital cardiovascular malformation
  category: Cardiovascular
  description: >-
    Congenital heart disease is a major source of early morbidity. Patent ductus
    arteriosus is the single most frequent lesion, followed by septal and
    valvular defects.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:38466850
    reference_title: The spectrum of heart defects in the TRAF7-related multiple congenital anomalies-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patent ductus arteriosus (PDA; not found in Mishra-Gorur et al.’s patients) is the most frequent feature,
      followed by septal and valvular defects.
    explanation: >-
      The ordering of cardiac lesion types, from the group that assembled the
      largest phenotype series.
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac defects, frequently severe, pose early-life complications.
    explanation: >-
      Supports the clinical weight this phenotype carries.
- name: Patent ductus arteriosus
  category: Cardiovascular
  description: >-
    Reported in 24 individuals in the 2020 core cohort; many required surgical repair.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital cardiac defects were also frequent: 24 patients had patent ductus arteriosus (many of which required
      surgical repair), nine had atrial and six had ventricular septal defects and 10 had anomalies of valves.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Abnormal facial shape
  category: Craniofacial
  description: >-
    A recognizable gestalt in which blepharophimosis is the most characteristic
    element, with arched eyebrows also noted. Ptosis, hypertelorism and ear and
    nose anomalies are described in the cohorts.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short
      neck, pectus carinatum, digital deviations, and patent ductus arteriosus.
    explanation: >-
      Establishes the recognizable gestalt and names blepharophimosis as its
      leading element.
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features, including arched eyebrows, contribute to the distinct gestalt.
    explanation: >-
      Adds arched eyebrows to the gestalt from the most recent series.
- name: Blepharophimosis
  category: Ophthalmologic
  description: >-
    A characteristic facial feature, reported in 33 individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost all patients presented with anomalies of the palpebral fissures; most frequently blepharophimosis (n=33),
      along with epicanthus (n=20), telecanthus (n=14), ptosis (n=19) and up- or downslanting palpebral fissures
      (n=11)
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Abnormal digit morphology
  category: Musculoskeletal
  description: >-
    Digital deviations are one of the three organ systems in the disease name.
    Brachydactyly and syndactyly are also reported.
  phenotype_term:
    preferred_term: Abnormal digit morphology
    term:
      id: HP:0011297
      label: Abnormal digit morphology
  evidence:
  - reference: PMID:29961569
    reference_title: "De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects,
      limb and digital anomalies, and dysmorphic features emerging as key unifying features.
    explanation: >-
      Establishes limb and digital anomalies as a unifying feature.
- name: Short neck
  category: Musculoskeletal
  description: >-
    Reported in 24 individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anomalies of the axial skeleton were frequent: short neck (n=24), pectus carinatum (n=17) and other chest
      shape anomalies (n=10, including barrel-shaped or narrow chest), rib anomalies (n=5), deviations of the vertebral
      column (n=7) and vertebral anomalies (n=14).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Pectus carinatum
  category: Musculoskeletal
  description: >-
    Reported in 17 individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anomalies of the axial skeleton were frequent: short neck (n=24), pectus carinatum (n=17) and other chest
      shape anomalies (n=10, including barrel-shaped or narrow chest), rib anomalies (n=5), deviations of the vertebral
      column (n=7) and vertebral anomalies (n=14).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Hearing impairment
  category: Otologic
  description: >-
    Conductive, sensorineural and mixed hearing loss occur. The 2020 cohort reported hearing loss in 21 individuals.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conductive and/or sensorineural hearing loss occurred in 21 cases.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Sleep disturbance
  category: Neurologic
  description: >-
    Reported sleep problems include sleep-wake transition disorders, sleep initiation or maintenance difficulties
    and excessive daytime sleepiness. These are distinct from the obstructive sleep apnea documented in an adult
    case.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency.
    explanation: >-
      Same sentence, recording sleep disturbance as a highlighted feature.
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As in other neurodevelopmental conditions, some kind of sleep disorder was reported for most of the patients
      (7/10) as assessed by SDSC scale.
    explanation: >-
      Reported screening result in the earlier version of the 2024 cohort.
- name: Growth delay
  category: Growth
  description: >-
    Growth deficiency is reported as part of a broader endocrine involvement.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency.
    explanation: >-
      Same sentence, recording growth deficiency.
- name: Autistic behavior
  category: Behavioral
  description: >-
    Autistic traits, rigidity in particular, are described in the cohort, and are
    reported as traits rather than as uniformly diagnosed autism.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autistic traits, notably rigidity, are observed in the cohort.
    explanation: >-
      The source for autistic traits, at the strength the source states.
- name: Delayed speech and language development
  category: Neurologic
  description: >-
    Expressive language is disproportionately affected, to the point that
    alternative communication methods are described as commonly needed.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Communication challenges, particularly in expressive language, are prevalent, necessitating alternative communication
      methods.
    explanation: >-
      Establishes the expressive-language emphasis and its functional
      consequence.
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had some form of developmental delay; intellectual disability (n=23) and/or speech delay (n=29)
      occurred in all but a small minority, while motor delay occurred in the majority (n=30).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Hypotonia
  category: Neurologic
  description: >-
    Reported in 17 individuals in the 2020 core cohort; neonatal hypotonia was reported in all 11 individuals in
    the later clinical series.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotonia was noted in 17 patients.
    explanation: >-
      Reported clinical finding in the source cohort.
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At birth, all patients showed hypotonia (11/11) with poor sucking (7/11), some of them requiring a feeding
      tube.
    explanation: >-
      Earlier version of the 2024 series; neonatal hypotonia and poor sucking counts agree with the accepted manuscript.
- name: Seizure
  category: Neurologic
  description: >-
    Epilepsy was reported in seven individuals in the 2020 core cohort; it is a variable feature.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autism spectrum disorder was observed in six cases and epilepsy in seven.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Optic atrophy
  category: Ophthalmologic
  description: >-
    Optic nerve atrophy is one documented cause of severe visual impairment. Refractive errors and strabismus are
    separate clinical findings.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including strabismus in most patients (8/11), myopia (3/11) and optic nerve atrophy (2/11).
    explanation: >-
      Earlier version of the 2024 cohort; optic atrophy was reported in two patients and confirmed in the accepted
      manuscript.
- name: Brain imaging abnormality
  category: Neurologic
  description: >-
    Brain imaging findings are heterogeneous, including ventriculomegaly, dysgyria, inferior cerebellar vermis hypoplasia
    and cerebral atrophy. No single lesion defines the syndrome. Specific findings are separately represented where
    reported.
  phenotype_term:
    preferred_term: Structural brain abnormality on imaging
    term:
      id: HP:0410263
      label: Brain imaging abnormality
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:32459067
    reference_title: "Sinus pericranii, skull defects, and structural brain anomalies in TRAF7-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the typical hallmarks of the TRAF7-related disorder, both subjects presented with a recognizable
      "pear-shaped" skull due to multiple craniosynostosis, sinus pericranii, skull base/cranio-cervical junction
      anomalies, dysgyria, and inferior cerebellar vermis hypoplasia.
    explanation: >-
      Records dysgyria and cerebellar vermis hypoplasia. Same sentence used for
      craniosynostosis, so the evidence_source is unchanged.
  - reference: PMID:38612512
    reference_title: The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance imaging indicated diffuse cerebral atrophy, and cervical computed tomography scan
      revealed disc bulging with spondylosis
    explanation: >-
      A different structural finding in an adult patient, which is the basis for
      describing the imaging abnormalities as heterogeneous rather than
      stereotyped.
- name: Obstructive sleep apnea
  category: Respiratory
  description: >-
    Severe obstructive sleep apnea in an adult case contributed to persistent dyspnea after aortic surgery and improved
    with CPAP. The authors considered short neck and vertebral abnormalities possible contributors. Other cohort
    sleep disturbances include sleep-wake transition disorders and daytime sleepiness; these are not all obstructive
    apnea.
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:38612512
    reference_title: The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The underlying cause of his symptoms was attributed to OSA, likely exacerbated by the vertebral anomaly and
      short neck associated with CAFDADD syndrome.
    explanation: >-
      Links the apnoea to the syndrome's own skeletal features rather than
      treating it as a coincidental comorbidity.
- name: Craniosynostosis
  category: Craniofacial
  description: >-
    A severe cranial subgroup has been described with multi-suture
    craniosynostosis, a pear-shaped skull, sinus pericranii and craniocervical
    junction anomalies. It is reported in a minority of patients and is not a
    core feature.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:32459067
    reference_title: "Sinus pericranii, skull defects, and structural brain anomalies in TRAF7-related disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the typical hallmarks of the TRAF7-related disorder, both subjects presented with a recognizable
      "pear-shaped" skull due to multiple craniosynostosis, sinus pericranii, skull base/cranio-cervical junction
      anomalies, dysgyria, and inferior cerebellar vermis hypoplasia.
    explanation: >-
      Describes the cranial subgroup this phenotype records, in two patients.
  - reference: PMID:34247275
    reference_title: "Multi-suture craniosynostosis in c.1570C>T (p.Arg524Trp) mutated TRAF7: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a child who presented with multi-suture craniosynostosis and had the uncommon c.1570C>T (p.Arg524Trp)
      variant of TRAF7.
    explanation: >-
      An independent case linking multi-suture craniosynostosis to one of the
      recurrent TRAF7 alleles, which is why the cranial subgroup is recorded as a
      real but minority feature rather than a one-family finding.
- name: Motor delay
  category: Neurologic
  description: >-
    Motor milestones were delayed in 30 individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had some form of developmental delay; intellectual disability (n=23) and/or speech delay (n=29)
      occurred in all but a small minority, while motor delay occurred in the majority (n=30).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability was recorded in 23 individuals in the 2020 core cohort; cognitive outcomes vary.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had some form of developmental delay; intellectual disability (n=23) and/or speech delay (n=29)
      occurred in all but a small minority, while motor delay occurred in the majority (n=30).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Feeding difficulties affected 24 individuals in the 2020 core cohort, often requiring tube feeding in infancy.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many patients presented with feeding difficulties (n=24), often requiring tube feeding in infancy.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Short stature
  category: Growth
  description: >-
    Short stature was noted in 12 individuals in the 2020 core cohort. In the later 11-person series, eight had
    height below -2 SD; IGF-1 and IGFBP-3 were normal when measured. These observations do not establish or exclude
    every possible endocrine cause of impaired growth.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short stature was noted in 12 cases, low weight in five and microcephaly or macrocephaly in a total of 10.
    explanation: >-
      Reported clinical finding in the source cohort.
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      most patients presented values of height below -2SD (8/11) (Figure 1), despite presenting normal IGF-1 and
      IGFBP-3 hormonal levels when they were analyzed.
    explanation: >-
      Cohort-specific growth and hormone observations from the preprint, also present in the accepted manuscript.
- name: Epicanthus
  category: Craniofacial
  description: >-
    Epicanthus was recorded in 20 individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost all patients presented with anomalies of the palpebral fissures; most frequently blepharophimosis (n=33),
      along with epicanthus (n=20), telecanthus (n=14), ptosis (n=19) and up- or downslanting palpebral fissures
      (n=11)
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Telecanthus
  category: Craniofacial
  description: >-
    Telecanthus was recorded in 14 individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost all patients presented with anomalies of the palpebral fissures; most frequently blepharophimosis (n=33),
      along with epicanthus (n=20), telecanthus (n=14), ptosis (n=19) and up- or downslanting palpebral fissures
      (n=11)
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Ptosis
  category: Ophthalmologic
  description: >-
    Ptosis was recorded in 19 individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost all patients presented with anomalies of the palpebral fissures; most frequently blepharophimosis (n=33),
      along with epicanthus (n=20), telecanthus (n=14), ptosis (n=19) and up- or downslanting palpebral fissures
      (n=11)
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Hypertelorism
  category: Craniofacial
  description: >-
    Hypertelorism was reported in 17 individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertelorism was reported in 17 cases.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Low-set ears
  category: Craniofacial
  description: >-
    Low-set ears are among the characteristic auricular findings.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ear anomalies (n=27) most frequently consisted of low-set, posteriorly rotated and/or protruding ears.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Posteriorly rotated ears
  category: Craniofacial
  description: >-
    Posteriorly rotated ears occur among the variable ear anomalies.
  phenotype_term:
    preferred_term: Posteriorly rotated ears
    term:
      id: HP:0000358
      label: Posteriorly rotated ears
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ear anomalies (n=27) most frequently consisted of low-set, posteriorly rotated and/or protruding ears.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Protruding ears
  category: Craniofacial
  description: >-
    Protruding ears occur among the variable ear anomalies.
  phenotype_term:
    preferred_term: Protruding ear
    term:
      id: HP:0000411
      label: Protruding ear
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ear anomalies (n=27) most frequently consisted of low-set, posteriorly rotated and/or protruding ears.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Bulbous nose
  category: Craniofacial
  description: >-
    A bulbous nasal tip was reported in 17 individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent facial features include a bulbous nasal tip (n=17), wide or flat nasal bridge (n=11), micro-
      or retrognathia, albeit typically mild (n=13) and a high or prominent forehead (n=11).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Micrognathia
  category: Craniofacial
  description: >-
    Micrognathia or retrognathia was reported as a combined category in 13 individuals; this is not a micrognathia-specific
    count.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      micro- or retrognathia, albeit typically mild (n=13)
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Retrognathia
  category: Craniofacial
  description: >-
    Retrognathia is reported, often mild; the cohort grouped it with micrognathia.
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      micro- or retrognathia, albeit typically mild (n=13)
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Submucous cleft palate
  category: Craniofacial
  description: >-
    Submucous cleft palate is among the palatal anomalies reported in the 2020 core cohort.
  phenotype_term:
    preferred_term: Submucous cleft palate
    term:
      id: HP:5201016
      label: Submucous cleft palate
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Palatal anomalies (n=15) included submucous cleft and velopharyngeal insufficiency.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Velopharyngeal insufficiency
  category: Craniofacial
  description: >-
    Velopharyngeal insufficiency is among the reported palatal abnormalities.
  phenotype_term:
    preferred_term: Velopharyngeal insufficiency
    term:
      id: HP:0000220
      label: Velopharyngeal insufficiency
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Palatal anomalies (n=15) included submucous cleft and velopharyngeal insufficiency.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Camptodactyly
  category: Musculoskeletal
  description: >-
    Camptodactyly was reported in ten individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly
      (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10),
      varus or valgus abnormalities (n=10) and sandal gap (n=5).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Brachydactyly
  category: Musculoskeletal
  description: >-
    Brachydactyly was reported in six individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly
      (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10),
      varus or valgus abnormalities (n=10) and sandal gap (n=5).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Syndactyly
  category: Musculoskeletal
  description: >-
    Syndactyly was reported in five individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Syndactyly
    term:
      id: HP:0001159
      label: Syndactyly
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly
      (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10),
      varus or valgus abnormalities (n=10) and sandal gap (n=5).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Overlapping toes
  category: Musculoskeletal
  description: >-
    Overlapping toes were reported in ten individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Overlapping toe
    term:
      id: HP:0001845
      label: Overlapping toe
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly
      (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10),
      varus or valgus abnormalities (n=10) and sandal gap (n=5).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Pes planus
  category: Musculoskeletal
  description: >-
    Pes planus was reported in ten individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly
      (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10),
      varus or valgus abnormalities (n=10) and sandal gap (n=5).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Sandal gap
  category: Musculoskeletal
  description: >-
    A sandal gap was reported in five individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Sandal gap
    term:
      id: HP:0001852
      label: Sandal gap
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although highly variable in nature, major anomalies of the hands were finger deviations (n=10), camptodactyly
      (n=10), brachydactyly (n=6) and syndactyly (n=5), and of the feet, overlapping toes (n=10), pes planus (n=10),
      varus or valgus abnormalities (n=10) and sandal gap (n=5).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Cervical spinal stenosis
  category: Musculoskeletal
  description: >-
    Cervical stenosis and spinal cord compression were clinically important in several patients.
  phenotype_term:
    preferred_term: Cervical spinal canal stenosis
    term:
      id: HP:0008445
      label: Cervical spinal canal stenosis
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Regarding the latter, cervical stenosis or spinal cord compression was of clinical concern in several cases.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Atrial septal defect
  category: Cardiovascular
  description: >-
    Atrial septal defects were reported in nine individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital cardiac defects were also frequent: 24 patients had patent ductus arteriosus (many of which required
      surgical repair), nine had atrial and six had ventricular septal defects and 10 had anomalies of valves.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Ventricular septal defect
  category: Cardiovascular
  description: >-
    Ventricular septal defects were reported in six individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital cardiac defects were also frequent: 24 patients had patent ductus arteriosus (many of which required
      surgical repair), nine had atrial and six had ventricular septal defects and 10 had anomalies of valves.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Strabismus was reported in ten individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anomalies of the eyes included refractive errors (n=10) and strabismus (n=10).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Refractive error
  category: Ophthalmologic
  description: >-
    Refractive errors were reported in ten individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Abnormality of refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anomalies of the eyes included refractive errors (n=10) and strabismus (n=10).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Renal anomalies
  category: Genitourinary
  description: >-
    Variable kidney anomalies were reported in ten individuals in the 2020 core cohort; the quoted summary does
    not specify their forms.
  phenotype_term:
    preferred_term: Abnormality of the kidney
    term:
      id: HP:0000077
      label: Abnormality of the kidney
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infrequent phenotypes included a range of kidney anomalies (n=10), cryptorchidism (n=7), hernias (n=11), inverted
      nipples (n=6) and lower limb edema (n=3).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Cryptorchidism
  category: Genitourinary
  description: >-
    Cryptorchidism was reported in seven individuals in the 2020 core cohort; a sex-specific denominator is not
    given in this summary.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infrequent phenotypes included a range of kidney anomalies (n=10), cryptorchidism (n=7), hernias (n=11), inverted
      nipples (n=6) and lower limb edema (n=3).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Hernia
  category: Gastrointestinal
  description: >-
    Hernias were reported in eleven individuals in the 2020 core cohort; locations are not specified in this summary.
  phenotype_term:
    preferred_term: Hernia
    term:
      id: HP:0100790
      label: Hernia
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infrequent phenotypes included a range of kidney anomalies (n=10), cryptorchidism (n=7), hernias (n=11), inverted
      nipples (n=6) and lower limb edema (n=3).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Inverted nipples
  category: Integument
  description: >-
    Inverted nipples were reported in six individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Inverted nipples
    term:
      id: HP:0003186
      label: Inverted nipples
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infrequent phenotypes included a range of kidney anomalies (n=10), cryptorchidism (n=7), hernias (n=11), inverted
      nipples (n=6) and lower limb edema (n=3).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Ventriculomegaly
  category: Neurologic
  description: >-
    Enlarged ventricles were the most frequent nonspecific MRI finding in the 2020 series.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a range of nonspecific anomalies on brain MRI (most frequently, enlarged ventricles).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Scoliosis
  category: Musculoskeletal
  description: >-
    Reported in six of eleven patients in the later clinical series.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Scoliosis (6/11) and kyphosis (4/11) were also present in a range of patients.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Kyphosis
  category: Musculoskeletal
  description: >-
    Reported in four of eleven patients in the later clinical series.
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Scoliosis (6/11) and kyphosis (4/11) were also present in a range of patients.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Joint hypermobility
  category: Musculoskeletal
  description: >-
    Reported in four of ten assessed patients in the later clinical series.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Joint hypermobility (4/10) or joint contractures (3/10) were also present in some cases.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Joint contracture
  category: Musculoskeletal
  description: >-
    Joint contractures were reported in three of ten assessed patients in the later clinical series.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Joint hypermobility (4/10) or joint contractures (3/10) were also present in some cases.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Bicuspid aortic valve
  category: Cardiovascular
  description: >-
    Reported in three of eleven patients in the later series and in the Korean adult case.
  phenotype_term:
    preferred_term: Bicuspid aortic valve
    term:
      id: HP:0001647
      label: Bicuspid aortic valve
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bicuspid aortic valve (3/ 11), atrioventricular canal and atrial septal defect (1/11).
    explanation: >-
      Reported clinical finding in the source cohort.
  - reference: PMID:38612512
    reference_title: "The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transesophageal and transthoracic echocardiography unveiled right ventricular dilatation without significant
      pulmonary hypertension, bicuspid aortic valve with aortic root aneurysm, and aortic regurgitation in the proband.
    explanation: >-
      Directly supports bicuspid aortic valve in the adult case mentioned in the description.
- name: Coarctation of aorta
  category: Cardiovascular
  description: >-
    Reported in four of eleven patients in the later clinical series.
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other cardiac defects included aortic coarctation (4/11) and valvular or septal defects (ventricular septal
      defect; 4/11)
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Hypospadias
  category: Genitourinary
  description: >-
    Reported in four of eight males in the later clinical series.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypospadias in half of the male cases (4/8).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Myopia
  category: Ophthalmologic
  description: >-
    Myopia was reported in three of eleven patients in the later clinical series.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      myopia (3/11) and optic nerve atrophy (2/11).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Gastroesophageal reflux
  category: Gastrointestinal
  description: >-
    Reflux and dysphagia were among digestive problems in the later series; their individual frequencies were not
    separately stated.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gastroesophageal reflux and dysphagia (three patients needed feeding through a nasogastric tube or a gastrostomy).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Dysphagia
  category: Gastrointestinal
  description: >-
    Dysphagia is reported as part of the digestive phenotype.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gastroesophageal reflux and dysphagia (three patients needed feeding through a nasogastric tube or a gastrostomy).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: High forehead
  category: Craniofacial
  description: >-
    High or prominent forehead was reported as a combined finding in eleven individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: High forehead
    term:
      id: HP:0000348
      label: High forehead
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent facial features include a bulbous nasal tip (n=17), wide or flat nasal bridge (n=11), micro-
      or retrognathia, albeit typically mild (n=13) and a high or prominent forehead (n=11).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Wide nasal bridge
  category: Craniofacial
  description: >-
    A wide nasal bridge is reported; the 2020 series grouped wide and flat bridges in its count.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent facial features include a bulbous nasal tip (n=17), wide or flat nasal bridge (n=11), micro-
      or retrognathia, albeit typically mild (n=13) and a high or prominent forehead (n=11).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Depressed nasal bridge
  category: Craniofacial
  description: >-
    A flat nasal bridge is reported; its frequency was not separated from a wide nasal bridge.
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other frequent facial features include a bulbous nasal tip (n=17), wide or flat nasal bridge (n=11), micro-
      or retrognathia, albeit typically mild (n=13) and a high or prominent forehead (n=11).
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Low body weight
  category: Growth
  description: >-
    Low body weight was reported in five individuals in the 2020 core cohort.
  phenotype_term:
    preferred_term: Decreased body weight
    term:
      id: HP:0004325
      label: Decreased body weight
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short stature was noted in 12 cases, low weight in five and microcephaly or macrocephaly in a total of 10.
    explanation: >-
      Reported clinical finding in the source cohort.
- name: Clinodactyly
  category: Musculoskeletal
  description: >-
    Clinodactyly was reported in five of eleven patients in the later series.
  phenotype_term:
    preferred_term: Clinodactyly
    term:
      id: HP:0030084
      label: Clinodactyly
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinodactyly was present in five cases (5/11) and brachydactyly in four cases.
    explanation: >-
      Reported clinical finding in the source cohort.
genetic:
- name: TRAF7
  association: Germline missense, WD40-repeat clustered
  gene_term:
    preferred_term: TRAF7
    term:
      id: hgnc:20456
      label: TRAF7
  variant_origin: GERMLINE
  notes: >-
    Recurrent WD40 missense variants predominate, including p.Arg655Gln. Some coiled-coil alleles are established,
    while others in the 2020 series remained uncertain. A single dominant-negative mechanism is not proven for every
    allele. Published inherited and mosaic cases support variable expressivity; they do not establish complete absence
    of penetrance in unaffected carriers.
  evidence:
  - reference: PMID:29961569
    reference_title: "De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6
      × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was
      unlikely to have occurred by chance.
    explanation: >-
      The statistical argument for causality in the discovery series, rather than
      a bare assertion of association.
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost all variants occur in the WD40 repeats and most are recurrent.
    explanation: >-
      Establishes the domain clustering and recurrence in the largest cohort.
- name: TRAF7 mosaicism
  association: Postzygotic mosaic multisystem presentation
  gene_term:
    preferred_term: TRAF7
    term:
      id: hgnc:20456
      label: TRAF7
  notes: >-
    A p.Arg641Cys mosaic case had developmental anomalies and meningiomatosis, with the variant detected at different
    levels in tumor and non-tumor tissues. This individual does not estimate tumor incidence in constitutional heterozygotes.
  evidence:
  - reference: PMID:35733823
    reference_title: "TRAF7 somatic mosaicism in a patient with bilateral optic nerve sheath meningiomas: illustrative case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional testing of unaffected tissues identified the same variant at lower allele frequencies, consistent
      with postzygotic somatic mosaicism.
    explanation: >-
      Multi-tissue testing distinguishes constitutional mosaicism from a tumor-only mutation.
diagnosis:
- name: TRAF7 sequencing and segregation analysis
  description: >-
    Exome sequencing, targeted panels or directed TRAF7 testing can identify a causative variant. A negative karyotype
    or chromosomal microarray does not exclude a sequence variant. Parental segregation testing helps establish
    de novo occurrence or familial transmission, and suspected mosaic cases may require sensitive testing of multiple
    tissues. Published cohorts predominantly contain missense variants; variant classification requires clinical
    and molecular context.
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:38612512
    reference_title: The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The initial tests included conventional karyotyping and chromosomal microarray analysis, but unfortunately,
      no pathogenic alterations were identified.
    explanation: >-
      Records that karyotype and array were uninformative in a confirmed case,
      which is the point about a prior negative array.
  - reference: PMID:38612512
    reference_title: The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger sequencing confirmed the segregation of the TRAF7 c.1964G>A; p.Arg655Gln variant with the phenotype
      and established the de novo autosomal dominant status of the heterozygous variant in the patient, but not
      in his parents and sibling.
    explanation: >-
      The parental-segregation step that establishes de novo status.
  - reference: PMID:38612512
    reference_title: The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant was classified as pathogenic according to ACMG guidelines, considering the following criteria:
      PS2, PM1, PM2, PP1, PP2, and PP3.
    explanation: >-
      A worked ACMG classification for the recurrent p.Arg655Gln allele, showing
      which criteria the evidence supports.
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although almost all TRAF7 variants were identified through trio exome sequencing, inclusion of TRAF7 on an
      NGS panel of genes mutated in neurocristopathy and craniofacial malformation syndromes led to the identification
      of two further individuals through diagnostic screening
    explanation: >-
      Primary evidence for both exome and targeted-panel diagnosis.
- name: Baseline cardiac assessment
  description: >-
    Cardiac assessment is central because congenital defects, especially patent ductus arteriosus, septal and valvular
    lesions, are common. Continued cardiology follow-up is tailored to the findings. An adult case with bicuspid
    aortic valve developed a progressive aortic root aneurysm requiring surgery.
  evidence:
  - reference: PMID:38466850
    reference_title: The spectrum of heart defects in the TRAF7-related multiple congenital anomalies-intellectual disability syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patent ductus arteriosus (PDA; not found in Mishra-Gorur et al.’s patients) is the most frequent feature,
      followed by septal and valvular defects.
    explanation: >-
      The lesion ordering that a baseline echocardiogram is looking for. Same
      sentence as the cardiovascular phenotype, so the evidence_source is
      unchanged.
  - reference: PMID:38612512
    reference_title: The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transesophageal and transthoracic echocardiography unveiled right ventricular dilatation without significant
      pulmonary hypertension, bicuspid aortic valve with aortic root aneurysm, and aortic regurgitation in the proband.
    explanation: >-
      The adult cardiac findings that argue for continued rather than one-off
      cardiac surveillance.
- name: Assessment for cervical stenosis
  description: >-
    Clinical follow-up should consider cervical stenosis or cord compression when relevant symptoms or vertebral
    abnormalities are present; these were clinically important in the core cohort.
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Regarding the latter, cervical stenosis or spinal cord compression was of clinical concern in several cases.
    explanation: >-
      Supports attention to this potentially consequential manifestation; no fixed screening interval is inferred.
treatments:
- name: Supportive multidisciplinary care
  description: >-
    Care is directed at the manifestations present, with cardiology, developmental, hearing, ophthalmologic, orthopedic
    and growth assessment. The 2024 cohort authors proposed a management schedule; this is an expert proposal from
    a small series rather than a validated consensus guideline. Disease-modifying treatment is not established in
    the reviewed literature.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our comprehensive analysis expands the phenotypic spectrum, emphasizing the need for oncological evaluations
      and proposing an evidence-based schedule for clinical management.
    explanation: >-
      The source of the proposed management schedule. Note it also calls for
      oncological evaluation, which is treated as an open question below rather
      than as an established surveillance recommendation here.
- name: Assisted learning and augmentative communication
  description: >-
    Developmental support includes assisted learning and alternative or augmentative communication tailored to expressive-language
    impairment.
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the use of alternative or augmentative communication methods is recommended for TRAF7 syndrome.
    explanation: >-
      Earlier version of the published clinical series; the recommendation also appears in the accepted manuscript.
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TRAF7 syndrome patients typically require assisted learning and may be at risk of cervical stenosis.
    explanation: >-
      Primary cohort supports assisted learning.
  therapeutic_modality: BEHAVIORAL
- name: Enteral feeding support
  description: >-
    Tube feeding may be needed for significant infant feeding problems; the approach is individualized to clinical
    need.
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many patients presented with feeding difficulties (n=24), often requiring tube feeding in infancy.
    explanation: >-
      Directly documents feeding support in the cohort.
- name: Cardiac surgery for structural lesions
  description: >-
    Surgical repair is used for appropriate cardiac lesions, including patent ductus arteriosus; an adult with progressive
    aortic root aneurysm underwent aortic root and valve replacement.
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital cardiac defects were also frequent: 24 patients had patent ductus arteriosus (many of which required
      surgical repair), nine had atrial and six had ventricular septal defects and 10 had anomalies of valves.
    explanation: >-
      Documents surgical treatment of PDA in the primary cohort.
  - reference: PMID:38612512
    reference_title: "The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequently, aortic root replacement using the Bentall procedure was performed.
    explanation: >-
      Documents the operation in the adult case.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac surgical repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
- name: Hearing assessment and rehabilitation
  description: >-
    Periodic hearing assessment can guide tympanic drainage or audiological devices as appropriate for the type
    of hearing loss.
  evidence:
  - reference: DOI:10.1101/2023.12.13.23299272
    reference_title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an early detection may facilitate therapeutic approaches such as tympanic drainages or the use of audiology
      devices
    explanation: >-
      Clinical series recommendation, cross-checked against the accepted manuscript.
- name: Continuous positive airway pressure
  description: >-
    CPAP alleviated symptoms of severe obstructive sleep apnea in a reported adult with TRAF7 syndrome. This is
    treatment of documented apnea, not a syndrome-wide intervention.
  evidence:
  - reference: PMID:38612512
    reference_title: "The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon re-evaluating OSA with polysomnography, it was discovered that continuous positive airway pressure support
      alleviated his symptoms.
    explanation: >-
      Direct case-level treatment response.
  therapeutic_modality: DEVICE
animal_models:
- name: Traf7 knockout mouse
  species: Mouse
  genotype: Traf7 germline and endothelial conditional knockout
  publication: PMID:37583551
  description: >-
    Global and endothelial Traf7 deletion caused midgestational lethality and impaired endothelial integrity, with
    reduced Klf2 expression. Postnatal endothelial deletion caused cerebral hemorrhage. These loss-of-function experiments
    inform the endothelial hypothesis discussed in this entry but are not heterozygous knock-ins of human syndrome
    alleles; they do not establish or disprove a common human dominant-negative mechanism.
  evidence:
  - reference: PMID:37583551
    reference_title: TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Targeted deletion of TRAF7 revealed that it is a crucial part of shear stress-responsive MEKK3-MEK5-ERK5 signaling
      pathway induced in endothelial cells by blood flow.
    explanation: >-
      Establishes what the model does show, which is the wild-type pathway rather
      than the disease mechanism.
- name: Traf7-depleted zebrafish
  species: Zebrafish
  genotype: Traf7 depletion; selected human-variant expression experiments
  publication: PMID:37043537
  description: >-
    Traf7 depletion produced altered heart looping, pharyngeal arches and neural crest markers, as well as impaired
    cilia. The anatomy and perturbation differ from human heterozygous missense disease.
  modeled_mechanisms:
  - target: Reduced cilium maintenance
    relationship: PERTURBS
    fidelity: MODERATE
    limitations: >-
      Depletion and overexpression do not reproduce endogenous patient-allele dosage. Cross-species ciliary phenotypes
      do not establish the frequency or severity of ciliary dysfunction in patients.
  evidence:
  - reference: PMID:37043537
    reference_title: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish
    explanation: >-
      Experimental developmental abnormalities in the two model organisms.
- name: Traf7-depleted and mutant-overexpressing Xenopus
  species: Xenopus tropicalis
  genotype: Traf7 depletion; selected human-variant expression experiments
  publication: PMID:37043537
  description: >-
    Developmental perturbation experiments produced cardiac, craniofacial and ciliary abnormalities. The frog experiments
    also tested overexpression of p.Thr601Ala and p.Val442Met; these are distinct from endogenous heterozygous patient-variant
    models.
  modeled_mechanisms:
  - target: Reduced cilium maintenance
    relationship: PERTURBS
    fidelity: MODERATE
    limitations: >-
      Depletion and overexpression do not reproduce endogenous patient-allele dosage. Cross-species ciliary phenotypes
      do not establish the frequency or severity of ciliary dysfunction in patients.
  evidence:
  - reference: PMID:37043537
    reference_title: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish
    explanation: >-
      Experimental developmental abnormalities in the two model organisms.
- name: Zebrafish rescue with coiled-coil TRAF7 variants
  species: Zebrafish
  genotype: traf7 ATG-morpholino with wild-type or mutant human TRAF7 mRNA
  publication: PMID:38178633
  description: >-
    Wild-type human or zebrafish TRAF7 rescued developmental abnormalities after knockdown; p.Lys346Glu, p.Arg371Gly
    and the coiled-coil deletion did not. Separate biochemical assays showed a trimer-stability defect for p.Lys346Glu
    but not p.Arg371Gly. Rescue failure alone does not prove dominant-negative action.
  evidence:
  - reference: PMID:38178633
    reference_title: The structure of TRAF7 coiled-coil trimer provides insight into its function in zebrafish embryonic development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the abnormal phenotypes due to Traf7 knockdown were largely rescued by wild-type zTraf7 or hTRAF7 mRNA but
      not by hTRAF7-CCD, hTRAF7-K346E, or hTRAF7-R371G mRNA.
    explanation: >-
      Direct variant-specific rescue comparison.
discussions:
- discussion_id: controversy_traf7_inherited_variants_and_chd
  prompt: >-
    Do inherited TRAF7 variants transmitted from unaffected parents cause
    isolated congenital heart disease, or are the three reported alleles
    (p.Val142Met, p.Val442Met, c.1998+2T>G) not pathogenic?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Heterozygous TRAF7 missense variant
  - phenotypes#Congenital cardiovascular malformation
  rationale: >-
    The PNAS report interpreted three variants found in an isolated-CHD cohort as causal despite transmission from
    apparently unaffected parents. A published letter challenged their pathogenicity based on population variation,
    inheritance and absence of the characteristic syndrome; the authors defended functional and computational results.
    This dispute concerns those alleles and does not negate affected-parent transmission established in syndrome
    families. Population loss-of-function tolerance alone also does not settle every allele-specific mechanism.
  evidence:
  - reference: PMID:37043537
    reference_title: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base
      meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects.
    explanation: >-
      The claim under dispute, stated by the authors who made it.
  - reference: PMID:38466850
    reference_title: The spectrum of heart defects in the TRAF7-related multiple congenital anomalies-intellectual disability syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All were inherited from healthy parents, while non-penetrance of TRAF7 variants has not been previously reported
      in the MCA-IDS.
    explanation: >-
      The letter challenges these three variants on the basis of unaffected transmitting parents; this is distinct
      from affected-parent transmission in established families.
  - reference: PMID:38466850
    reference_title: The spectrum of heart defects in the TRAF7-related multiple congenital anomalies-intellectual disability syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the gnomAD probability of being loss-of-function intolerant of TRAF7 is 0.02, suggesting good tolerance
      to heterozygous loss-of-function variants in the general population, and arguing against c.1998+2T>G causing
      a CHD.
    explanation: >-
      The population-genetic argument against the splice allele specifically,
      which is the one that would establish haploinsufficiency.
  - reference: PMID:38466853
    reference_title: "Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Experimentally, overexpression of p.Val442Met consistently phenocopies TRAF7 knockdown in Xenopus and zebrafish.
    explanation: >-
      The authors' functional rebuttal. Graded MODEL_ORGANISM because the sentence
      reports the Xenopus and zebrafish result.
- discussion_id: hypothesis_traf7_endothelial_mekk3_erk5_klf2_branch
  prompt: >-
    TRAF7 sits upstream of the shear-responsive MEKK3-MEK5-ERK5-KLF2 endothelial
    pathway. Does that branch contribute to the congenital cardiovascular
    malformations of this syndrome, or only to the vascular-integrity failure
    seen when Traf7 is deleted outright?
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  attaches_to:
  - pathophysiology#Heterozygous TRAF7 missense variant
  - phenotypes#Congenital cardiovascular malformation
  rationale: >-
    Global and endothelial Traf7 deletion impairs vascular integrity and Klf2 expression in mice. TRAF7 depletion
    also reduces shear-induced ERK5 phosphorylation in cultured endothelial cells. These experiments establish normal
    TRAF7 function, but the contribution of this pathway to human missense-variant disease remains unproven. The
    clinical predominance of patent ductus arteriosus makes vessel-wall mechanisms worth testing alongside neural
    crest and ciliary hypotheses.
  evidence:
  - reference: PMID:37583551
    reference_title: TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      They displayed significantly lower expression of transcription factor Klf2, an essential regulator of vascular
      hemodynamic forces downstream of the MEKK3-MEK-ERK5 signaling pathway.
    explanation: >-
      Places TRAF7 upstream of the KLF2 axis in the mouse, which is the
      observation this hypothesis rests on and the limit of what is shown.
  - reference: PMID:37583551
    reference_title: TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Downregulation of TRAF7 as well as SCRIB inhibited fluid shear stress-induced phosphorylation of ERK5 in cultured
      endothelial cells.
    explanation: >-
      Supports the endothelial signaling branch in cell experiments, without demonstrating a patient-variant effect.
- discussion_id: gap_traf7_germline_somatic_overlap_and_tumor_risk
  prompt: >-
    How do allele identity, mosaic distribution and tissue context distinguish developmental TRAF7 disease from
    tumor-associated TRAF7 alterations, and is tumor incidence increased in constitutional carriers?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Heterozygous TRAF7 missense variant
  - treatments#Supportive multidisciplinary care
  rationale: >-
    Germline and somatic variant spectra are largely distinct, but absolute mutual exclusivity is inaccurate. The
    2020 cohort noted p.Arg524Trp in both syndrome patients and a meningioma carrying an activating SMO variant,
    leaving the TRAF7 contribution to that tumor uncertain. The 2024 p.Arg653Leu syndrome variant affects the same
    residue as other tumor substitutions. A mosaic p.Arg641Cys case combines developmental anomalies and meningiomatosis.
    These observations do not quantify tumor risk for constitutional heterozygotes. Proposed oncological follow-up
    is based on sparse observations; one reported endometrioid carcinoma occurred in a carrier of a coiled-coil
    variant of uncertain significance.
  proposed_experiments:
  - experiment_id: exp_traf7_allele_matched_interactome
    name: Side-by-side interactome comparison of germline-type and somatic-type TRAF7 alleles
    description: >-
      Express matched sets of recurrent germline (p.Arg655Gln, p.Arg524Trp,
      p.Phe617Leu) and somatic meningioma TRAF7 alleles in one cell background and
      compare their interactomes by affinity purification mass spectrometry,
      focusing on IFT57, CYLD, MEKK3 and NEMO, together with ubiquitin ligase
      activity and cilium assembly readouts.
    would_support:
    - discussions#gap_traf7_germline_somatic_overlap_and_tumor_risk
    supporting_outcome:
    - >-
      Reproducible allele-dependent differences would support distinct molecular effects in the tested system.
    refuting_outcome:
    - >-
      No detectable difference would weaken that particular assay-level hypothesis without establishing biological
      equivalence or predicting tumor risk.
    decision_criterion: >-
      Compare prespecified interaction and ciliary readouts across alleles, with expression matching and independent
      replication; interpret negative results within assay sensitivity.
  - experiment_id: exp_traf7_tumour_incidence_cohort
    name: Longitudinal tumour-incidence study in a germline TRAF7 cohort
    description: >-
      Follow an international registry cohort of individuals with confirmed
      germline TRAF7 variants with a defined imaging and clinical protocol,
      reporting age-specific incidence of meningioma, mesothelioma and other
      tumours against population expectation.
    supporting_outcome:
    - >-
      Excess age-specific incidence would support increased tumor susceptibility; surveillance benefit would still
      require separate assessment.
    refuting_outcome:
    - >-
      Sufficiently precise incidence estimates near population expectation would constrain the magnitude of possible
      excess risk.
    decision_criterion: >-
      Estimate age-specific risk with confidence intervals and adequate follow-up, separating constitutional and
      mosaic carriers; failure to detect an increase does not establish absence of risk.
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To the best of our knowledge, there is only one syndromic variant, p.(Arg524Trp) (de novo or maternal mosaic
      in four unrelated cases here) that has also been reported in a tumor sample.
    explanation: >-
      Explicit exception to the broad non-overlap claim; the following text notes a co-occurring activating SMO
      variant.
  - reference: PMID:35733823
    reference_title: "TRAF7 somatic mosaicism in a patient with bilateral optic nerve sheath meningiomas: illustrative case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case involved a 15-year-old girl with bilateral optic nerve sheath meningiomas, diffuse meningiomatosis,
      and syndromic features, including craniosynostosis, brain anomalies, syndactyly, brachydactyly, epicanthus,
      and patent ductus arteriosus.
    explanation: >-
      Mosaic developmental and neoplastic overlap in one patient, not a constitutional-carrier risk estimate.
  - reference: PMID:38569228
    reference_title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A novel missense variant, p.(Arg653Leu), further underscores the complex relationship between germline TRAF7
      variants and somatic changes linked to meningiomas.
    explanation: >-
      Different amino-acid substitutions can affect the same residue.
datasets:
- accession: geo:GSE229698
  title: TRAF7 is an essential regulator of vascular integrity
  description: >-
    RNA sequencing of developing mouse embryos after global or endothelial Traf7 deletion, used to assess altered
    gene expression and the vascular-integrity hypothesis. This is model-organism transcriptomics, not the human
    syndrome fibroblast dataset.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  publication: PMID:37583551
  evidence:
  - reference: GEO:GSE229698
    reference_title: TRAF7 is an essential regulator of vascular integrity
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Objective: to present first in vivo experimental evidence of TRAF7 function by using global and endothelium-specific
      TRAF7 knockout mice and comparing transcriptomes of developing embryos.
    explanation: >-
      Fetched GEO summary confirms the study identity and experimental context.
clinical_trials: []
notes: >-
  Clinical frequencies depend on ascertainment and the denominator examined for each finding. Counts from the 2020
  core cohort do not imply that every feature was assessed in all 42 individuals. The 2023 preprint and 2024 publication
  describe the same clinical series and are not independent cohorts. Developmental delay is variable and is not
  an obligatory lifetime finding. Tumor-only TRAF7 alterations are a distinct clinical context; mosaic overlap and
  uncertainty about constitutional-carrier tumor risk are retained explicitly. Molecular paths from TRAF7 to many
  clinical findings remain unresolved.
experimental_models:
- name: TRAF7 syndrome patient fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Skin biopsies from patients and controls
  publication: PMID:32376980
  description: >-
    Patient fibroblasts were assessed by targeted qPCR and RNA sequencing with and without TNF stimulation. Three
    patients and six controls entered RNA sequencing, and a fourth patient contributed to selected validation.
  modeled_mechanisms:
  - target: Dysregulation of developmental gene expression
    relationship: MEASURES
    fidelity: MODERATE
    limitations: >-
      Skin fibroblasts are not embryonic cardiac or neural crest tissues; the sample is small and restricted to
      selected WD40 alleles.
  evidence:
  - reference: PMID:32376980
    reference_title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We used samples from the three patients and the six controls, with and without TNFα treatment.
    explanation: >-
      Describes the transcriptomic comparison.
- name: HEK293 TRAF7-IFT57 binding assay
  experimental_model_type: CELL_LINE
  cell_source: HEK293 cells expressing wild-type or selected TRAF7 variants
  publication: PMID:37043537
  description: >-
    Coimmunoprecipitation compares binding to IFT57 for wild-type TRAF7 and selected tumor or developmental variants.
  modeled_mechanisms:
  - target: Reduced TRAF7-IFT57 binding
    relationship: MEASURES
    fidelity: MODERATE
    limitations: >-
      Heterologous overexpression and selected alleles limit generalization to the entire syndrome.
  evidence:
  - reference: PMID:37043537
    reference_title: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We observed substantially diminished interactions of IFT57 with tumor- as well as CHD-associated TRAF7 mutants
      (Fig. 6C) upon overexpression in HEK293 cells.
    explanation: >-
      Measured interaction in the named cell system.
references:
- reference: DOI:10.1101/2023.12.13.23299272
  title: "Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review"
- reference: PMID:29961569
  title: "De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features."
- reference: PMID:32376980
  title: Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.
- reference: PMID:32459067
  title: "Sinus pericranii, skull defects, and structural brain anomalies in TRAF7-related disorder."
- reference: PMID:34247275
  title: "Multi-suture craniosynostosis in c.1570C>T (p.Arg524Trp) mutated TRAF7: a case report."
- reference: PMID:35733823
  title: "TRAF7 somatic mosaicism in a patient with bilateral optic nerve sheath meningiomas: illustrative case."
- reference: PMID:37043537
  title: Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
- reference: PMID:37067385
  title: Novel mosaic TRAF7 likely pathogenic variant in an African American family.
- reference: PMID:37583551
  title: TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development.
- reference: PMID:38178633
  title: The structure of TRAF7 coiled-coil trimer provides insight into its function in zebrafish embryonic development.
- reference: PMID:38466850
  title: The spectrum of heart defects in the TRAF7-related multiple congenital anomalies-intellectual disability syndrome.
- reference: PMID:38466853
  title: "Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease."
- reference: PMID:38569228
  title: "Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review."
- reference: PMID:38612512
  title: "The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant."
- reference: PMID:41372821
  title: "TRAF7 in signaling and disease: emerging mechanisms and clinical implications."

📚

References & Deep Research

References

15

DOI:10.1101/2023.12.13.23299272

Expanding the phenotypic spectrum of TRAF7 syndrome: report of eleven new cases and literature review

No top-level findings curated for this source.

PMID:29961569

De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features.

No top-level findings curated for this source.

PMID:32376980

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.

No top-level findings curated for this source.

PMID:32459067

Sinus pericranii, skull defects, and structural brain anomalies in TRAF7-related disorder.

No top-level findings curated for this source.

PMID:34247275

Multi-suture craniosynostosis in c.1570C>T (p.Arg524Trp) mutated TRAF7: a case report.

No top-level findings curated for this source.

PMID:35733823

TRAF7 somatic mosaicism in a patient with bilateral optic nerve sheath meningiomas: illustrative case.

No top-level findings curated for this source.

PMID:37043537

Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

No top-level findings curated for this source.

PMID:37067385

Novel mosaic TRAF7 likely pathogenic variant in an African American family.

No top-level findings curated for this source.

PMID:37583551

TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development.

No top-level findings curated for this source.

PMID:38178633

The structure of TRAF7 coiled-coil trimer provides insight into its function in zebrafish embryonic development.

No top-level findings curated for this source.

PMID:38466850

The spectrum of heart defects in the TRAF7-related multiple congenital anomalies-intellectual disability syndrome.

No top-level findings curated for this source.

PMID:38466853

Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease.

No top-level findings curated for this source.

PMID:38569228

Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review.

No top-level findings curated for this source.

PMID:38612512

The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.

No top-level findings curated for this source.

PMID:41372821

TRAF7 in signaling and disease: emerging mechanisms and clinical implications.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review TRAF7 syndrome using clinical and mechanistic full texts · 2026-10-04T05:28:03Z · View source

Reviewed the existing TRAF7 syndrome entry before its first REVIEW history event. This inherited developmental disorder is in scope; tumor-only TRAF7 disease remains a separate clinical context. Created an isolated branch from origin/main cfde41b269c18edbe48a8686b9cb6c55ebb0c5cd and explicitly rebased before reviewing. No open disorder/history PR overlapped at preflight. The older issue 8923 concerns placement before this entry existed and is not closed by this review. Existing history is unchanged. Source audit: read the original disorder, its creation history, and the matching genuine Falcon report and citation companion. Used the full 2020 clinical/transcriptomic study (PMID:32376980), including the core-cohort definition, familial transmission, clinical counts, fibroblast methods, differential-expression thresholds, validation results, and tumor-variant exception. Read the full 2023 PNAS experiments (PMID:37043537) relevant to somatic-allele dominant effects, developmental variant overexpression, IFT57 binding, ciliary transport and neural crest models; read the published letter and reply (PMID:38466850/38466853). Used the structural, biochemical and rescue results of PMID:38178633, the mouse/endothelial results and dataset record from PMID:37583551, and the full adult case PMID:38612512. Checked the 2025 review PMID:41372821 against those primary sources rather than importing its generalized non-overlap and dominant-negative assertions. Retrieved and read the full mosaic meningiomatosis case PMID:35733823 and the familial-mosaic abstract PMID:37067385. The 2024 clinical paper PMID:38569228 remained abstract-only through the PMID fetcher. Retrieved its accepted manuscript from the University of Barcelona repository and its full 2023 preprint through DOI:10.1101/2023.12.13.23299272. Read clinical results, genetics, management and discussion, and compared the primary manuscript tables with the preprint/report. Quotes from the cleaner preprint extraction are explicitly attributed to that version; it is not treated as an independent cohort. The manuscript includes a previously reported individual and conflicting table counts, so neither case totals nor inconsistent aggregate percentages were imported. Preserved both full-text caches and the preprint PDF. The accepted manuscript URL cache has a URL-derived title generated by the fetcher; it is retained as an audit source, not used as a falsely titled publication. The discovery paper PMID:29961569 remained abstract-level after PMID, DOI, PMC and Europe PMC attempts (blocked or unavailable routes); its experiment context was also checked against the later primary papers' discussion. Craniosynostosis case abstracts PMID:32459067 and PMID:34247275 were used. PMID:41201137 remains unavailable and no title-only claim is imported. Corrected inheritance and variant interpretation: added established affected-mother transmission to twins and mosaic-mother transmission to a non-mosaic son. Kept the separate dispute over three isolated-CHD variants inherited from apparently unaffected parents. Removed a universal dominant-negative classification: the strongest heterodimer interference experiments tested somatic meningioma alleles, and the coiled-coil study found reduced trimer stability for Lys346Glu but not Arg371Gly. Both alleles failed fish rescue, which does not prove identical molecular effects. Corrected ERK experiments from patient-derived cells to overexpression assays, retaining allele dependence. Split IFT57 binding from ciliary maintenance and qualified the neural crest route as a model-derived hypothesis. Removed unsupported neural-crest-to-developmental-delay/digital-anomaly edges. Used primary patient-fibroblast results, distinguishing 76 basal/90 TNF DEGs from the relaxed 726-gene enrichment analysis; no causal ERK-to-transcriptome chain is asserted. Corrected the absolute germline/somatic non-overlap claim: Arg524Trp appeared in a tumor also carrying an activating SMO variant, Arg653Leu affects a residue mutated differently in tumors, and a mosaic Arg641Cys case combined developmental anomalies and meningiomatosis. None estimates constitutional-carrier tumor risk. Tumor surveillance remains an uncertain clinical proposal, not a validated screening regimen. Revised proposed experiments so a negative assay or underpowered incidence study cannot establish biological equivalence or absence of risk. Expanded clinical findings using exact primary-cohort counts and clearly scoped later-series observations: motor delay, intellectual disability, feeding difficulties, short stature, palatal abnormalities, individual facial/digital findings, pes planus, scoliosis/kyphosis, cervical stenosis, septal and valvular defects, hearing loss, refractive/ocular findings, renal/genital findings and hernia. Did not infer feature-specific denominators from the 42-person cohort or population penetrance from small selected series. Removed the false single-adult claim and separated nonspecific sleep disturbance from obstructive apnea. Added assisted learning/augmentative communication, enteral feeding, cardiac surgery, hearing rehabilitation, CPAP response and cervical assessment. Negative chromosome testing is a case observation, not a universal diagnostic rule. Added frog/fish and cell models with dosage and tissue limitations. The null mouse remains normal-function/hypothesis context rather than a failed heterozygous knock-in. Verified and cached GEO:GSE229698; no retired shared accession file was used. Deep-research completeness checklist: phenotype coverage adequate after the additions above; feature counts retain source/cohort context instead of importing the report's pooled percentages. Subtypes N/A: no established separately mapped disease subtypes; craniosynostosis and mosaicism are variable presentations. Pathophysiology adequate after atomic-node and experimental-context corrections, with unresolved routes stated. Treatments/trials adequate for available supportive-care reports; an official ClinicalTrials.gov TRAF7 OR CAFDADD query returned no studies. Genetics adequate with recurrence, familial transmission, mosaicism and allele-specific uncertainty. Biomarkers/diagnostics adequate for molecular confirmation, segregation, cardiac assessment and clinically relevant cervical disease; no established diagnostic biomarker threshold. References: central disease-specific primary sources and available full texts consumed; no matching GeneReviews or StatPearls chapter in the offline Bookshelf index. Overall consumption adequate; unrelated tumor signaling, unverified title-only claims and pooled frequencies with inconsistent denominators were not imported. All new evidence titles were copied from cache metadata, with study relevance and source grading checked. Batched schema, ontology and reference validation passed: 125/125 snippets, zero unavailable/skipped snippets, 141 titles, zero issues. Two subsequent treatment-support snippets from the same validated sources also verified, bringing the final offline count to 127/127. Dataset verification passed. Additional local entity, causal-target, coarse-phenotype, qualifier, duplicate-key and enum checks passed. Whole-tree folded-text, snippet length/grading/title, reference-title, empty-snippet, environmental-evidence and cache integrity/order gates passed. Gene-activity grounding passed against origin/main; the disorder page rendered.

Create: Cardiac, Facial, and Digital Anomalies with Developmental Delay (MONDO:0032572, TRAF7) · 2026-09-03T23:46:33Z · View source

entry_type DISEASE. MONDO:0032572 has only syndromic disease and hereditary disease as parents, so there is nothing it could be a subtype of. TRAF7 previously appeared in kb/ only in Meningioma, as a recurrent somatic driver. Keeping the two apart was the main curation risk and was handled at the sentence level rather than at the paper level: every citation here was checked to confirm it is about germline syndrome patients, and PMID:37043537, which spans both diseases, is cited only for sentences that explicitly name the germline or inherited arm or the shared molecular mechanism. Two independent sources (PMID:41372821, PMID:37583551) state that germline and somatic TRAF7 mutations do not overlap despite both being recurrent missense changes in the same region; that non-overlap and its unexplained cause are curated as a KNOWLEDGE_GAP, together with the separate clinical question of whether germline carriers have excess tumour risk. No tumour predisposition is asserted. A CONTROVERSY discussion records the published PNAS exchange over whether three inherited TRAF7 variants cause isolated congenital heart disease (PMID:37043537 vs PMID:38466850 and the reply PMID:38466853); because that is unresolved, the entry describes the syndrome as predominantly de novo and does not assert incomplete penetrance. Per-feature frequencies were deliberately omitted: the widely quoted percentages over 68 aggregated cases are in full-text tables not present in the reference cache, so no snippet could verify them, and the phenotype descriptions instead record only the qualitative ordering the abstracts support. Developmental delay is curated as frequent but not obligate, on the strength of the 2024 series reporting individuals whose early psychomotor delay resolved. The Traf7 null mouse link is FAILS_TO_RECAPITULATE with limitations and evidence, because complete loss is embryonic lethal in mouse while human heterozygotes survive, and no knock-in of a recurrent human allele exists. Module conformance to ciliopathy_dysfunction and cranial_suture_premature_fusion was considered and rejected, recorded in notes. Deep research: falcon, 8/8 references verified, 0 confabulation, preflight PASS with TRAF7 mentioned 64 times. Note issue #8923 is an open Review issue on the same MONDO term assigned to another curator; it carries no PR and is flagged in the PR body. Review follow-up (PR 10820): added five phenotypes that could be snippet-verified (hypotonia, seizure, ocular abnormality, brain imaging abnormality, obstructive sleep apnea), all from PMID:38612512 which the first pass fetched but did not cite, plus the Accogli dysgyria/vermis sentence for the imaging phenotype. Added a diagnosis section (trio exome with the point that a normal array does not exclude, parental segregation, a worked ACMG classification, and baseline plus continued cardiac assessment), external_assertions for OMIM:618164 and ORPHA:592570, and an EMERGING_HYPOTHESIS discussion for the endothelial MEKK3-MEK5-ERK5-KLF2 branch rather than a pathophysiology node, because the human cardiovascular lesions are structural malformations and nothing links them to the vascular-integrity failure the mouse shows. Four aggregated-table features remain uncurated because no cached source states them: motor delay distinct from global delay, palate/mouth anomalies, pes planus/valgus, and scoliosis; scoliosis in particular is named in PMID:38612512 only in its Loeys-Dietz comparison, so quoting it would misattribute the finding.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 33 citations 2026-09-03T16:32:01.347223

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: cardiac, facial, and digital anomalies with developmental delay (CAFDADD), caused by germline de novo TRAF7 missense variants (NOT somatic TRAF7 mutations in meningioma)
MONDO ID: MONDO:0032572 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on cardiac, facial, and digital anomalies with developmental delay (CAFDADD), caused by germline de novo TRAF7 missense variants (NOT somatic TRAF7 mutations in meningioma) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive research report: germline TRAF7-related CAFDADD

Scope and evidence boundary

This report concerns cardiac, facial, and digital anomalies with developmental delay (CAFDADD) caused by germline heterozygous TRAF7 variants. It does not treat sporadic, somatic TRAF7-mutant meningioma as CAFDADD. Tumor literature is mentioned only where it informs molecular biology or the still-unproven question of tumor surveillance.

The evidence base remains small: a seven-person discovery series in 2018, a 45-person series in 2020 (42-person core phenotype set), several case reports, and a 2024 synthesis totaling 68 reported individuals. Consequently, percentages describe published, clinically ascertained cases—not population risks—and are vulnerable to referral and publication bias. (castillavallmanya2020phenotypicspectrumand pages 2-3, tokita2018denovomissense pages 2-3, palmamilla2023expandingthephenotypic pages 15-17)

Domain	Established finding	Quantitative evidence	Evidence type	Key limitation
Scope and identifiers	Cardiac, facial, and digital anomalies with developmental delay (CAFDADD), also called TRAF7 syndrome or TRAF7-related neurodevelopmental disorder; MONDO:0032572, OMIM phenotype 618164, ORPHA:592570. The target is the germline developmental syndrome, not TRAF7-mutant meningioma. (OpenTargets Search: cardiac facial and digital anomalies with developmental delay-TRAF7, palmamilla2023expandingthephenotypic pages 1-3)	One associated causal target, TRAF7, is recorded for MONDO:0032572.	Aggregated disease resources and literature review	No dedicated ICD-10, ICD-11, or MeSH disease code was identified.
Cause and inheritance	Usually caused by a heterozygous germline TRAF7 missense variant, most often arising de novo; variants cluster in C-terminal WD40 repeats. Rare inherited developmental variants with unaffected carrier parents and postzygotic mosaicism demonstrate exceptions and incomplete penetrance. (palmamilla2023expandingthephenotypic pages 8-10, castillavallmanya2020phenotypicspectrumand pages 2-3, mishragorur2023pleiotropicroleof pages 3-4)	Discovery series: 6/7 confirmed de novo; the seventh lacked paternal testing. In the 45-patient study, 20 amino-acid positions were affected and p.Arg655Gln occurred in 13 index cases. (castillavallmanya2020phenotypicspectrumand pages 2-3, tokita2018denovomissense pages 2-3)	Human genetic cohorts and segregation studies	Penetrance cannot be estimated reliably; inherited variants reported in a congenital-heart-disease study may not reproduce classic CAFDADD fully.
Variant spectrum	Recurrent variants include p.Arg655Gln, p.Arg524Trp, p.Phe617Leu, and substitutions at Ser558; most pathogenic syndromic variants alter conserved WD40 residues. The recent cohort added p.Arg653Leu; coiled-coil p.Lys346Glu illustrates a less-certain non-WD40 class. (palmamilla2023expandingthephenotypic pages 8-10, palmamilla2023expandingthephenotypic pages 3-5, castillavallmanya2020phenotypicspectrumand pages 2-3)	Eleven-person series: 8 distinct variants, 7 in WD40 repeats; p.Arg655Gln occurred in 4 unrelated individuals. All were absent from gnomAD v4. (palmamilla2023expandingthephenotypic pages 8-10)	Human sequencing and computational interpretation	Functional validation is unequal across variants; pathogenicity of some coiled-coil variants remains uncertain.
Core neurodevelopmental phenotype	Congenital or infantile hypotonia and developmental delay, especially expressive-language and motor delay, are central but variably severe; cognition ranges from normal or near-normal to intellectual disability. (palmamilla2023expandingthephenotypic pages 3-5, palmamilla2023expandingthephenotypic pages 8-10)	Among 68 reported cases: global developmental delay or intellectual disability 90.7%, speech delay 90.4%, motor delay 85.7%, hypotonia 84.8%, autism-spectrum traits 17.7%, seizures 19.0%, and structural neuroimaging abnormalities 79.3%. (palmamilla2023expandingthephenotypic pages 15-17)	Aggregated human case synthesis	Denominators vary by feature; ascertainment and publication bias may inflate frequencies.
Craniofacial and sensory phenotype	The recognizable gestalt includes blepharophimosis or ptosis, hypertelorism, abnormal ears and nose, palate or mouth anomalies, micrognathia or retrognathia, and a short or broad neck. Hearing and visual impairment can worsen communication and independence. (palmamilla2023expandingthephenotypic pages 5-8, palmamilla2023expandingthephenotypic pages 10-13)	Among 68 cases: ptosis or blepharophimosis approximately 64–75%, abnormal ears 72.3%, abnormal nose 65.6%, palate or mouth anomalies 74.5%, hearing loss 61.0%, and visual abnormalities 45.5%. (palmamilla2023expandingthephenotypic pages 15-17)	Aggregated human case synthesis	Definitions differ among reports; hearing loss may be conductive, sensorineural, or mixed.
Cardiac phenotype	Congenital cardiovascular disease is a major source of early morbidity. Patent ductus arteriosus is characteristic, but septal, valvular, arch, outflow-tract, and complex lesions occur. (tokita2018denovomissense pages 2-3)	Among 68 cases: any cardiovascular involvement 85.1%, patent ductus arteriosus 58.2%, valvular or septal defects 53.7%, coarctation 6.0%, pulmonary-artery stenosis 3.0%, and persistent left superior vena cava 4.5%. (palmamilla2023expandingthephenotypic pages 15-17)	Aggregated human case synthesis	The spectrum is broad, and genotype–cardiac-phenotype correlations are not established.
Digital and skeletal phenotype	Digital deviation, brachydactyly, syndactyly or other hand and foot anomalies, pectus carinatum, scoliosis, and pes planus or valgus are common. Craniosynostosis, sinus pericranii, and cranio-cervical anomalies define a reported severe cranial subgroup. (palmamilla2023expandingthephenotypic pages 5-8, palmamilla2023expandingthephenotypic pages 15-17)	Among 68 cases: digital anomalies 76.9%, pectus carinatum 45.5%, scoliosis 20.0%, and pes planus or valgus 33.3%. (palmamilla2023expandingthephenotypic pages 15-17)	Human cohorts and case reports	Craniosynostosis and sinus pericranii were reported in few patients and should not be considered universal.
Molecular mechanism	The strongest model is altered TRAF7 function, often dominant-negative rather than simple haploinsufficiency. Mutant proteins can heterodimerize with wild-type TRAF7, interact less with IFT57, and disturb ciliogenesis, intraflagellar transport, and neural-crest development. (mishragorur2023pleiotropicroleof pages 8-8, mishragorur2023pleiotropicroleof pages 8-9)	Zebrafish left-right-organizer ciliary beat frequency fell from 50.5 ± 7.14 Hz in controls to 33.47 ± 19.15 Hz in Traf7 morphants, p=6.5×10⁻⁹. (mishragorur2023pleiotropicroleof pages 6-7)	In vitro biochemistry; Xenopus and zebrafish models	The complete chain has not been demonstrated in patient embryonic tissues; knockdown and overexpression models do not precisely reproduce heterozygous human alleles.
Vascular signaling mechanism	TRAF7 supports endothelial integrity through the shear-responsive MEKK3–MEK5–ERK5–KLF2 pathway and interactions with SCRIB; disruption may contribute to cardiovascular abnormalities. (tsitsikov2023traf7isan pages 1-2, tsitsikov2023traf7isan pages 7-9)	Endothelial Traf7-null mice: 0% knockout live births versus 25% expected, N=81, χ²=27, p<0.0001; mutants developed fragmented vessels and died around embryonic day 10. (tsitsikov2023traf7isan pages 7-9)	Mouse knockout, embryonic RNA-seq, and HUVEC or HEK293 assays	Complete mouse deletion is embryonically lethal and substantially more severe than heterozygous human missense disease.
Diagnosis	Confirmation should use trio exome or genome sequencing, or an appropriate developmental-disorder or congenital-heart-disease panel, followed by ACMG/AMP interpretation and parental segregation testing. Baseline assessment should include echocardiography, development and speech, audiology, ophthalmology, growth and endocrine review, neurologic examination, and targeted brain or spine imaging. (castillavallmanya2020phenotypicspectrumand pages 2-3, palmamilla2023expandingthephenotypic pages 3-5, tokita2018denovomissense pages 2-3)	A representative p.Arg655Gln case was classified pathogenic using PS2, PM1, PM2, PP1, PP2, and PP3. (kim2024thefirstkorean pages 5-6)	Human clinical sequencing and case-series recommendations	No validated clinical criteria, biochemical biomarker, enzyme assay, or newborn-screening test exists.
Management	Care is supportive and phenotype-directed: cardiology intervention, early physical and occupational therapy, speech and feeding therapy, augmentative communication, hearing and vision treatment, plus orthopedic, neurologic, sleep, and endocrine care. (palmamilla2023expandingthephenotypic pages 8-10, palmamilla2023expandingthephenotypic pages 5-8)	In one 11-person cohort, sleep disorders affected 7/10, hearing loss 11/11, heart defects 10/11, and stature below −2 SD 8/11. (palmamilla2023expandingthephenotypic pages 5-8)	Human case-series recommendations	No disease-modifying drug, genotype-guided pharmacotherapy, gene, RNA, or cell therapy, or relevant interventional trial was identified.
Tumor boundary and surveillance	Somatic TRAF7-mutant meningioma is not CAFDADD. A few germline or mosaic syndrome cases with tumors prompted suggestions to consider oncology review after puberty, but cancer-risk magnitude and an evidence-based imaging schedule remain unproven. (palmamilla2023expandingthephenotypic pages 10-13, palmamilla2023expandingthephenotypic pages 8-10)	Reports cited two patients with meningioma and one adult with endometrioid adenocarcinoma; these are isolated observations, not incidence estimates. (palmamilla2023expandingthephenotypic pages 10-13, palmamilla2023expandingthephenotypic pages 8-10)	Human case reports and expert opinion	Routine serial tumor imaging is not an established consensus standard; benefits and harms are unknown.
Epidemiology and prognosis gaps	CAFDADD is ultra-rare, but prevalence, incidence, sex ratio, life expectancy, mortality, standardized quality-of-life scores, and validated prognostic biomarkers are unknown. Outcomes vary, and some early hypotonia or delay may improve. (palmamilla2023expandingthephenotypic pages 8-10, palmamilla2023expandingthephenotypic pages 1-3)	The recent synthesis tabulated 68 reported cases; this is a literature case count, not prevalence. (palmamilla2023expandingthephenotypic pages 15-17)	Literature synthesis	Published cases are referral- and publication-biased; long-term adult natural-history data are sparse.
Experimental models	Systems include patient fibroblasts, HEK293 and HUVEC assays, Xenopus and zebrafish knockdown or mutant-expression models, and global or endothelial conditional mouse knockouts. They support roles in transcriptional regulation, cilia and IFT, neural crest, heart development, and vascular integrity. (mishragorur2023pleiotropicroleof pages 6-7, mishragorur2023pleiotropicroleof pages 3-4, castillavallmanya2020phenotypicspectrumand pages 9-10, tsitsikov2023traf7isan pages 4-7)	Global Traf7-null mice showed significant genotype depletion by E11.5, N=17 and p=0.0047, and at birth, N=352 and p=0.0001. (tsitsikov2023traf7isan pages 4-7)	Patient-derived cells, in vitro systems, fish and amphibian models, and mouse genetics	No validated heterozygous knock-in model of a recurrent CAFDADD allele or naturally occurring homologous veterinary disease was identified.

Table: High-confidence knowledge-base summary for germline TRAF7-related CAFDADD, including clinical frequencies, mechanisms, diagnosis, management, evidence gaps, and models. Somatic TRAF7-mutant meningioma is included only as a disease boundary and limited surveillance context.

1. Disease information

Definition

CAFDADD is an ultra-rare, congenital, multisystem Mendelian neurodevelopmental disorder characterized by a recognizable craniofacial gestalt, developmental and especially speech/motor delay, congenital cardiovascular malformations, and digital or broader skeletal anomalies. Hypotonia, feeding difficulty, hearing impairment, growth deficiency, ophthalmologic abnormalities, sleep disturbance, and nonspecific brain abnormalities are frequent but variably expressed. (palmamilla2023expandingthephenotypic pages 5-8, palmamilla2023expandingthephenotypic pages 1-3, palmamilla2023expandingthephenotypic pages 15-17)

The landmark abstract concluded that de novo missense variants in TRAF7 “cause developmental delay, congenital anomalies, and dysmorphic features.” In its seven individuals, assessed motor and/or speech delay occurred in 5/5, congenital heart disease in 6/7, and digital and facial abnormalities in 7/7. [Tokita et al., published 5 July 2018; PMID: 29961569; DOI/URL: https://doi.org/10.1016/j.ajhg.2018.06.005]. (tokita2018denovomissense pages 2-3)

Identifiers and synonyms

MONDO: MONDO:0032572.
OMIM phenotype: 618164.
Orphanet: ORPHA:592570.
Causal gene: TRAF7; Open Targets links MONDO:0032572 to TRAF7/ENSG00000131653 through five evidence records. (OpenTargets Search: cardiac facial and digital anomalies with developmental delay-TRAF7, palmamilla2023expandingthephenotypic pages 1-3)
Common names: CAFDADD; TRAF7 syndrome; TRAF7-related disorder; TRAF7-related neurodevelopmental disorder; TRAF7-related multiple congenital anomalies–intellectual disability syndrome. “Blepharophimosis–mental retardation syndrome” has been used for an overlapping presentation but should not obscure the molecular diagnosis. (palmamilla2023expandingthephenotypic pages 1-3, kim2024thefirstkorean pages 5-6)
ICD-10/ICD-11 and MeSH: no dedicated disease-specific code or descriptor was identified. Coding therefore generally uses manifestations, such as congenital heart defect, developmental delay, or congenital malformation syndrome.

The evidence is primarily aggregated disease-level literature derived from individually phenotyped patients, not EHR population surveillance. OMIM, Orphanet, MONDO, and Open Targets aggregate those reports. (OpenTargets Search: cardiac facial and digital anomalies with developmental delay-TRAF7, castillavallmanya2020phenotypicspectrumand pages 2-3)

2. Etiology, risk, and protective factors

Causal factor

The established cause is a heterozygous germline pathogenic or likely pathogenic TRAF7 variant, predominantly a missense substitution affecting a conserved residue in a C-terminal WD40 repeat. Most classic cases are de novo. In the discovery series, six of seven were confirmed de novo; paternal testing was unavailable in the remaining individual. (palmamilla2023expandingthephenotypic pages 8-10, tokita2018denovomissense pages 2-3)

The disorder is best considered autosomal dominant with predominantly de novo occurrence. Rare inherited p.Val142Met, p.Val442Met, and splice c.1998+2T>G developmental variants were found with apparently unaffected carrier parents, supporting incomplete penetrance for at least some variant classes. Postzygotic mosaic TRAF7 disease has also been reported. These exceptional CHD/mosaic presentations should not be assumed to have the same penetrance or full phenotype as recurrent de novo WD40 variants. (mishragorur2023pleiotropicroleof pages 3-4, mishragorur2023pleiotropicroleof pages 8-9)

Risk factors

Genetic: a pathogenic germline TRAF7 allele is the principal risk factor. No reproducible modifier gene, susceptibility locus, founder allele, polygenic score, or genotype-specific prognostic marker has been established.
Parental age, sex, ancestry, family history: no reliable associations are known. A de novo disorder usually has a negative family history.
Environmental, infectious, lifestyle, occupational: no causal or modifying exposure has been demonstrated.
Protective factors: no protective allele, diet, medication, behavior, or exposure is known.
Gene–environment interaction: unstudied. Developmental shear stress is biologically relevant to endothelial TRAF7 signaling, but this is a physiological mechanical input—not an established environmental CAFDADD risk factor. (tsitsikov2023traf7isan pages 1-2, tsitsikov2023traf7isan pages 7-9)

3. Phenotypes

The most comprehensive recent table combined 68 published cases. Frequencies use differing feature-specific denominators and should be stored with provenance rather than interpreted as unbiased penetrance. (palmamilla2023expandingthephenotypic pages 15-17)

Phenotype	Type, onset, course and impact	Published frequency	Suggested HPO term
Global developmental delay/intellectual disability	Neurodevelopmental sign; infancy/childhood; severity variable. Early delay can improve, and a minority attain near-normal cognition, but many require lifelong educational support.	90.7%	HP:0001263; HP:0001249
Speech/language delay	Developmental/functional; usually early childhood; expressive communication is especially affected and may require augmentative communication.	90.4%	HP:0000750; HP:0002474
Motor delay	Developmental sign; infancy; sometimes improves with age and therapy.	85.7%	HP:0001270
Hypotonia	Neurologic sign; commonly neonatal/infantile; variable and potentially improving. Impairs feeding and gross-motor acquisition.	84.8%	HP:0001252
Autism/autistic traits	Behavioral; childhood; rigidity and reduced cognitive flexibility may occur even without formal ASD.	17.7%	HP:0000729
Seizures/epilepsy	Neurologic; infancy or childhood; variable. One recent case began at 2 months and was controlled with monotherapy.	19.0%	HP:0001250
Abnormal brain imaging	Imaging sign; congenital/developmental, often nonspecific—ventriculomegaly, dysgyria, cysts, hydrocephalus, or vermian hypoplasia.	79.3%	HP:0410263 plus lesion-specific terms
Ptosis/blepharophimosis	Physical sign; congenital and generally stable; contributes to the facial gestalt and can obstruct vision.	approximately 64–75%	HP:0000508; HP:0000581
Ear/nose abnormalities	Congenital dysmorphism; usually stable.	72.3%/65.6%	HP:0000377; HP:0000366; HP:0000431
Palate/mouth abnormalities	Congenital physical/feeding or speech manifestation.	74.5%	HP:0000175; feature-specific term
Hearing loss	Sensory sign; congenital or childhood, conductive and/or sensorineural; worsens language acquisition and participation.	61.0%	HP:0000365
Visual abnormality	Sensory sign; congenital/childhood; ranges from refractive or ocular anomalies to cortical blindness/optic atrophy.	45.5%	HP:0000504; HP:0100704; HP:0000648
Congenital cardiovascular defect	Structural sign; prenatal/neonatal; stable unless repaired, but severity ranges from asymptomatic PDA to life-threatening complex disease.	85.1%	HP:0001627
Patent ductus arteriosus	Congenital cardiac lesion; may cause early morbidity and require closure.	58.2%	HP:0001643
Valvular/septal defect	Congenital cardiac lesion; variable severity.	53.7%	HP:0001654 and lesion-specific terms
Digital anomaly	Congenital physical sign; generally stable; includes deviations, brachydactyly and syndactyly, affecting dexterity variably.	76.9%	HP:0011297; HP:0001156; HP:0001166
Pectus carinatum	Skeletal manifestation; congenital/childhood, often more evident with growth.	45.5%	HP:0000768
Scoliosis	Musculoskeletal sign; childhood/adolescence and potentially progressive.	20.0%	HP:0002650
Pes planus/valgus	Musculoskeletal sign; childhood, potentially affecting gait.	33.3%	HP:0001763; HP:0001772

These figures are supported by the 68-case synthesis: motor delay 85.7%, speech delay 90.4%, global delay/ID 90.7%, hypotonia 84.8%, autism traits 17.7%, seizures 19.0%, imaging abnormalities 79.3%, cardiovascular involvement 85.1%, PDA 58.2%, valvular/septal defects 53.7%, digital anomalies 76.9%, hearing loss 61.0%, and visual abnormalities 45.5%. (palmamilla2023expandingthephenotypic pages 15-17)

Additional clinically important manifestations include prenatal cystic hygroma, single umbilical artery, polyhydramnios and fetal growth restriction; neonatal poor sucking; tube or gastrostomy feeding in severe dysphagia; short stature/endocrine abnormalities; broad or short neck; pectus deformity; hernia, genitourinary and renal findings; and sleep-disordered breathing. In the recent 11-person cohort, hypotonia was 11/11, poor sucking 7/11, MRI abnormality 9/11, heart defect 10/11, PDA 6/11, sleep disorder 7/10, hearing loss 11/11, visual abnormality 9/11, digital anomaly 11/11, and height below −2 SD 8/11. (palmamilla2023expandingthephenotypic pages 3-5, palmamilla2023expandingthephenotypic pages 5-8)

A cranial subgroup has multiple craniosynostosis, pear-shaped skull, sinus pericranii, skull-base/craniocervical anomalies, dysgyria, and inferior cerebellar-vermis hypoplasia; these are important but not universal findings. [Accogli et al., published 2020; DOI: https://doi.org/10.1002/bdr2.1711]. (palmamilla2023expandingthephenotypic pages 10-13)

No CAFDADD-specific EQ-5D, SF-36, PROMIS, caregiver-burden, or other standardized quality-of-life study was identified. Functional burden is inferred from cardiac procedures, feeding support, sensory loss, communication impairment, developmental disability, sleep disturbance, and orthopedic needs. (palmamilla2023expandingthephenotypic pages 8-10, palmamilla2023expandingthephenotypic pages 5-8)

4. Genetic and molecular information

Gene and protein

TRAF7 encodes TNF receptor-associated factor 7, a 670-amino-acid intracellular signaling protein and E3 ubiquitin ligase. Its architecture comprises an N-terminal RING finger, adjacent zinc finger, coiled-coil region, and seven C-terminal WD40 repeats. Unlike canonical TRAFs, its C terminus is dominated by WD40 repeats rather than a conventional TRAF-C domain. (palmamilla2023expandingthephenotypic pages 3-5, castillavallmanya2020phenotypicspectrumand pages 1-2)

Useful identifiers are HGNC:20456, NCBI Gene 84231, Ensembl ENSG00000131653, and OMIM gene 606692. The Open Targets disease association independently records ENSG00000131653 as the sole associated target for MONDO:0032572. (OpenTargets Search: cardiac facial and digital anomalies with developmental delay-TRAF7)

Variant spectrum and classification

Most established variants are heterozygous missense alleles clustered in WD40 repeats. Recurrent changes include p.Arg655Gln, p.Arg524Trp, p.Phe617Leu/Phe617Ser, and substitutions at Ser558; p.Arg655Gln occurred in 13 index cases in the 2020 cohort and in four unrelated members of the recent 11-case cohort. The latter added novel p.Arg653Leu; seven of eight variants were in WD40 repeats, while p.Lys346Glu affected the coiled-coil region. (palmamilla2023expandingthephenotypic pages 8-10, castillavallmanya2020phenotypicspectrumand pages 2-3)

The original four disease variants were absent from ExAC and gnomAD. All eight variants in the 2023/2024 cohort were absent from gnomAD v4, affected conserved residues, and were computationally deleterious. Population absence supports PM2 but does not independently prove pathogenicity. (palmamilla2023expandingthephenotypic pages 8-10, tokita2018denovomissense pages 2-3)

A representative NM_032271.3:c.1964G>A, p.Arg655Gln allele was heterozygous and de novo and classified pathogenic using ACMG/AMP PS2, PM1, PM2, PP1, PP2 and PP3. [Kim et al., published March 2024; DOI: https://doi.org/10.3390/ijms25073701]. (kim2024thefirstkorean pages 5-6)

Functional consequence

The recurrence and regional clustering of missense variants, together with a low reported gnomAD pLI of 0.02 and scarcity of classic truncating CAFDADD alleles, argue against simple haploinsufficiency as the universal mechanism. The leading model is altered function, commonly dominant-negative, although mechanism may vary by allele. Mutant TRAF7 can heterodimerize with wild-type protein and interfere with its function; the c.1998+2T>G allele provides evidence that haploinsufficiency can occur in a partially penetrant CHD presentation. (castillavallmanya2020phenotypicspectrumand pages 2-3, castillavallmanya2020phenotypicspectrumand pages 1-2, mishragorur2023pleiotropicroleof pages 8-9)

No validated modifier genes, syndrome-specific episignature, recurrent chromosomal abnormality, DNA-methylation signature, or structural rearrangement causing classic CAFDADD has been established. Somatic TRAF7 tumor variants must not be classified as germline CAFDADD variants solely because they occur in the same gene.

5. Environmental information

CAFDADD is a genetic developmental disorder. No toxin, radiation, pollution, occupation, smoking, alcohol, diet, exercise pattern, medication, bacterium, virus, fungus, or parasite is known to cause or trigger it. No lifestyle intervention prevents expression after conception, and there is no evidence for infectious transmission or zoonosis.

6. Mechanism and pathophysiology

Ordered causal chain

A heterozygous germline TRAF7 missense variant—usually in a WD40 repeat—leads to altered TRAF7 folding, partner recognition and/or oligomeric function; for several alleles, a dominant-negative effect is experimentally supported. (castillavallmanya2020phenotypicspectrumand pages 1-2, mishragorur2023pleiotropicroleof pages 8-9)
Altered TRAF7 leads to impaired interaction with IFT57 and abnormal intraflagellar transport; this is demonstrated in cell and Xenopus assays but not directly in human embryonic tissue. (mishragorur2023pleiotropicroleof pages 8-8, mishragorur2023pleiotropicroleof pages 9-10)
Defective intraflagellar transport results in shortened, fewer, structurally abnormal or hypomotile cilia and disturbed left–right organizer signaling. (mishragorur2023pleiotropicroleof pages 6-7, mishragorur2023pleiotropicroleof pages 8-8)
Ciliary dysfunction leads to abnormal neural-crest specification/migration and laterality-dependent morphogenesis—demonstrated in Xenopus and zebrafish and inferred in humans. (mishragorur2023pleiotropicroleof pages 3-4, mishragorur2023pleiotropicroleof pages 8-9)
Branch A: neural-crest and ciliary disruption results in craniofacial, pharyngeal-arch, cardiac-outflow and digital/skeletal maldevelopment; the final human linkage is strongly plausible but incompletely demonstrated. (mishragorur2023pleiotropicroleof pages 3-4)
Branch B: altered TRAF7/SCRIB/MEKK3–MEK5–ERK5 signaling leads to reduced shear-responsive ERK5 phosphorylation and KLF2/KLF4 regulation in endothelium. (tsitsikov2023traf7isan pages 1-2, ihuoma2025reviewofthe pages 6-7)
Impaired endothelial developmental signaling results in deficient vessel integrity and cardiovascular morphogenesis in knockout mice; contribution to human septal, valvular, arch and ductal lesions is inferred. (tsitsikov2023traf7isan pages 7-9, tsitsikov2023traf7isan pages 4-7)
Branch C: broader perturbation of MAPK/JNK/p38, NF-κB and transcriptional regulation may lead to altered cell survival, apoptosis, proliferation and differentiation; this is biological context, not a fully validated patient-level causal chain. (palmamilla2023expandingthephenotypic pages 3-5, castillavallmanya2020phenotypicspectrumand pages 1-2)
These embryonic tissue-patterning abnormalities result in the congenital cardiac, facial, digital, skeletal, brain and sensory phenotype, while downstream developmental consequences lead to hypotonia, feeding difficulty, delayed motor/language acquisition and variable intellectual/behavioral disability. (palmamilla2023expandingthephenotypic pages 5-8, palmamilla2023expandingthephenotypic pages 15-17)

Experimental detail

Cilia/IFT and neural crest. TRAF7 was identified as an IFT57-binding partner. CHD-associated V442M and T601A and another mutant showed reduced IFT57 interaction. Xenopus Traf7 depletion severely retarded anterograde IFT80-GFP, retrograde IFT43-GFP and IFT57-GFP transport and produced electron-dense ciliary blebs. Zebrafish morphants had reduced or paralyzed left–right-organizer cilia; mean beat frequency decreased from 50.5 ± 7.14 Hz to 33.47 ± 19.15 Hz (p=6.5×10⁻⁹). Knockdown reduced sox10 and disorganized pharyngeal arches, while Xenopus showed altered Sox10/Twist, abnormal heart looping, edema and craniofacial defects. (mishragorur2023pleiotropicroleof pages 6-7, mishragorur2023pleiotropicroleof pages 8-8, mishragorur2023pleiotropicroleof pages 3-4)

Endothelium. Global Traf7-null and Tie2-Cre endothelial-knockout mouse embryos developed discontinuous, fragmented and poorly branched vessels, hemorrhage and death near E10. No endothelial-knockout pups were born—0% observed versus 25% expected (N=81; χ²=27; p<0.0001). RNA-seq identified HIF-1-pathway changes, reduced Klf2, increased Bnip3 and reduced Nppc/Serpina6. TRAF7 associates with SCRIB, MEKK3 and MEK5; TRAF7 or SCRIB reduction suppressed shear-induced ERK5 phosphorylation. (tsitsikov2023traf7isan pages 7-9, tsitsikov2023traf7isan pages 4-7, tsitsikov2023traf7isan pages 2-4)

Human fibroblast transcriptomics. Four patient and six control fibroblast lines were analyzed by qRT-PCR and RNA-seq, including TNFα exposure. Differentially expressed genes were found, but available evidence did not establish a reproducible clinical biomarker or complete causal pathway; the authors specifically cautioned that coiled-coil and WD40 variants may require separate functional evaluation. (castillavallmanya2020phenotypicspectrumand pages 2-3, castillavallmanya2020phenotypicspectrumand pages 9-10)

No CAFDADD-specific single-cell atlas, spatial transcriptomic map, metabolomic/lipidomic signature, proteomic biomarker, CRISPR screen, or validated multi-omics classifier is available.

Suggested ontology annotations

GO biological process: protein ubiquitination (GO:0016567); MAPK cascade (GO:0000165); cilium assembly (GO:0060271); intraciliary transport (GO:0042073); neural crest cell development (GO:0014032); heart morphogenesis (GO:0003007); blood-vessel development (GO:0001568); regulation of apoptotic process (GO:0042981).
GO cellular component: cilium (GO:0005929); intraciliary transport particle (GO:0030990); cytoplasm (GO:0005737); ubiquitin ligase complex (GO:0000151).
Cell Ontology: neural crest cell (CL:0000333); endothelial cell (CL:0000115); vascular endothelial cell (CL:0002139); cardiomyocyte (CL:0000746); fibroblast (CL:0000057). These are mechanistically implicated or experimentally used; they are not all proven primary targets in human tissue.

7. Anatomical structures affected

Primary systems are cardiovascular, nervous/neurodevelopmental, craniofacial/sensory and musculoskeletal. Cardiac sites include ductus arteriosus, valves, atrial/ventricular septa, aortic arch and outflow tract. Craniofacial involvement includes eyelids/palpebral fissures, ears, nose, palate, mandible, skull sutures and craniocervical junction. Nervous-system sites include brain ventricles, cortex, cerebellar vermis, optic pathways and spinal cord; hands, feet, digits, sternum and spine are commonly involved. (tokita2018denovomissense pages 2-3, palmamilla2023expandingthephenotypic pages 5-8, palmamilla2023expandingthephenotypic pages 10-13, palmamilla2023expandingthephenotypic pages 15-17)

Suggested UBERON annotations include heart (UBERON:0000948), ductus arteriosus (UBERON:0002092), blood vessel (UBERON:0001981), brain (UBERON:0000955), spinal cord (UBERON:0002240), eye (UBERON:0000970), ear (UBERON:0001690), skull (UBERON:0003129), hand (UBERON:0002398), foot (UBERON:0002387), and digit (UBERON:0002544). Laterality is not a defining feature, although laterality defects/heterotaxy occurred in selected developmental-variant cases. (mishragorur2023pleiotropicroleof pages 3-4)

At the subcellular level, the most relevant compartments are the cilium/IFT apparatus, cytoplasm, and protein complexes containing TRAF7, IFT57, SCRIB, MEKK3 and MEK5. Mitochondrial, lysosomal or ER pathology has not been established.

8. Temporal development

The initiating lesion is present from conception. Structural manifestations are congenital and may be detected prenatally through cystic hygroma, single umbilical artery, polyhydramnios, growth restriction or cardiac malformation. Hypotonia, poor feeding and cardiac complications commonly emerge neonatally; motor and language delay become evident in infancy or early childhood. (palmamilla2023expandingthephenotypic pages 3-5, tokita2018denovomissense pages 2-3)

CAFDADD is chronic and lifelong rather than episodic or relapsing. Structural malformations are usually stable unless surgically corrected, while scoliosis, growth deficiency, sleep-disordered breathing and cardiovascular complications can evolve. Hypotonia and developmental delay may improve; expressive-language, hearing and behavioral difficulties can persist. There is no validated stage system, remission definition, progression rate or critical therapeutic window, although early cardiac recognition, hearing correction, feeding support and developmental intervention are clinically important. (palmamilla2023expandingthephenotypic pages 8-10, palmamilla2023expandingthephenotypic pages 5-8)

9. Inheritance and population

Pattern: autosomal dominant, usually de novo. (tokita2018denovomissense pages 2-3)
Penetrance: apparently high for recurrent classic de novo WD40 variants among ascertained patients, but not quantifiable. Unaffected parents carrying selected inherited variants demonstrate incomplete penetrance. (mishragorur2023pleiotropicroleof pages 3-4, mishragorur2023pleiotropicroleof pages 8-9)
Expressivity: markedly variable, from severe complex congenital heart disease and intellectual disability to improving development or near-normal cognition. (palmamilla2023expandingthephenotypic pages 8-10)
Anticipation: not reported.
Parental germline mosaicism: theoretically relevant to recurrence counseling but no reliable frequency is established. Postzygotic affected-person mosaicism is documented.
Founder effects, consanguinity and carrier frequency: none established; consanguinity is not mechanistically expected to increase a predominantly de novo dominant disorder.
Prevalence/incidence: unknown. The 68 compiled cases are a literature count, not a prevalence estimate. (palmamilla2023expandingthephenotypic pages 15-17)
Sex/ancestry/geography: no valid sex ratio or enriched population is established. The 11-person Spanish cohort contained eight males and three females, but this is not epidemiologic evidence. Cases have been reported across ancestries, including the first Korean report in 2024. (palmamilla2023expandingthephenotypic pages 3-5, kim2024thefirstkorean pages 5-6)

For an affected individual with a constitutional heterozygous variant, transmission risk is theoretically 50% per conception, modified by reproductive fitness and variant penetrance. For unaffected parents of a proven de novo case, recurrence risk is low but above zero because gonadal mosaicism cannot be excluded.

10. Diagnostics

Clinical and genetic approach

Recognize the combination of blepharophimosis/ptosis and characteristic facial morphology, congenital heart disease, digital or pectus abnormalities, hypotonia and developmental/speech delay.
Perform trio exome or genome sequencing, or a broad developmental-disorder/congenital-heart-disease panel containing TRAF7. Confirm reportable variants and test parents by Sanger sequencing or an equivalent method. The 2020 cohort used exome, targeted capture and Sanger sequencing. (castillavallmanya2020phenotypicspectrumand pages 2-3)
Interpret with ACMG/AMP criteria, considering de novo status, WD40 hotspot/domain location, population absence, recurrence and phenotype match. Do not apply tumor-only annotations as germline pathogenic evidence without constitutional interpretation. (palmamilla2023expandingthephenotypic pages 8-10, kim2024thefirstkorean pages 5-6)

WGS may identify coding, splice and structural alternatives missed by WES, but no CAFDADD-specific yield comparison exists. WES has demonstrated utility and remains a practical first-line test. Single-gene TRAF7 sequencing is reasonable when the gestalt is strong, but broad testing is preferable in nonspecific developmental delay. CMA remains useful for detecting alternative copy-number diagnoses; karyotype, FISH, mitochondrial and repeat-expansion testing are not tests for CAFDADD unless another diagnosis is suspected.

There is no diagnostic blood/urine biochemical marker, enzyme assay, biopsy pattern, metabolomic signature, epigenetic signature or liquid-biopsy test.

Baseline phenotyping after diagnosis

Recommended evaluation includes echocardiography and cardiology consultation; growth/endocrine assessment; developmental, cognitive, speech/language and behavioral evaluation; feeding/swallow review; audiology; ophthalmology; neurologic examination with EEG for suspected seizures; sleep assessment; orthopedic/spine examination; and brain/spine imaging when neurologic, cranial or tethered-cord findings warrant it. (palmamilla2023expandingthephenotypic pages 3-5, tokita2018denovomissense pages 2-3, palmamilla2023expandingthephenotypic pages 5-8)

Differential diagnosis

Important differentials include KAT6B-related disorders/Ohdo syndrome, FAT1-related disease, RASopathies including Costello syndrome, connective-tissue disorders, and other blepharophimosis–developmental-delay or syndromic CHD conditions. Distinguishing evidence is a pathogenic constitutional TRAF7 variant plus the characteristic combined phenotype. (palmamilla2023expandingthephenotypic pages 10-13)

No universally accepted clinical diagnostic criteria, newborn screen, carrier-screening program, or population screening program exists. Prenatal or preimplantation genetic testing is technically possible once a familial pathogenic variant is known.

11. Outcome and prognosis

Long-term natural history is poorly defined. No five- or ten-year survival, life-expectancy estimate, mortality rate or disease-specific mortality statistic exists. Early morbidity is driven mainly by severe congenital heart disease, feeding/aspiration risk, sensory impairment and developmental disability. Later burdens may include orthopedic disease, sleep apnea and unresolved cardiovascular complications. (palmamilla2023expandingthephenotypic pages 5-8, palmamilla2023expandingthephenotypic pages 8-10)

The 36-year-old Korean individual demonstrates survival into adulthood and the need for adult cardiology: bicuspid aortic valve, aortic-root aneurysm and regurgitation required a Bentall operation. Persistent dyspnea was subsequently attributed to obstructive sleep apnea and improved with continuous positive airway pressure, illustrating that symptoms may have multiple treatable causes. (kim2024thefirstkorean pages 5-6)

Prognosis is highly variable. Some children show improvement in hypotonia and early psychomotor delay and may achieve normal or near-normal later cognition; others require lifelong communication and daily-living support. No validated prognostic biomarker or genotype-based outcome calculator exists. (palmamilla2023expandingthephenotypic pages 8-10)

A few tumors have been observed in germline/mosaic TRAF7-related individuals, including meningiomas and one endometrioid adenocarcinoma. These isolated reports do not establish incidence, penetrance or causality and should not be conflated with the common somatic TRAF7 alterations in sporadic meningioma. (palmamilla2023expandingthephenotypic pages 10-13, palmamilla2023expandingthephenotypic pages 8-10)

12. Treatment

No disease-modifying pharmacotherapy, approved TRAF7-targeted treatment, gene therapy, genome editing, ASO/siRNA, mRNA therapy, cell therapy or syndrome-specific immunotherapy exists. No relevant interventional clinical trial was identified. Tumor-directed TRAF7 research should not be extrapolated to children with germline CAFDADD.

Management is individualized and supportive:

Cardiology: surveillance and lesion-specific medical, catheter or surgical treatment—e.g., PDA closure, repair of septal/outflow/arch disease, or valve/aortic-root surgery. Suggested NCIT concepts: Echocardiography; Cardiac Surgery; Patent Ductus Arteriosus Closure.
Development: early physical therapy, occupational therapy, special education and neuropsychology. NCIT: Physical Therapy; Occupational Therapy; Early Intervention.
Communication: speech/language therapy and augmentative or alternative communication when expressive language is limited. NCIT: Speech Therapy.
Feeding: nutrition, feeding/swallow therapy, aspiration precautions, and nasogastric or gastrostomy support when necessary. NCIT: Nutritional Support; Gastrostomy.
Hearing/vision: periodic audiology; tympanostomy/drainage or hearing devices where indicated; ophthalmic correction and ptosis management. Hearing treatment may improve communication. (palmamilla2023expandingthephenotypic pages 8-10)
Neurology: standard antiseizure therapy for epilepsy; one recent patient achieved control with monotherapy. (palmamilla2023expandingthephenotypic pages 5-8)
Sleep/respiratory: polysomnography for symptoms, sleep-hygiene/medical treatment, and CPAP for obstructive sleep apnea when indicated. (kim2024thefirstkorean pages 5-6)
Musculoskeletal: orthopedic surveillance, physiotherapy, bracing or surgery according to scoliosis, foot deformity, craniosynostosis or craniocervical disease.
Growth/endocrine and behavioral care: longitudinal growth/puberty review and individualized psychological/psychiatric support. (palmamilla2023expandingthephenotypic pages 8-10, palmamilla2023expandingthephenotypic pages 5-8)

There are no disease-specific response rates, adverse-event datasets, pharmacogenomic recommendations or validated treatment algorithm.

13. Prevention

Primary prevention by lifestyle or vaccination is not applicable. For reproductive prevention, genetic counseling should explain de novo dominant inheritance, residual gonadal-mosaicism risk, and options for prenatal diagnosis or preimplantation genetic testing when the familial variant is known.

Secondary prevention consists of early molecular diagnosis and prompt evaluation for cardiac, hearing, vision, feeding, developmental and neurologic complications. Population newborn or carrier screening is not currently justified by available evidence.

Tertiary prevention includes cardiology follow-up, hearing correction, developmental and communication intervention, aspiration and sleep-apnea management, orthopedic monitoring and seizure treatment. Some authors propose oncology review after puberty, but no validated cancer-screening modality or interval exists; routine serial MRI should therefore be individualized rather than presented as consensus care. (palmamilla2023expandingthephenotypic pages 10-13, palmamilla2023expandingthephenotypic pages 8-10)

Routine immunization should follow general population guidance; CAFDADD is not an infectious or primary immunodeficiency disorder based on current clinical evidence.

14. Other species and natural disease

No naturally occurring CAFDADD-equivalent disease, TRAF7 syndrome, breed predisposition or veterinary transmission syndrome was identified in companion animals, livestock or wildlife. There is no zoonotic potential.

Orthologous TRAF7 genes are evolutionarily conserved in vertebrates, enabling experimental work in mouse (Mus musculus, NCBI Taxon 10090), zebrafish (Danio rerio, 7955), and western clawed frog (Xenopus tropicalis, 8364). Conservation supports comparative developmental biology but does not establish spontaneous disease in those species. (mishragorur2023pleiotropicroleof pages 6-7, mishragorur2023pleiotropicroleof pages 3-4)

15. Model organisms and experimental systems

Mouse

Global Traf7 deletion using E2a-Cre and endothelial deletion using Tie2-Cre cause hemorrhage, fragmented vessels, cardiac abnormalities and embryonic death around E10. Global-knockout genotype depletion became significant by E11.5 (N=17, p=0.0047) and at birth (N=352, p=0.0001). Inducible postnatal endothelial deletion using Cdh5(PAC)-CreERT2 causes focal cerebral hemorrhage. These models establish essential endothelial and vascular functions but are much more severe than heterozygous human missense disease. [Tsitsikov et al., published August 2023; DOI: https://doi.org/10.1016/j.isci.2023.107474]. (tsitsikov2023traf7isan pages 4-7, tsitsikov2023traf7isan pages 21-23, ihuoma2025reviewofthe pages 4-6)

Zebrafish and Xenopus

Traf7 knockdown/morphant models reproduce abnormal heart looping, edema, pharyngeal-arch disorganization, reduced neural-crest markers, craniofacial skeletal abnormalities, hydrocephalus, renal cysts and defective ciliary motility. Mutant-mRNA expression supports dominant effects for selected variants. These systems are useful for neural crest, cilia, laterality and cardiogenesis, but morpholino depletion and overexpression are imperfect models of a constitutional heterozygous human allele. (mishragorur2023pleiotropicroleof pages 6-7, mishragorur2023pleiotropicroleof pages 3-4, mishragorur2023pleiotropicroleof pages 8-9)

Cellular systems

Patient fibroblasts have supported transcriptomic investigation; HEK293 cells have been used for protein interaction and mutant-expression assays; HUVECs model endothelial shear responses. These systems implicate IFT57, SCRIB and MEKK3–MEK5–ERK5–KLF2 signaling but do not recreate human embryonic tissue patterning. (mishragorur2023pleiotropicroleof pages 8-8, castillavallmanya2020phenotypicspectrumand pages 9-10, tsitsikov2023traf7isan pages 13-15)

No validated recurrent-variant heterozygous knock-in mouse, patient-derived iPSC cardiac/neural-crest model, organoid model, or high-throughput therapeutic-screening platform was identified.

Evidence-weighted conclusions

High confidence: CAFDADD is a germline, usually de novo autosomal-dominant TRAF7 missense disorder with characteristic neurodevelopmental, craniofacial, cardiac and digital/skeletal abnormalities. (OpenTargets Search: cardiac facial and digital anomalies with developmental delay-TRAF7, tokita2018denovomissense pages 2-3, palmamilla2023expandingthephenotypic pages 15-17)
Moderate-to-high confidence: recurrent WD40 missense alleles act through altered function, often dominant-negative, rather than uniform haploinsufficiency. (castillavallmanya2020phenotypicspectrumand pages 2-3, mishragorur2023pleiotropicroleof pages 8-9)
Moderate mechanistic confidence: disrupted IFT57-dependent ciliary transport, neural-crest development and endothelial MEKK3–MEK5–ERK5–KLF2 signaling plausibly connect TRAF7 dysfunction to the phenotype; much of this chain rests on cell, fish, amphibian and knockout-mouse models rather than direct human embryonic evidence. (mishragorur2023pleiotropicroleof pages 6-7, mishragorur2023pleiotropicroleof pages 8-8, tsitsikov2023traf7isan pages 7-9)
Clinical practice: diagnosis is molecular, preferably by trio sequencing; management is multidisciplinary and manifestation-directed. No disease-modifying therapy or relevant trial exists. (palmamilla2023expandingthephenotypic pages 8-10, castillavallmanya2020phenotypicspectrumand pages 2-3, palmamilla2023expandingthephenotypic pages 5-8)
Major gaps: unbiased epidemiology, penetrance, adult natural history, survival, quality of life, variant-specific functional validation, tumor-risk quantification, validated surveillance guidelines, and faithful heterozygous knock-in models remain unavailable.

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(mishragorur2023pleiotropicroleof pages 3-4): Ketu Mishra-Gorur, Tanyeri Barak, Leon D. Kaulen, Octavian Henegariu, Sheng Chih Jin, Stephanie Marie Aguilera, Ezgi Yalbir, Gizem Goles, Sayoko Nishimura, Danielle Miyagishima, Lydia Djenoune, Selin Altinok, Devendra K. Rai, Stephen Viviano, Andrew Prendergast, Cynthia Zerillo, Kent Ozcan, Burcin Baran, Leman Sencar, Nukte Goc, Yanki Yarman, A. Gulhan Ercan-Sencicek, Kaya Bilguvar, Richard P. Lifton, Jennifer Moliterno, Angeliki Louvi, Shiaulou Yuan, Engin Deniz, Martina Brueckner, and Murat Gunel. Pleiotropic role of traf7 in skull-base meningiomas and congenital heart disease. Proceedings of the National Academy of Sciences of the United States of America, Apr 2023. URL: https://doi.org/10.1073/pnas.2214997120, doi:10.1073/pnas.2214997120. This article has 20 citations and is from a highest quality peer-reviewed journal.
(palmamilla2023expandingthephenotypic pages 3-5): Carmen Palma-Milla, Aina Prat-Planas, Emma Soengas-Gonda, Mónica Centeno-Pla, Jaime Sánchez-Pozo, Irene Lazaro-Rodriguez, Juan F. Quesada-Espinosa, Ana Arteche-Lopez, Jonathan Olival, Marta Pacio-Miguez, María Palomares-Bralo, Fernando Santos-Simarro, Ramón Cancho-Candela, María Vázquez-López, Veronica Seidel, Antonio F Martinez-Monseny, Didac Casas-Alba, Daniel Grinberg, Susanna Balcells, Mercedes Serrano, Raquel Rabionet, Miguel A. Martin, and Roser Urreizti. Expanding the phenotypic spectrum of traf7 syndrome: report of eleven new cases and literature review. MedRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.23299272, doi:10.1101/2023.12.13.23299272. This article has 0 citations.
(palmamilla2023expandingthephenotypic pages 5-8): Carmen Palma-Milla, Aina Prat-Planas, Emma Soengas-Gonda, Mónica Centeno-Pla, Jaime Sánchez-Pozo, Irene Lazaro-Rodriguez, Juan F. Quesada-Espinosa, Ana Arteche-Lopez, Jonathan Olival, Marta Pacio-Miguez, María Palomares-Bralo, Fernando Santos-Simarro, Ramón Cancho-Candela, María Vázquez-López, Veronica Seidel, Antonio F Martinez-Monseny, Didac Casas-Alba, Daniel Grinberg, Susanna Balcells, Mercedes Serrano, Raquel Rabionet, Miguel A. Martin, and Roser Urreizti. Expanding the phenotypic spectrum of traf7 syndrome: report of eleven new cases and literature review. MedRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.23299272, doi:10.1101/2023.12.13.23299272. This article has 0 citations.
(palmamilla2023expandingthephenotypic pages 10-13): Carmen Palma-Milla, Aina Prat-Planas, Emma Soengas-Gonda, Mónica Centeno-Pla, Jaime Sánchez-Pozo, Irene Lazaro-Rodriguez, Juan F. Quesada-Espinosa, Ana Arteche-Lopez, Jonathan Olival, Marta Pacio-Miguez, María Palomares-Bralo, Fernando Santos-Simarro, Ramón Cancho-Candela, María Vázquez-López, Veronica Seidel, Antonio F Martinez-Monseny, Didac Casas-Alba, Daniel Grinberg, Susanna Balcells, Mercedes Serrano, Raquel Rabionet, Miguel A. Martin, and Roser Urreizti. Expanding the phenotypic spectrum of traf7 syndrome: report of eleven new cases and literature review. MedRxiv, Dec 2023. URL: https://doi.org/10.1101/2023.12.13.23299272, doi:10.1101/2023.12.13.23299272. This article has 0 citations.
(mishragorur2023pleiotropicroleof pages 8-8): Ketu Mishra-Gorur, Tanyeri Barak, Leon D. Kaulen, Octavian Henegariu, Sheng Chih Jin, Stephanie Marie Aguilera, Ezgi Yalbir, Gizem Goles, Sayoko Nishimura, Danielle Miyagishima, Lydia Djenoune, Selin Altinok, Devendra K. Rai, Stephen Viviano, Andrew Prendergast, Cynthia Zerillo, Kent Ozcan, Burcin Baran, Leman Sencar, Nukte Goc, Yanki Yarman, A. Gulhan Ercan-Sencicek, Kaya Bilguvar, Richard P. Lifton, Jennifer Moliterno, Angeliki Louvi, Shiaulou Yuan, Engin Deniz, Martina Brueckner, and Murat Gunel. Pleiotropic role of traf7 in skull-base meningiomas and congenital heart disease. Proceedings of the National Academy of Sciences of the United States of America, Apr 2023. URL: https://doi.org/10.1073/pnas.2214997120, doi:10.1073/pnas.2214997120. This article has 20 citations and is from a highest quality peer-reviewed journal.
(mishragorur2023pleiotropicroleof pages 8-9): Ketu Mishra-Gorur, Tanyeri Barak, Leon D. Kaulen, Octavian Henegariu, Sheng Chih Jin, Stephanie Marie Aguilera, Ezgi Yalbir, Gizem Goles, Sayoko Nishimura, Danielle Miyagishima, Lydia Djenoune, Selin Altinok, Devendra K. Rai, Stephen Viviano, Andrew Prendergast, Cynthia Zerillo, Kent Ozcan, Burcin Baran, Leman Sencar, Nukte Goc, Yanki Yarman, A. Gulhan Ercan-Sencicek, Kaya Bilguvar, Richard P. Lifton, Jennifer Moliterno, Angeliki Louvi, Shiaulou Yuan, Engin Deniz, Martina Brueckner, and Murat Gunel. Pleiotropic role of traf7 in skull-base meningiomas and congenital heart disease. Proceedings of the National Academy of Sciences of the United States of America, Apr 2023. URL: https://doi.org/10.1073/pnas.2214997120, doi:10.1073/pnas.2214997120. This article has 20 citations and is from a highest quality peer-reviewed journal.
(mishragorur2023pleiotropicroleof pages 6-7): Ketu Mishra-Gorur, Tanyeri Barak, Leon D. Kaulen, Octavian Henegariu, Sheng Chih Jin, Stephanie Marie Aguilera, Ezgi Yalbir, Gizem Goles, Sayoko Nishimura, Danielle Miyagishima, Lydia Djenoune, Selin Altinok, Devendra K. Rai, Stephen Viviano, Andrew Prendergast, Cynthia Zerillo, Kent Ozcan, Burcin Baran, Leman Sencar, Nukte Goc, Yanki Yarman, A. Gulhan Ercan-Sencicek, Kaya Bilguvar, Richard P. Lifton, Jennifer Moliterno, Angeliki Louvi, Shiaulou Yuan, Engin Deniz, Martina Brueckner, and Murat Gunel. Pleiotropic role of traf7 in skull-base meningiomas and congenital heart disease. Proceedings of the National Academy of Sciences of the United States of America, Apr 2023. URL: https://doi.org/10.1073/pnas.2214997120, doi:10.1073/pnas.2214997120. This article has 20 citations and is from a highest quality peer-reviewed journal.
(tsitsikov2023traf7isan pages 1-2): Erdyni N. Tsitsikov, Khanh P. Phan, Yufeng Liu, Alla V. Tsytsykova, Mike Kinter, Lauren Selland, Lori Garman, Courtney Griffin, and Ian F. Dunn. Traf7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development. Aug 2023. URL: https://doi.org/10.1016/j.isci.2023.107474, doi:10.1016/j.isci.2023.107474. This article has 15 citations and is from a peer-reviewed journal.
(tsitsikov2023traf7isan pages 7-9): Erdyni N. Tsitsikov, Khanh P. Phan, Yufeng Liu, Alla V. Tsytsykova, Mike Kinter, Lauren Selland, Lori Garman, Courtney Griffin, and Ian F. Dunn. Traf7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development. Aug 2023. URL: https://doi.org/10.1016/j.isci.2023.107474, doi:10.1016/j.isci.2023.107474. This article has 15 citations and is from a peer-reviewed journal.
(kim2024thefirstkorean pages 5-6): Kyung Hee Kim, Ji Yoon Han, Joonhong Park, and Jung Sun Cho. The first korean case with cardiac, facial, and digital anomalies with developmental delay caused by de novo traf7 p.arg655gln variant. International Journal of Molecular Sciences, 25:3701, Mar 2024. URL: https://doi.org/10.3390/ijms25073701, doi:10.3390/ijms25073701. This article has 1 citations.
(castillavallmanya2020phenotypicspectrumand pages 9-10): Laura Castilla-Vallmanya, Kaja K. Selmer, Clémantine Dimartino, Raquel Rabionet, Bernardo Blanco-Sánchez, Sandra Yang, Margot R.F. Reijnders, Antonie J. van Essen, Myriam Oufadem, Magnus D. Vigeland, Barbro Stadheim, Gunnar Houge, Helen Cox, Helen Kingston, Jill Clayton-Smith, Jeffrey W. Innis, Maria Iascone, Anna Cereda, Sara Gabbiadini, Wendy K. Chung, Victoria Sanders, Joel Charrow, Emily Bryant, John Millichap, Antonio Vitobello, Christel Thauvin, Frederic Tran Mau-Them, Laurence Faivre, Gaetan Lesca, Audrey Labalme, Christelle Rougeot, Nicolas Chatron, Damien Sanlaville, Katherine M. Christensen, Amelia Kirby, Raymond Lewandowski, Rachel Gannaway, Maha Aly, Anna Lehman, Lorne Clarke, Luitgard Graul-Neumann, Christiane Zweier, Davor Lessel, Bernarda Lozic, Ingvild Aukrust, Ryan Peretz, Robert Stratton, Thomas Smol, Anne Dieux-Coëslier, Joanna Meira, Elizabeth Wohler, Nara Sobreira, Erin M. Beaver, Jennifer Heeley, Lauren C. Briere, Frances A. High, David A. Sweetser, Melissa A. Walker, Catherine E. Keegan, Parul Jayakar, Marwan Shinawi, Wilhelmina S. Kerstjens-Frederikse, Dawn L. Earl, Victoria M. Siu, Emma Reesor, Tony Yao, Robert A. Hegele, Olena M. Vaske, Shannon Rego, Kevin A. Shapiro, Brian Wong, Michael J. Gambello, Marie McDonald, Danielle Karlowicz, Roberto Colombo, Alessandro Serretti, Lynn Pais, Anne O’Donnell-Luria, Alison Wray, Simon Sadedin, Belinda Chong, Tiong Y. Tan, John Christodoulou, Susan M. White, Anne Slavotinek, Deborah Barbouth, Dayna Morel Swols, Mélanie Parisot, Christine Bole-Feysot, Patrick Nitschké, Véronique Pingault, Arnold Munnich, Megan T. Cho, Valérie Cormier-Daire, Susanna Balcells, Stanislas Lyonnet, Daniel Grinberg, Jeanne Amiel, Roser Urreizti, and Christopher T. Gordon. Phenotypic spectrum and transcriptomic profile associated with germline variants in traf7. Jul 2020. URL: https://doi.org/10.1038/s41436-020-0792-7, doi:10.1038/s41436-020-0792-7. This article has 38 citations and is from a highest quality peer-reviewed journal.
(tsitsikov2023traf7isan pages 4-7): Erdyni N. Tsitsikov, Khanh P. Phan, Yufeng Liu, Alla V. Tsytsykova, Mike Kinter, Lauren Selland, Lori Garman, Courtney Griffin, and Ian F. Dunn. Traf7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development. Aug 2023. URL: https://doi.org/10.1016/j.isci.2023.107474, doi:10.1016/j.isci.2023.107474. This article has 15 citations and is from a peer-reviewed journal.
(castillavallmanya2020phenotypicspectrumand pages 1-2): Laura Castilla-Vallmanya, Kaja K. Selmer, Clémantine Dimartino, Raquel Rabionet, Bernardo Blanco-Sánchez, Sandra Yang, Margot R.F. Reijnders, Antonie J. van Essen, Myriam Oufadem, Magnus D. Vigeland, Barbro Stadheim, Gunnar Houge, Helen Cox, Helen Kingston, Jill Clayton-Smith, Jeffrey W. Innis, Maria Iascone, Anna Cereda, Sara Gabbiadini, Wendy K. Chung, Victoria Sanders, Joel Charrow, Emily Bryant, John Millichap, Antonio Vitobello, Christel Thauvin, Frederic Tran Mau-Them, Laurence Faivre, Gaetan Lesca, Audrey Labalme, Christelle Rougeot, Nicolas Chatron, Damien Sanlaville, Katherine M. Christensen, Amelia Kirby, Raymond Lewandowski, Rachel Gannaway, Maha Aly, Anna Lehman, Lorne Clarke, Luitgard Graul-Neumann, Christiane Zweier, Davor Lessel, Bernarda Lozic, Ingvild Aukrust, Ryan Peretz, Robert Stratton, Thomas Smol, Anne Dieux-Coëslier, Joanna Meira, Elizabeth Wohler, Nara Sobreira, Erin M. Beaver, Jennifer Heeley, Lauren C. Briere, Frances A. High, David A. Sweetser, Melissa A. Walker, Catherine E. Keegan, Parul Jayakar, Marwan Shinawi, Wilhelmina S. Kerstjens-Frederikse, Dawn L. Earl, Victoria M. Siu, Emma Reesor, Tony Yao, Robert A. Hegele, Olena M. Vaske, Shannon Rego, Kevin A. Shapiro, Brian Wong, Michael J. Gambello, Marie McDonald, Danielle Karlowicz, Roberto Colombo, Alessandro Serretti, Lynn Pais, Anne O’Donnell-Luria, Alison Wray, Simon Sadedin, Belinda Chong, Tiong Y. Tan, John Christodoulou, Susan M. White, Anne Slavotinek, Deborah Barbouth, Dayna Morel Swols, Mélanie Parisot, Christine Bole-Feysot, Patrick Nitschké, Véronique Pingault, Arnold Munnich, Megan T. Cho, Valérie Cormier-Daire, Susanna Balcells, Stanislas Lyonnet, Daniel Grinberg, Jeanne Amiel, Roser Urreizti, and Christopher T. Gordon. Phenotypic spectrum and transcriptomic profile associated with germline variants in traf7. Jul 2020. URL: https://doi.org/10.1038/s41436-020-0792-7, doi:10.1038/s41436-020-0792-7. This article has 38 citations and is from a highest quality peer-reviewed journal.
(mishragorur2023pleiotropicroleof pages 9-10): Ketu Mishra-Gorur, Tanyeri Barak, Leon D. Kaulen, Octavian Henegariu, Sheng Chih Jin, Stephanie Marie Aguilera, Ezgi Yalbir, Gizem Goles, Sayoko Nishimura, Danielle Miyagishima, Lydia Djenoune, Selin Altinok, Devendra K. Rai, Stephen Viviano, Andrew Prendergast, Cynthia Zerillo, Kent Ozcan, Burcin Baran, Leman Sencar, Nukte Goc, Yanki Yarman, A. Gulhan Ercan-Sencicek, Kaya Bilguvar, Richard P. Lifton, Jennifer Moliterno, Angeliki Louvi, Shiaulou Yuan, Engin Deniz, Martina Brueckner, and Murat Gunel. Pleiotropic role of traf7 in skull-base meningiomas and congenital heart disease. Proceedings of the National Academy of Sciences of the United States of America, Apr 2023. URL: https://doi.org/10.1073/pnas.2214997120, doi:10.1073/pnas.2214997120. This article has 20 citations and is from a highest quality peer-reviewed journal.
(ihuoma2025reviewofthe pages 6-7): Jennifer Ihuoma, Sherwin Tavakol, Sharon Negri, Cade Ballard, Khanh Phan, Albert Orock, Zeke Reyff, Madison Milan, Eva Troyano-Rodriguez, Rakesh Rudraboina, Anna Csiszar, Anthony C. Johnson, Ian F. Dunn, and Stefano Tarantini. Review of the role of traf7 in brain endothelial integrity and cerebrovascular aging. Life, 15(8):1280, Aug 2025. URL: https://doi.org/10.3390/life15081280, doi:10.3390/life15081280. This article has 10 citations.
(tsitsikov2023traf7isan pages 2-4): Erdyni N. Tsitsikov, Khanh P. Phan, Yufeng Liu, Alla V. Tsytsykova, Mike Kinter, Lauren Selland, Lori Garman, Courtney Griffin, and Ian F. Dunn. Traf7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development. Aug 2023. URL: https://doi.org/10.1016/j.isci.2023.107474, doi:10.1016/j.isci.2023.107474. This article has 15 citations and is from a peer-reviewed journal.
(tsitsikov2023traf7isan pages 21-23): Erdyni N. Tsitsikov, Khanh P. Phan, Yufeng Liu, Alla V. Tsytsykova, Mike Kinter, Lauren Selland, Lori Garman, Courtney Griffin, and Ian F. Dunn. Traf7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development. Aug 2023. URL: https://doi.org/10.1016/j.isci.2023.107474, doi:10.1016/j.isci.2023.107474. This article has 15 citations and is from a peer-reviewed journal.
(ihuoma2025reviewofthe pages 4-6): Jennifer Ihuoma, Sherwin Tavakol, Sharon Negri, Cade Ballard, Khanh Phan, Albert Orock, Zeke Reyff, Madison Milan, Eva Troyano-Rodriguez, Rakesh Rudraboina, Anna Csiszar, Anthony C. Johnson, Ian F. Dunn, and Stefano Tarantini. Review of the role of traf7 in brain endothelial integrity and cerebrovascular aging. Life, 15(8):1280, Aug 2025. URL: https://doi.org/10.3390/life15081280, doi:10.3390/life15081280. This article has 10 citations.
(tsitsikov2023traf7isan pages 13-15): Erdyni N. Tsitsikov, Khanh P. Phan, Yufeng Liu, Alla V. Tsytsykova, Mike Kinter, Lauren Selland, Lori Garman, Courtney Griffin, and Ian F. Dunn. Traf7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development. Aug 2023. URL: https://doi.org/10.1016/j.isci.2023.107474, doi:10.1016/j.isci.2023.107474. This article has 15 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	5
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	60
Resolved	58
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	4
Terms named correctly	0
Terms named as a different term	2
Terms whose name is worth a second look	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0032572 (6 mentions) - the report calls it "if available"; MONDO calls it cardiac, facial, and digital anomalies with developmental delay
GO:0005929 (1 mention) - the report calls it "GO cellular component: cilium"; GO calls it cilium**

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0016567 (1 mention) - the report calls it "GO biological process: protein ubiquitination"; GO calls it protein ubiquitination**
CL:0000333 (1 mention) - the report calls it "Cell Ontology: neural crest cell"; CL calls it migratory neural crest cell**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

Ask OpenScientist

OpenScientist Report

Mappings

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

External Assertions

Medical Actions

Diagnosis

Prevalence

Related Datasets

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive research report: germline TRAF7-related CAFDADD

Scope and evidence boundary

1. Disease information

Definition

Identifiers and synonyms

2. Etiology, risk, and protective factors

Causal factor

Risk factors

3. Phenotypes

4. Genetic and molecular information

Gene and protein

Variant spectrum and classification

Functional consequence

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Experimental detail

Suggested ontology annotations

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and genetic approach

Baseline phenotyping after diagnosis

Differential diagnosis

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Mouse

Zebrafish and Xenopus

Cellular systems

Evidence-weighted conclusions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver