developmental delay with or without dysmorphic facies and autism

Mendelian MONDO:0032760 Pathograph 30 Show in embeddings browser Mendelian neurodevelopmental disorder hereditary disease

Developmental delay with or without dysmorphic facies and autism (DEDDFA) is a rare autosomal dominant, de novo neurodevelopmental disorder caused by heterozygous missense variants in TRRAP, the scaffolding subunit that recruits histone acetyltransferase (HAT) complexes to chromatin. Core features are global developmental delay and a wide range of intellectual functioning, frequently reaching intellectual disability. The published cohort resolves into two genotype-correlated clinical spectra: a complex multisystem malformation syndrome (brain, heart, kidney and genitourinary anomalies) associated with missense variants clustering around p.Ala1043Thr, and a spectrum manifesting with autism spectrum disorder and/or intellectual disability with epilepsy. Facial dysmorphism is seen across both spectra.

Ask OpenScientist

Ask a research question about developmental delay with or without dysmorphic facies and autism. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Mappings
1
Inheritance
4
Pathophys.
20
Phenotypes
1
Gaps
30
Pathograph
1
Genes
5
Medical Actions
1
Models
2
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0100465 complex neurodevelopmental disorder with or without congenital anomalies Not Yet Curated
skos:broadMatch MONDO
MONDO:0100465 is the broad ClinGen disease-entity term under which the TRRAP gene-disease validity assertion is curated. It denotes the same TRRAP-related phenotype at a broader, clinically defined level than this OMIM-anchored term (MONDO:0032760, OMIM:618454), so the relation is broadMatch rather than exactMatch. broadMatch does not retire the mapped concept from the curation queue and does not license copying the ClinGen validity tier onto this entry; see genetic.notes.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
The disorder is caused by heterozygous TRRAP variants that are de novo or apparently de novo in affected individuals; low-level maternal mosaicism was documented in the mother of two affected sisters, a recurrence-risk consideration.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:30827496 SUPPORT Human Clinical
"Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals."
De novo heterozygous variants in affected individuals establish an autosomal dominant mode of inheritance arising mainly from new mutation.
PMID:30827496 SUPPORT Human Clinical
"two sisters who had inherited a variant from a mother with low-level mosaicism"
Documents low-level maternal mosaicism as a recurrence-risk consideration for an otherwise de novo disorder.
?

Discussions and Knowledge Gaps

1
Do the clustered TRRAP missense variants act by gain-of-function or dominant-negative mechanisms, and what accounts for the genotype-phenotype branch between the multisystem malformation spectrum and the ASD/epilepsy spectrum?
KNOWLEDGE GAP OPEN gap_trrap_functional_impact
Attached to
pathophysiology#TRRAP missense variant disrupting HAT-complex scaffold function pathophysiology#Altered neurodevelopmental gene expression pathophysiology#Disrupted embryonic organ and craniofacial morphogenesis
The defining report proposes gain-of-function or dominant-negative effects for the clustered variants and notes the absence of loss-of-function variants, but the functional consequence is not demonstrated, and the only direct molecular data are patient-fibroblast RNA-seq changes. The mechanistic basis for the genotype-correlated split into two clinical spectra is unexplained.
⚙

Pathophysiology

4
TRRAP missense variant disrupting HAT-complex scaffold function
A heterozygous de novo missense variant alters TRRAP, the scaffolding subunit that recruits histone acetyltransferase (HAT) complexes to chromatin, perturbing its role in regulating HAT activity.
TRRAP hgnc:12347 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TRRAP (hgnc:12347). hgnc:12347 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: DE_NOVO
histone acetyltransferase regulator activity GO:0035034 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal histone acetyltransferase regulator activity (GO:0035034). GO:0035034 is a molecular function from the Gene Ontology.
Downstream
Dysregulated histone acetylation and transcription Altered TRRAP perturbs HAT-complex-mediated histone acetylation and downstream transcriptional regulation.
Show evidence (2 references)
PMID:30827496 SUPPORT BACKGROUND Other
"This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP)."
Establishes TRRAP as the scaffolding subunit that recruits HAT complexes to chromatin, the activity disrupted by the variant.
PMID:30827496 SUPPORT Human Clinical
"Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals."
Identifies the recurrent TRRAP missense variants as the initiating lesion in affected individuals.
Dysregulated histone acetylation and transcription
Perturbed TRRAP-dependent recruitment of HAT complexes alters histone lysine acetylation and RNA polymerase II-dependent transcription, the chromatin-level consequence of the variant.
internal peptidyl-lysine (histone) acetylation GO:0018393 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal internal peptidyl-lysine (histone) acetylation, annotated with internal peptidyl-lysine acetylation (GO:0018393). GO:0018393 is a biological process from the Gene Ontology. regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology.
Downstream
Altered neurodevelopmental gene expression Dysregulated chromatin acetylation changes the expression of genes governing neuronal function.
Disrupted embryonic organ and craniofacial morphogenesis Altered chromatin regulation during development disrupts morphogenesis of multiple organ systems and the face.
Show evidence (1 reference)
PMID:30827496 SUPPORT BACKGROUND Other
"Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression."
Supports histone lysine acetylation as a key regulator of gene expression, the process disrupted downstream of altered TRRAP.
Altered neurodevelopmental gene expression
RNA sequencing of patient-derived skin fibroblasts shows altered expression of genes implicated in neuronal function and ion transport, linking the chromatin defect to a dysregulated neurodevelopmental gene-expression program. The fibroblast finding is a surrogate tissue; the inference to neural cells is not directly demonstrated.
regulation of gene expression GO:0010468 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of gene expression (GO:0010468). GO:0010468 is a biological process from the Gene Ontology. nervous system development GO:0007399 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal nervous system development (GO:0007399). GO:0007399 is a biological process from the Gene Ontology.
Downstream
Global developmental delay Disrupted neurodevelopmental gene expression impairs developmental progress.
Intellectual disability Impaired neurodevelopment contributes to the range of intellectual functioning, often reaching intellectual disability.
Autistic behavior Altered neuronal gene expression contributes to autism spectrum disorder in the second clinical spectrum.
Seizure Dysregulated neuronal and ion-transport gene expression contributes to epilepsy in the second clinical spectrum.
Microcephaly Impaired neurodevelopment contributes to reduced head size reported in affected individuals.
Hypotonia Neurodevelopmental disruption contributes to hypotonia on neurological examination.
Show evidence (1 reference)
PMID:30827496 SUPPORT In Vitro
"RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport."
Direct patient-cell transcriptomic evidence of dysregulated expression of neuronal-function and ion-transport genes.
Disrupted embryonic organ and craniofacial morphogenesis
Altered TRRAP-dependent chromatin regulation during embryogenesis disrupts morphogenesis of the brain, heart, kidney and genitourinary system and of craniofacial structures, producing the multisystem malformations and facial dysmorphism of the first clinical spectrum.
embryonic morphogenesis GO:0048598 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal embryonic morphogenesis (GO:0048598). GO:0048598 is a biological process from the Gene Ontology.
Animal models
trrap-knockout zebrafish Zebrafish partially recapitulates The knockout reproduces reduced head/eye size and ventral pharyngeal arch and tooth-mineralization defects, modeling disrupted craniofacial morphogenesis.
Downstream
Abnormal brain morphology Malformations of the brain in the multisystem spectrum.
Cerebellar vermis hypoplasia The most common structural brain anomaly in the multisystem spectrum.
Abnormal heart morphology Cardiac malformations in the multisystem spectrum.
Abnormal renal morphology Renal malformations in the multisystem spectrum.
Abnormal genital morphology External and internal genital anomalies in the multisystem spectrum.
Abnormal facial shape Craniofacial dysmorphogenesis producing facial dysmorphism across both spectra.
Cleft upper lip Orofacial clefting in the multisystem spectrum.
Cleft palate Orofacial clefting in the multisystem spectrum.
Upslanted palpebral fissure Component of the facial dysmorphism.
Epicanthus Component of the facial dysmorphism.
Telecanthus Component of the facial dysmorphism.
Wide nasal bridge Component of the facial dysmorphism.
Smooth philtrum Component of the facial dysmorphism.
Thin upper lip vermilion Component of the facial dysmorphism.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired..."
Supports multisystem malformations of brain, heart, kidney and genitourinary system as a core consequence.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for developmental delay with or without dysmorphic facies and autism Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

20
Cardiovascular 1
Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac malformation, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired..."
Reports malformations of the heart; the abstract names the organ system but not the specific malformation.
Genitourinary 2
Abnormal renal morphology FREQUENT HP:0012210 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal renal morphology (HP:0012210). HP:0012210 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Abnormal renal morphology, namely multicystic dysplastic kidney, hydronephrosis, a duplicate kidney, and/or a small kidney, was described in 60% (6/10) of individuals"
Reports a variable spectrum of renal malformations in 60% of imaged multisystem-spectrum individuals.
Abnormal genital morphology Abnormality of the genital system HP:0000078 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Genital anomaly, annotated with Abnormality of the genital system (HP:0000078). HP:0000078 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Three males (3/6; 50%) had external-genitalia anomalies, including microphallus, hypoplastic scrotum, and cryptorchidism, and two females (2/7; 29%) had a duplicated vagina and/or uterus."
Reports a variable spectrum of external and internal genital anomalies in the multisystem spectrum.
Head and Neck 10
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"The last available occipitofrontal-circumference measurements revealed microcephaly (ranging from -2.8 to -5 standard deviations"
Directly reports microcephaly (-2.8 to -5 SD) in the multisystem-spectrum cohort; the full text gives a frequency of 46% (6/13).
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip."
Reports facial dysmorphism across both clinical groups.
Upslanted palpebral fissure HP:0000582 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Upslanted palpebral fissures, annotated with Upslanted palpebral fissure (HP:0000582). HP:0000582 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip."
Lists upslanted palpebral fissures among the facial features.
Epicanthus HP:0000286 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epicanthus (HP:0000286). HP:0000286 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip."
Lists epicanthus among the facial features.
Telecanthus HP:0000506 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Telecanthus (HP:0000506). HP:0000506 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip."
Lists telecanthus among the facial features.
Wide nasal bridge HP:0000431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide nasal bridge (HP:0000431). HP:0000431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip."
Lists a wide nasal bridge among the facial features.
Smooth philtrum HP:0000319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad and smooth philtrum, annotated with Smooth philtrum (HP:0000319). HP:0000319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip."
Lists a broad and smooth philtrum among the facial features.
Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin upper lip, annotated with Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip."
Lists a thin upper lip among the facial features.
Cleft upper lip FREQUENT HP:0000204 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft lip, annotated with Cleft upper lip (HP:0000204). HP:0000204 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"cleft lip and palate (5/13; 38%)"
Reports cleft lip and palate in 38% of the multisystem-spectrum cohort.
Cleft palate FREQUENT HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"cleft lip and palate (5/13; 38%)"
Reports cleft lip and palate in 38% of the multisystem-spectrum cohort.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Neurological examination revealed hypotonia in 31% (4/13) of individuals."
Reports hypotonia in 31% of the multisystem-spectrum cohort.
Nervous System 6
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"13 individuals with variants in the codon 1031-1159 region had global developmental delay and apparent ID"
Directly reports global developmental delay in the multisystem-spectrum cohort.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired..."
Reports intellectual disability and a wide range of intellectual functioning in affected individuals.
Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy."
Reports autism spectrum disorder as a feature of the second clinical spectrum.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy."
Reports epilepsy as a feature of the second clinical spectrum.
Abnormal brain morphology HP:0012443 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brain malformation, annotated with Abnormal brain morphology (HP:0012443). HP:0012443 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired..."
Reports malformations of the brain; the abstract names the organ system but not the specific malformation.
Cerebellar vermis hypoplasia FREQUENT HP:0001320 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar vermis hypoplasia (HP:0001320). HP:0001320 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"seven of those 10 (70%) showed structural brain anomalies, including cerebellar vermis hypoplasia (6/10)"
Reports cerebellar vermis hypoplasia as the most frequent structural brain anomaly in imaged individuals.
🧬

Genetic Associations

1
TRRAP (Causative heterozygous de novo or apparently de novo TRRAP missense variants; variants of the first clinical spectrum cluster around c.3127G>A p.(Ala1043Thr).)
Gene: TRRAP hgnc:12347 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRRAP (hgnc:12347). hgnc:12347 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (3 references)
PMID:30827496 SUPPORT Human Clinical
"Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals."
Identifies the recurrent clustered missense variant defining the first clinical spectrum.
PMID:30827496 SUPPORT BACKGROUND Other
"TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation."
Extreme missense constraint supports the pathogenicity of recurrent missense variants in this gene.
PMID:30827496 SUPPORT Human Clinical
"suggesting a model in which specific domains are affected and haploinsufficiency is unlikely, at least for clustering variants."
Supports a dominant mechanism in which clustered domain-affecting missense variants act other than by haploinsufficiency.
💊

Medical Actions

5
Supportive and developmental care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
No disease-specific therapy exists; management is supportive and directed at developmental delay and intellectual disability, with early intervention and multidisciplinary developmental support.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired..."
Developmental delay and intellectual disability with markedly impaired basic life functions support supportive developmental care as the management target.
Physical and occupational therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Physical and occupational therapy support motor and adaptive-function needs in affected children with global developmental delay.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"13 individuals with variants in the codon 1031-1159 region had global developmental delay and apparent ID"
Global developmental delay in affected individuals supports developmental therapies as phenotype-directed supportive care.
Speech and language therapy
Action: speech and language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech and language therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Platform: Behavioral / lifestyle
Speech-language therapy supports communication needs associated with global developmental delay and intellectual disability.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"13 individuals with variants in the codon 1031-1159 region had global developmental delay and apparent ID"
Global developmental delay supports speech-language therapy as phenotype-directed supportive care.
Anti-seizure pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anticonvulsant agent NCIT:C264 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticonvulsant agent (NCIT:C264). NCIT:C264 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Anti-seizure medication is indicated for individuals in the second clinical spectrum who develop epilepsy.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy."
Epilepsy in the second clinical spectrum is the target of anti-seizure pharmacotherapy.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling addresses the de novo, autosomal dominant inheritance and the residual recurrence risk from documented low-level maternal mosaicism.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals."
The de novo origin of variants supports genetic counseling on recurrence risk.
🔬

Diagnosis

1
Exome or genome sequencing
Molecular diagnosis rests on identifying a heterozygous pathogenic TRRAP missense variant, typically by trio exome or genome sequencing or a neurodevelopmental gene panel including TRRAP.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Results: A heterozygous (de novo) TRRAP missense variant establishes the molecular diagnosis.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"These variants were identified either by trio or solo exome sequencing (ES) from research and clinical cohorts."
The defining cohort's TRRAP variants were identified by trio or solo exome sequencing, supporting exome sequencing as the diagnostic approach.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
The defining report described 24 individuals with TRRAP variants; no prevalence or incidence estimate is available.
Show evidence (1 reference)
PMID:30827496 SUPPORT Human Clinical
"Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals."
Establishes the small number of individuals reported in the literature.
🐁

Animal Models

1
trrap-knockout zebrafish knockout
A trrap gene-knockout zebrafish line recapitulates craniofacial and head/eye size reductions, providing a loss-of-function model of a TRRAP-associated human disorder.
Species
Zebrafish
Genotype
trrap gene-knockout (loss-of-function)
Genes
trrap hgnc:12347 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns trrap (hgnc:12347). hgnc:12347 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:34934055
Pathograph links
Disrupted embryonic organ and craniofacial morphogenesis partially recapitulates fidelity: moderate observes: tissue The knockout reproduces reduced head/eye size and ventral pharyngeal arch and tooth-mineralization defects, modeling disrupted craniofacial morphogenesis.
Limitations: The model is a complete loss-of-function knockout, whereas the human disorder is caused by heterozygous missense variants proposed to act by gain-of-function or dominant-negative mechanisms rather than haploinsufficiency; the knockout therefore tests loss of function rather than the human disease allele mechanism.
Readouts
Ventral pharyngeal arch size
Direction: DECREASED
Interpretation: Structural correlate of disrupted craniofacial morphogenesis in the model.
Show evidence (1 reference)
PMID:34934055 SUPPORT Model Organism
"The size of the ventral pharyngeal arches was reduced and the mineralization of teeth was impaired in the trrap mutants."
Reports the reduced pharyngeal arch size and impaired tooth mineralization measured in the mutants.
Show evidence (1 reference)
PMID:34934055 SUPPORT Model Organism
"The trrap zebrafish mutants exhibited smaller eyes and heads than the wild-type zebrafish."
The knockout reproduces reduced head and eye size, a craniofacial/growth correlate of the human phenotype.
Show evidence (1 reference)
PMID:34934055 SUPPORT Model Organism
"To investigate the physiological functions of Trrap, we established trrap gene-knockout zebrafish and examined loss-of-function phenotypes in the mutants."
Establishes the trrap-knockout zebrafish as the model system.
{ }

Source YAML

click to show 
name: developmental delay with or without dysmorphic facies and autism
creation_date: "2026-10-12T13:10:00Z"
description: >-
  Developmental delay with or without dysmorphic facies and autism (DEDDFA) is a
  rare autosomal dominant, de novo neurodevelopmental disorder caused by
  heterozygous missense variants in TRRAP, the scaffolding subunit that recruits
  histone acetyltransferase (HAT) complexes to chromatin. Core features are
  global developmental delay and a wide range of intellectual functioning,
  frequently reaching intellectual disability. The published cohort resolves into
  two genotype-correlated clinical spectra: a complex multisystem malformation
  syndrome (brain, heart, kidney and genitourinary anomalies) associated with
  missense variants clustering around p.Ala1043Thr, and a spectrum manifesting
  with autism spectrum disorder and/or intellectual disability with epilepsy.
  Facial dysmorphism is seen across both spectra.
category: Mendelian
parents:
- Mendelian neurodevelopmental disorder
- hereditary disease
synonyms:
- DEDDFA
- TRRAP-related neurodevelopmental disorder
disease_term:
  preferred_term: developmental delay with or without dysmorphic facies and autism
  term:
    id: MONDO:0032760
    label: developmental delay with or without dysmorphic facies and autism
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    The disorder is caused by heterozygous TRRAP variants that are de novo or
    apparently de novo in affected individuals; low-level maternal mosaicism was
    documented in the mother of two affected sisters, a recurrence-risk
    consideration.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through an international collaboration, 17 distinct de novo or apparently de
      novo variants were identified in TRRAP in 24 individuals.
    explanation: >-
      De novo heterozygous variants in affected individuals establish an
      autosomal dominant mode of inheritance arising mainly from new mutation.
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two sisters who had inherited a variant from a mother with low-level
      mosaicism
    explanation: >-
      Documents low-level maternal mosaicism as a recurrence-risk consideration
      for an otherwise de novo disorder.
genetic:
- name: TRRAP
  association: >-
    Causative heterozygous de novo or apparently de novo TRRAP missense variants;
    variants of the first clinical spectrum cluster around c.3127G>A p.(Ala1043Thr).
  gene_term:
    preferred_term: TRRAP
    term:
      id: hgnc:12347
      label: TRRAP
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    All reported pathogenic variants are missense; no loss-of-function variants
    were reported in the defining cohort, and the authors argue haploinsufficiency
    is unlikely for the clustered variants. They propose gain-of-function or
    dominant-negative effects, but a definite functional-impact category is not
    established, so none is bound here.
    ClinGen's Intellectual Disability and Autism Gene Curation Expert Panel rates
    the TRRAP gene-disease relationship Definitive (autosomal dominant), but
    records that assertion against the ClinGen disease-entity term
    MONDO:0100465 (complex neurodevelopmental disorder with or without congenital
    anomalies) rather than against this entry's OMIM-derived term MONDO:0032760.
    Because the ClinGen MONDO term is neither this entry's disease_term, a
    has_subtypes term, nor an exactMatch mapping, the validity assertion is not
    copied into gene_disease_validity.
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with this phenotype had missense variants clustering around the
      c.3127G>A p.(Ala1043Thr) variant identified in five individuals.
    explanation: >-
      Identifies the recurrent clustered missense variant defining the first
      clinical spectrum.
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      TRRAP is evolutionarily conserved and is among the top five genes intolerant
      to missense variation.
    explanation: >-
      Extreme missense constraint supports the pathogenicity of recurrent missense
      variants in this gene.
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      suggesting a model in which specific domains are affected and
      haploinsufficiency is unlikely, at least for clustering variants.
    explanation: >-
      Supports a dominant mechanism in which clustered domain-affecting missense
      variants act other than by haploinsufficiency.
pathophysiology:
- name: TRRAP missense variant disrupting HAT-complex scaffold function
  description: >-
    A heterozygous de novo missense variant alters TRRAP, the scaffolding subunit
    that recruits histone acetyltransferase (HAT) complexes to chromatin,
    perturbing its role in regulating HAT activity.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TRRAP
    term:
      id: hgnc:12347
      label: TRRAP
  genetic_context:
    variant_origin: DE_NOVO
  molecular_functions:
  - preferred_term: histone acetyltransferase regulator activity
    modifier: ABNORMAL
    term:
      id: GO:0035034
      label: histone acetyltransferase regulator activity
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      This process is controlled by histone acetyltransferases (HATs/KATs) found
      in multiprotein complexes that are recruited to chromatin by the scaffolding
      subunit transformation/transcription domain-associated protein (TRRAP).
    explanation: >-
      Establishes TRRAP as the scaffolding subunit that recruits HAT complexes to
      chromatin, the activity disrupted by the variant.
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through an international collaboration, 17 distinct de novo or apparently de
      novo variants were identified in TRRAP in 24 individuals.
    explanation: >-
      Identifies the recurrent TRRAP missense variants as the initiating lesion in
      affected individuals.
  downstream:
  - target: Dysregulated histone acetylation and transcription
    description: >-
      Altered TRRAP perturbs HAT-complex-mediated histone acetylation and
      downstream transcriptional regulation.
- name: Dysregulated histone acetylation and transcription
  description: >-
    Perturbed TRRAP-dependent recruitment of HAT complexes alters histone lysine
    acetylation and RNA polymerase II-dependent transcription, the chromatin-level
    consequence of the variant.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: internal peptidyl-lysine (histone) acetylation
    modifier: ABNORMAL
    term:
      id: GO:0018393
      label: internal peptidyl-lysine acetylation
  - preferred_term: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      Acetylation of the lysine residues in histones and other DNA-binding
      proteins plays a major role in regulation of eukaryotic gene expression.
    explanation: >-
      Supports histone lysine acetylation as a key regulator of gene expression,
      the process disrupted downstream of altered TRRAP.
  downstream:
  - target: Altered neurodevelopmental gene expression
    description: >-
      Dysregulated chromatin acetylation changes the expression of genes governing
      neuronal function.
  - target: Disrupted embryonic organ and craniofacial morphogenesis
    description: >-
      Altered chromatin regulation during development disrupts morphogenesis of
      multiple organ systems and the face.
- name: Altered neurodevelopmental gene expression
  description: >-
    RNA sequencing of patient-derived skin fibroblasts shows altered expression of
    genes implicated in neuronal function and ion transport, linking the chromatin
    defect to a dysregulated neurodevelopmental gene-expression program. The
    fibroblast finding is a surrogate tissue; the inference to neural cells is not
    directly demonstrated.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: regulation of gene expression
    modifier: ABNORMAL
    term:
      id: GO:0010468
      label: regulation of gene expression
  - preferred_term: nervous system development
    modifier: ABNORMAL
    term:
      id: GO:0007399
      label: nervous system development
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RNA sequencing analysis of skin fibroblasts derived from affected
      individuals skin fibroblasts showed significant changes in the expression of
      several genes implicated in neuronal function and ion transport.
    explanation: >-
      Direct patient-cell transcriptomic evidence of dysregulated expression of
      neuronal-function and ion-transport genes.
  downstream:
  - target: Global developmental delay
    description: Disrupted neurodevelopmental gene expression impairs developmental progress.
  - target: Intellectual disability
    description: Impaired neurodevelopment contributes to the range of intellectual functioning, often reaching intellectual disability.
  - target: Autistic behavior
    description: Altered neuronal gene expression contributes to autism spectrum disorder in the second clinical spectrum.
  - target: Seizure
    description: Dysregulated neuronal and ion-transport gene expression contributes to epilepsy in the second clinical spectrum.
  - target: Microcephaly
    description: Impaired neurodevelopment contributes to reduced head size reported in affected individuals.
  - target: Hypotonia
    description: Neurodevelopmental disruption contributes to hypotonia on neurological examination.
- name: Disrupted embryonic organ and craniofacial morphogenesis
  description: >-
    Altered TRRAP-dependent chromatin regulation during embryogenesis disrupts
    morphogenesis of the brain, heart, kidney and genitourinary system and of
    craniofacial structures, producing the multisystem malformations and facial
    dysmorphism of the first clinical spectrum.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: embryonic morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0048598
      label: embryonic morphogenesis
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first is a complex, multi-systemic syndrome associated with various
      malformations of the brain, heart, kidneys, and genitourinary system and
      characterized by a wide range of intellectual functioning; a number of
      affected individuals have intellectual disability (ID) and markedly impaired
      basic life functions.
    explanation: >-
      Supports multisystem malformations of brain, heart, kidney and
      genitourinary system as a core consequence.
  downstream:
  - target: Abnormal brain morphology
    description: Malformations of the brain in the multisystem spectrum.
  - target: Cerebellar vermis hypoplasia
    description: The most common structural brain anomaly in the multisystem spectrum.
  - target: Abnormal heart morphology
    description: Cardiac malformations in the multisystem spectrum.
  - target: Abnormal renal morphology
    description: Renal malformations in the multisystem spectrum.
  - target: Abnormal genital morphology
    description: External and internal genital anomalies in the multisystem spectrum.
  - target: Abnormal facial shape
    description: Craniofacial dysmorphogenesis producing facial dysmorphism across both spectra.
  - target: Cleft upper lip
    description: Orofacial clefting in the multisystem spectrum.
  - target: Cleft palate
    description: Orofacial clefting in the multisystem spectrum.
  - target: Upslanted palpebral fissure
    description: Component of the facial dysmorphism.
  - target: Epicanthus
    description: Component of the facial dysmorphism.
  - target: Telecanthus
    description: Component of the facial dysmorphism.
  - target: Wide nasal bridge
    description: Component of the facial dysmorphism.
  - target: Smooth philtrum
    description: Component of the facial dysmorphism.
  - target: Thin upper lip vermilion
    description: Component of the facial dysmorphism.
phenotypes:
- name: Global developmental delay
  category: Neurodevelopmental
  diagnostic: true
  description: Global developmental delay is a core feature reported in affected individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      13 individuals with variants in the codon 1031-1159 region had global
      developmental delay and apparent ID
    explanation: >-
      Directly reports global developmental delay in the multisystem-spectrum
      cohort.
- name: Intellectual disability
  category: Neurodevelopmental
  diagnostic: true
  description: >-
    Affected individuals show a wide range of intellectual functioning, with many
    reaching intellectual disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first is a complex, multi-systemic syndrome associated with various
      malformations of the brain, heart, kidneys, and genitourinary system and
      characterized by a wide range of intellectual functioning; a number of
      affected individuals have intellectual disability (ID) and markedly impaired
      basic life functions.
    explanation: >-
      Reports intellectual disability and a wide range of intellectual functioning
      in affected individuals.
- name: Autistic behavior
  category: Neurodevelopmental
  description: >-
    Autism spectrum disorder characterizes the second clinical spectrum and is
    part of the disorder's defining name.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy.
    explanation: Reports autism spectrum disorder as a feature of the second clinical spectrum.
- name: Seizure
  category: Neurologic
  description: Epilepsy is reported in the second clinical spectrum.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy.
    explanation: Reports epilepsy as a feature of the second clinical spectrum.
- name: Microcephaly
  category: Growth
  frequency: FREQUENT
  description: >-
    Microcephaly was reported in 46% (6/13) of individuals in the
    multisystem-spectrum cohort.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The last available occipitofrontal-circumference measurements revealed
      microcephaly (ranging from -2.8 to -5 standard deviations
    explanation: >-
      Directly reports microcephaly (-2.8 to -5 SD) in the multisystem-spectrum
      cohort; the full text gives a frequency of 46% (6/13).
- name: Abnormal facial shape
  category: Craniofacial
  description: Facial dysmorphism is seen across both clinical spectra.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial dysmorphism was seen in both groups and included upslanted palpebral
      fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and
      smooth philtrum, and a thin upper lip.
    explanation: Reports facial dysmorphism across both clinical groups.
- name: Upslanted palpebral fissure
  category: Craniofacial
  description: Part of the characteristic facial dysmorphism.
  phenotype_term:
    preferred_term: Upslanted palpebral fissures
    term:
      id: HP:0000582
      label: Upslanted palpebral fissure
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial dysmorphism was seen in both groups and included upslanted palpebral
      fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and
      smooth philtrum, and a thin upper lip.
    explanation: Lists upslanted palpebral fissures among the facial features.
- name: Epicanthus
  category: Craniofacial
  description: Part of the characteristic facial dysmorphism.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial dysmorphism was seen in both groups and included upslanted palpebral
      fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and
      smooth philtrum, and a thin upper lip.
    explanation: Lists epicanthus among the facial features.
- name: Telecanthus
  category: Craniofacial
  description: Part of the characteristic facial dysmorphism.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial dysmorphism was seen in both groups and included upslanted palpebral
      fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and
      smooth philtrum, and a thin upper lip.
    explanation: Lists telecanthus among the facial features.
- name: Wide nasal bridge
  category: Craniofacial
  description: Part of the characteristic facial dysmorphism.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial dysmorphism was seen in both groups and included upslanted palpebral
      fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and
      smooth philtrum, and a thin upper lip.
    explanation: Lists a wide nasal bridge among the facial features.
- name: Smooth philtrum
  category: Craniofacial
  description: Part of the characteristic facial dysmorphism.
  phenotype_term:
    preferred_term: Broad and smooth philtrum
    term:
      id: HP:0000319
      label: Smooth philtrum
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial dysmorphism was seen in both groups and included upslanted palpebral
      fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and
      smooth philtrum, and a thin upper lip.
    explanation: Lists a broad and smooth philtrum among the facial features.
- name: Thin upper lip vermilion
  category: Craniofacial
  description: Part of the characteristic facial dysmorphism.
  phenotype_term:
    preferred_term: Thin upper lip
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial dysmorphism was seen in both groups and included upslanted palpebral
      fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and
      smooth philtrum, and a thin upper lip.
    explanation: Lists a thin upper lip among the facial features.
- name: Abnormal brain morphology
  category: Nervous system
  description: Malformations of the brain occur in the multisystem spectrum.
  phenotype_term:
    preferred_term: Brain malformation
    term:
      id: HP:0012443
      label: Abnormal brain morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first is a complex, multi-systemic syndrome associated with various
      malformations of the brain, heart, kidneys, and genitourinary system and
      characterized by a wide range of intellectual functioning; a number of
      affected individuals have intellectual disability (ID) and markedly impaired
      basic life functions.
    explanation: >-
      Reports malformations of the brain; the abstract names the organ system but
      not the specific malformation.
- name: Abnormal heart morphology
  category: Cardiovascular
  description: Cardiac malformations occur in the multisystem spectrum.
  phenotype_term:
    preferred_term: Cardiac malformation
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first is a complex, multi-systemic syndrome associated with various
      malformations of the brain, heart, kidneys, and genitourinary system and
      characterized by a wide range of intellectual functioning; a number of
      affected individuals have intellectual disability (ID) and markedly impaired
      basic life functions.
    explanation: >-
      Reports malformations of the heart; the abstract names the organ system but
      not the specific malformation.
- name: Abnormal renal morphology
  category: Renal
  frequency: FREQUENT
  description: >-
    A spectrum of renal malformations (multicystic dysplastic kidney,
    hydronephrosis, duplicate kidney, small kidney) occurs in the multisystem
    spectrum.
  phenotype_term:
    preferred_term: Abnormal renal morphology
    term:
      id: HP:0012210
      label: Abnormal renal morphology
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Abnormal renal morphology, namely multicystic dysplastic kidney,
      hydronephrosis, a duplicate kidney, and/or a small kidney, was described in
      60% (6/10) of individuals
    explanation: >-
      Reports a variable spectrum of renal malformations in 60% of imaged
      multisystem-spectrum individuals.
- name: Abnormal genital morphology
  category: Genitourinary
  description: >-
    External- and internal-genital anomalies occur in the multisystem spectrum,
    including microphallus, hypoplastic scrotum, cryptorchidism, and duplicated
    vagina and/or uterus.
  phenotype_term:
    preferred_term: Genital anomaly
    term:
      id: HP:0000078
      label: Abnormality of the genital system
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three males (3/6; 50%) had external-genitalia anomalies, including
      microphallus, hypoplastic scrotum, and cryptorchidism, and two females (2/7;
      29%) had a duplicated vagina and/or uterus.
    explanation: >-
      Reports a variable spectrum of external and internal genital anomalies in
      the multisystem spectrum.
- name: Cerebellar vermis hypoplasia
  category: Nervous system
  frequency: FREQUENT
  description: >-
    Cerebellar vermis hypoplasia was the most common structural brain anomaly on
    MRI in the multisystem spectrum.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      seven of those 10 (70%) showed structural brain anomalies, including
      cerebellar vermis hypoplasia (6/10)
    explanation: >-
      Reports cerebellar vermis hypoplasia as the most frequent structural brain
      anomaly in imaged individuals.
- name: Cleft upper lip
  category: Craniofacial
  frequency: FREQUENT
  description: Cleft lip (with palate) occurs in the multisystem spectrum.
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0000204
      label: Cleft upper lip
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cleft lip and palate (5/13; 38%)"
    explanation: Reports cleft lip and palate in 38% of the multisystem-spectrum cohort.
- name: Cleft palate
  category: Craniofacial
  frequency: FREQUENT
  description: Cleft palate (with lip) occurs in the multisystem spectrum.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cleft lip and palate (5/13; 38%)"
    explanation: Reports cleft lip and palate in 38% of the multisystem-spectrum cohort.
- name: Hypotonia
  category: Neurologic
  frequency: FREQUENT
  description: Hypotonia was found on neurological examination in the multisystem spectrum.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological examination revealed hypotonia in 31% (4/13) of individuals."
    explanation: Reports hypotonia in 31% of the multisystem-spectrum cohort.
animal_models:
- name: trrap-knockout zebrafish
  species: Zebrafish
  genotype: trrap gene-knockout (loss-of-function)
  category: knockout
  description: >-
    A trrap gene-knockout zebrafish line recapitulates craniofacial and head/eye
    size reductions, providing a loss-of-function model of a TRRAP-associated human
    disorder.
  genes:
  - preferred_term: trrap
    term:
      id: hgnc:12347
      label: TRRAP
  publication: PMID:34934055
  modeled_mechanisms:
  - target: Disrupted embryonic organ and craniofacial morphogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The knockout reproduces reduced head/eye size and ventral pharyngeal arch
      and tooth-mineralization defects, modeling disrupted craniofacial
      morphogenesis.
    limitations: >-
      The model is a complete loss-of-function knockout, whereas the human disorder
      is caused by heterozygous missense variants proposed to act by
      gain-of-function or dominant-negative mechanisms rather than haploinsufficiency;
      the knockout therefore tests loss of function rather than the human disease
      allele mechanism.
    readouts:
    - name: Ventral pharyngeal arch size
      target: Disrupted embryonic organ and craniofacial morphogenesis
      direction: DECREASED
      interpretation: Structural correlate of disrupted craniofacial morphogenesis in the model.
      evidence:
      - reference: PMID:34934055
        reference_title: Involvement of the zebrafish trrap gene in craniofacial development.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The size of the ventral pharyngeal arches was reduced and the
          mineralization of teeth was impaired in the trrap mutants.
        explanation: Reports the reduced pharyngeal arch size and impaired tooth mineralization measured in the mutants.
    evidence:
    - reference: PMID:34934055
      reference_title: Involvement of the zebrafish trrap gene in craniofacial development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The trrap zebrafish mutants exhibited smaller eyes and heads than the wild-type zebrafish.
      explanation: The knockout reproduces reduced head and eye size, a craniofacial/growth correlate of the human phenotype.
  evidence:
  - reference: PMID:34934055
    reference_title: Involvement of the zebrafish trrap gene in craniofacial development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To investigate the physiological functions of Trrap, we established trrap
      gene-knockout zebrafish and examined loss-of-function phenotypes in the
      mutants.
    explanation: Establishes the trrap-knockout zebrafish as the model system.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    The defining report described 24 individuals with TRRAP variants; no
    prevalence or incidence estimate is available.
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through an international collaboration, 17 distinct de novo or apparently de
      novo variants were identified in TRRAP in 24 individuals.
    explanation: Establishes the small number of individuals reported in the literature.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    Molecular diagnosis rests on identifying a heterozygous pathogenic TRRAP
    missense variant, typically by trio exome or genome sequencing or a
    neurodevelopmental gene panel including TRRAP.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: >-
    A heterozygous (de novo) TRRAP missense variant establishes the molecular
    diagnosis.
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These variants were identified either by trio or solo exome sequencing (ES)
      from research and clinical cohorts.
    explanation: >-
      The defining cohort's TRRAP variants were identified by trio or solo exome
      sequencing, supporting exome sequencing as the diagnostic approach.
treatments:
- name: Supportive and developmental care
  description: >-
    No disease-specific therapy exists; management is supportive and directed at
    developmental delay and intellectual disability, with early intervention and
    multidisciplinary developmental support.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first is a complex, multi-systemic syndrome associated with various
      malformations of the brain, heart, kidneys, and genitourinary system and
      characterized by a wide range of intellectual functioning; a number of
      affected individuals have intellectual disability (ID) and markedly impaired
      basic life functions.
    explanation: >-
      Developmental delay and intellectual disability with markedly impaired basic
      life functions support supportive developmental care as the management target.
- name: Physical and occupational therapy
  description: >-
    Physical and occupational therapy support motor and adaptive-function needs in
    affected children with global developmental delay.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      13 individuals with variants in the codon 1031-1159 region had global
      developmental delay and apparent ID
    explanation: >-
      Global developmental delay in affected individuals supports developmental
      therapies as phenotype-directed supportive care.
- name: Speech and language therapy
  description: >-
    Speech-language therapy supports communication needs associated with global
    developmental delay and intellectual disability.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      13 individuals with variants in the codon 1031-1159 region had global
      developmental delay and apparent ID
    explanation: >-
      Global developmental delay supports speech-language therapy as
      phenotype-directed supportive care.
- name: Anti-seizure pharmacotherapy
  description: >-
    Anti-seizure medication is indicated for individuals in the second clinical
    spectrum who develop epilepsy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy.
    explanation: Epilepsy in the second clinical spectrum is the target of anti-seizure pharmacotherapy.
- name: Genetic counseling
  description: >-
    Genetic counseling addresses the de novo, autosomal dominant inheritance and
    the residual recurrence risk from documented low-level maternal mosaicism.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30827496
    reference_title: >-
      Missense Variants in the Histone Acetyltransferase Complex Component Gene
      TRRAP Cause Autism and Syndromic Intellectual Disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through an international collaboration, 17 distinct de novo or apparently de
      novo variants were identified in TRRAP in 24 individuals.
    explanation: >-
      The de novo origin of variants supports genetic counseling on recurrence
      risk.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100465
      label: complex neurodevelopmental disorder with or without congenital anomalies
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0100465 is the broad ClinGen disease-entity term under which the
      TRRAP gene-disease validity assertion is curated. It denotes the same
      TRRAP-related phenotype at a broader, clinically defined level than this
      OMIM-anchored term (MONDO:0032760, OMIM:618454), so the relation is
      broadMatch rather than exactMatch. broadMatch does not retire the mapped
      concept from the curation queue and does not license copying the ClinGen
      validity tier onto this entry; see genetic.notes.
discussions:
- discussion_id: gap_trrap_functional_impact
  prompt: >-
    Do the clustered TRRAP missense variants act by gain-of-function or
    dominant-negative mechanisms, and what accounts for the genotype-phenotype
    branch between the multisystem malformation spectrum and the ASD/epilepsy
    spectrum?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#TRRAP missense variant disrupting HAT-complex scaffold function
  - pathophysiology#Altered neurodevelopmental gene expression
  - pathophysiology#Disrupted embryonic organ and craniofacial morphogenesis
  rationale: >-
    The defining report proposes gain-of-function or dominant-negative effects for
    the clustered variants and notes the absence of loss-of-function variants, but
    the functional consequence is not demonstrated, and the only direct molecular
    data are patient-fibroblast RNA-seq changes. The mechanistic basis for the
    genotype-correlated split into two clinical spectra is unexplained.
references:
- reference: PMID:30827496
  title: >-
    Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP
    Cause Autism and Syndromic Intellectual Disability.
  findings: []
- reference: PMID:34934055
  title: Involvement of the zebrafish trrap gene in craniofacial development.
  findings: []
notes: >-
  Curated from the defining TRRAP cohort (Cogne et al., Am J Hum Genet 2019,
  PMID:30827496, full text) and a zebrafish trrap-knockout study (PMID:34934055).
  Per-phenotype frequencies and the specific malformations (cleft lip and palate,
  cerebellar vermis hypoplasia, renal and genital anomalies, hypotonia,
  microcephaly) are taken from the full-text results and Table 2. The two
  genotype-correlated clinical spectra (multisystem malformations clustering
  around p.Ala1043Thr vs ASD/ID with epilepsy) are represented as branches of one
  pathograph rather than as separate has_subtypes; the entry is a single
  gene-defined leaf disorder. MONDO models the ClinGen curation entity
  (MONDO:0100465) and this OMIM-derived term (MONDO:0032760, OMIM:618454) as
  separate concepts for the same TRRAP disorder; MONDO:0100465 is recorded under
  mappings.mondo_mappings as a broadMatch, and genetic.notes records why the
  ClinGen validity tier is not copied here.
📚

References & Deep Research

References

2
PMID:30827496
Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.
No top-level findings curated for this source.
PMID:34934055
Involvement of the zebrafish trrap gene in craniofacial development.
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 (1)

Create: Developmental_Delay_With_Or_Without_Dysmorphic_Facies_And_Autism · 2026-10-12T14:35:47Z · View source

De novo curation of the TRRAP-related neurodevelopmental disorder (MONDO:0032760, OMIM:618454, DEDDFA) from the defining Cogne et al. 2019 AJHG cohort (PMID:30827496, abstract-only cache) and a zebrafish trrap-knockout model (PMID:34934055). Gene binding hgnc:12347 TRRAP verified by lookup. Pathograph: 4-node chain from the HAT-complex scaffold lesion (GO:0035034) through dysregulated histone acetylation/transcription to a neurodevelopmental branch and an embryonic/craniofacial morphogenesis branch; all 16 phenotypes causally connected. Two genotype-correlated clinical spectra modeled as pathograph branches, not has_subtypes. gene_disease_validity omitted because ClinGen's Definitive TRRAP assertion is recorded against the ClinGen entity MONDO:0100465, not this OMIM-derived term. All validation gates clean: validate-disorders 34/34 snippets and 36 titles, validate-terms, gene-activity-grounding (ref origin/main), entity-refs, causal-targets, coarse-phenotypes, enum/duplicate keys. DR report used as leads only.

Claude Code ▸
Research report: developmental delay with or without dysmorphic facies and autism (TRRAP-related; MONDO:0032760)
claude-haiku-5-5, claude-sonnet-5-5 6 citations 2026-10-12T14:11:43.133393

Research report: developmental delay with or without dysmorphic facies and autism (TRRAP-related; MONDO:0032760)

Verification status. I checked the following in this session: the Cogné 2019 cohort data (via PMC6407527), the ClinGen gene-validity row already in the repo, the repo stub, the PanelApp listing, and the Trrap mouse-knockout lethality (via search snippets). The MIM number #618454 comes from a conference poster and one search snippet, so confirm it in OMIM before binding. Everything else is marked "not verified" or "from memory". No curation entry exists yet. The stub stubs/Developmental_Delay_With_Or_Without_Dysmorphic_Facies_And_Autism.yaml is UNDECIDED and lists one causal gene, hgnc:12347 (TRRAP). I have not edited the repo.

1. Disease information

  • Overview. This is an autosomal dominant neurodevelopmental disorder caused by heterozygous, mostly de novo, missense variants in TRRAP. Core features are global developmental delay and intellectual disability. Variable features include autism, seizures, facial dysmorphism, and malformations of the brain, heart, kidney, genitalia and palate.
  • Identifiers.
  • MONDO:0032760.
  • OMIM phenotype #618454. This is secondary-source only, from the LSU Health case-report poster, and is unconfirmed.
  • The TRRAP gene MIM is 603015, as listed on PanelApp.
  • HGNC: hgnc:12347.
  • Orphanet, ICD-10 and MeSH: not checked.
  • Synonyms. DEDDFA (abbreviation not verified). Also described as "TRRAP-related neurodevelopmental disorder".
  • Overlap with ClinGen's broader term. ClinGen curates TRRAP against a different, broader MONDO term, "complex neurodevelopmental disorder with or without congenital anomalies" (MONDO:0100465). The rating is Definitive, autosomal dominant, from the Intellectual Disability and Autism GCEP, dated 2022-07-19: CGGV:assertion_03424cde-a847-4bd0-91eb-9707a7e51fa2-2022-07-19T100000.000Z. This row is in kb/genes/ingest/clingen_gene_validity.tsv. The assertion belongs to MONDO:0100465, not to this entry's term. Under the repo's "assertion must be for this entry's disease" rule, record it only if you decide the two terms are the same entity, or map with an exactMatch.
  • Source level. Findings come from individual patients in sequencing cohorts, aggregated by the papers cited below. This is not an EHR-derived resource.
  • Lump/split note. Cogné et al. describe two genotype-defined phenotypic clusters (see section 3). They are not separate named diseases, so the default is one entry with has_subtypes or per-phenotype notes, not two entries.

2. Etiology

  • Cause. Heterozygous missense variants in TRRAP. In the primary cohort, 17 distinct variants occurred in 24 individuals, mostly de novo or "apparently de novo" (parentage not confirmed). Source: Cogné et al., Am J Hum Genet 2019, PMID:30827496.
  • Genetic risk and modifiers. No modifier genes are known (not found).
  • Environmental risk, protective factors and gene–environment interactions. None identified.

3. Phenotypes (Cogné 2019, Table 2)

The paper compares individuals with variants in the codon 1031–1159 cluster to those outside it.

Phenotype In cluster (codons 1031–1159) Outside cluster Suggested HPO
Global developmental delay 13/13 11/11 HP:0001263
Intellectual disability 11/11 6/9 HP:0001249
Autism spectrum disorder 0/13 5/11 HP:0000717
Seizures 1/13 4/11 HP:0001250
Microcephaly 6/13 1/11 HP:0000252
Cardiac malformation 9/12 1/3 HP:0001627
Renal malformation 5/13 0/4 HP:0000077 (coarse; prefer a more specific term)
Genital malformation 5/13 0/11 HP:0000078
Cleft lip/palate 5/13 0/11 HP:0000202 / HP:0000175
  • Facial dysmorphism. It was present in 19/24 (79%). Features were upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge, a broad smooth philtrum and a thin upper lip. Suggested HPO terms: HP:0000582 (upslanted palpebral fissures), HP:0000286 (epicanthus), HP:0000319 (smooth philtrum). I have not looked these up in this session, so check each CURIE and label against the ontology before binding.
  • Brain MRI. 7 of 10 scanned cluster individuals had structural anomalies. The most common was cerebellar vermis hypoplasia, in 6/10.
  • Neurology. Peripheral neuropathy was severe in one individual. Lower-limb hyperreflexia was noted in five others.
  • Two clusters.
  • Cluster 1 (codons 1031–1159, centred on p.Ala1043Thr) is the multisystem malformation syndrome with ID.
  • The outside-cluster group shows ASD and/or ID with epilepsy.
  • Note the naming tension: the cluster-1 variants carry no ASD in this cohort, while the disease name includes "autism". Ascertainment and sample size limit the conclusion.
  • Later case report. The LSU poster reports a 9-year-old with a de novo variant in the 1031–1159 region who fits the OMIM phenotype. It is a single case and a poster, so do not cite it as evidence.
  • Onset, progression and quality of life. Onset is developmental (infancy to childhood). Progression and quality-of-life data were not found.

4. Genetic and molecular information

  • Gene. TRRAP (transformation/transcription domain-associated protein, 3q… locus not verified). It is a large pseudokinase scaffold in the SAGA and TIP60 histone acetyltransferase complexes.
  • Variants.
  • All are missense.
  • Recurrent: p.Ala1043Thr (c.3127G>A) in 5 individuals, and p.Glu1106Lys and p.Gly1883Arg in 2 each.
  • Thirteen individuals carried variants in codons 1031–1159. Clustering was significant (p = 9×10⁻⁸). A second, smaller aggregate sits at codons 1859–1932.
  • No loss-of-function variants and no intragenic deletions (DECIPHER) were reported.
  • Constraint. Missense z = 10.1 (ExAC), among the top five genes by missense intolerance. pLI = 1.00.
  • Functional consequence. The authors propose gain-of-function or dominant-negative effects for the clustered variants. They consider haploinsufficiency likely lethal prenatally, since no LoF variants were seen. This is inferred, not demonstrated.
  • Origin. De novo germline. Two sisters inherited a variant from a mother with low-level mosaicism, and p.Pro1932Leu is listed as germline mosaicism.
  • Epigenetic and chromosomal. Not applicable. No specific methylation signature has been reported (not found).

5. Environmental information

None is established. There are no known infectious or toxic triggers.

6. Mechanism and pathophysiology

Causal chain. 1. A de novo heterozygous missense variant changes TRRAP. Clustered variants fall near codons 1031–1159 (inferred to be a hotspot domain; the specific domain was not confirmed). 2. The altered protein is thought to act as gain-of-function or dominant-negative in SAGA/TIP60 histone acetyltransferase complexes (inferred, not demonstrated here). 3. Dysregulated chromatin acetylation and transcription follows. This step is also inferred. The only direct data are the fibroblast RNA-seq findings below. 4. Disrupted neurodevelopment results, giving global developmental delay and intellectual disability. 5. The mechanism branches. Variants in the cluster are linked to multisystem malformations (heart, kidney, genitalia, palate, cerebellar vermis). Variants outside it are linked to ASD and seizures. The cause of the branching is unexplained.

Direct supporting data. - Fibroblast RNA-seq from two individuals (p.Leu805Phe and p.Trp1866Cys; both outside the cluster) versus two controls showed mostly upregulated genes. GO enrichment pointed to adrenergic receptor signalling, neuronal function and potassium/ATP-sensitive ion transport. Cogné et al. did not report HAT-activity or p53 assays. They acknowledge that non-HAT TRRAP interactions could account for the signature. - Suggested ontology terms: GO:0016573 (histone acetylation), GO:0006357 (regulation of transcription by RNA polymerase II), and the SAGA and NuA4 complexes in the GO cellular-component branch. Look all of these up before binding. Candidate Cell Ontology terms are neural progenitor cell or neuron.

Cell and tissue context. Neural progenitors are implicated by animal data. A search snippet of a 2021 zebrafish paper says Nestin-Cre conditional deletion of Trrap in mice causes premature differentiation of neural progenitors. I did not retrieve the original mouse paper.

7. Anatomical structures affected

Brain (cerebellar vermis), heart, kidney, genitalia, palate and face; occasionally peripheral nerves. Suggested UBERON terms (to be looked up): cerebellar vermis, heart, kidney. Subcellular: nucleus and chromatin, in the SAGA/TIP60 complexes.

8. Temporal development

Onset is congenital to infantile. The course appears stable. I found no natural-history, remission or critical-period data.

9. Inheritance and population

  • Inheritance. Autosomal dominant, with de novo variants predominating. HP:0000006 is the mode-of-inheritance term. Mosaic parental transmission is documented (see section 4).
  • Epidemiology. No prevalence or incidence data found. Penetrance, expressivity, sex ratio and founder effects: not reported.

10. Diagnostics

  • Genetic testing. Exome sequencing, trio where possible, or a gene panel including TRRAP. TRRAP is Green on the PanelApp intellectual disability panel. Cogné et al. found variants mainly by exome sequencing and through GeneMatcher.
  • Imaging. Brain MRI for cerebellar vermis hypoplasia.
  • Differential diagnosis, screening and criteria. Not researched. There are no formal criteria.

11. Outcome and prognosis

No survival, mortality or quality-of-life data found. Lifelong intellectual disability is expected, based on 100% GDD in the cohort.

12. Treatment

No disease-specific therapy. Management is supportive: early intervention, speech, physical and occupational therapy, and seizure treatment where present. Suggested NCIT terms: NCIT:C15747 (Supportive Care), NCIT:C15302 (Physical Therapy), NCIT:C15315 (Rehabilitation). Both are in this repo's list of common NCIT terms. No clinical trials, pharmacogenomics or gene therapy were found.

13. Prevention

Genetic counselling is warranted. Recurrence risk is low for de novo cases but not zero, given documented parental mosaicism and germline mosaicism in this cohort.

14–15. Other species and model organisms

  • Mouse. Complete Trrap loss is embryonic lethal. A 2001 study (Herceg et al., Nat Genet; I did not retrieve the PMID, so verify before citing) found that null mutation of Trrap causes peri-implantation lethality from blocked blastocyst proliferation. A figshare record carries a related title.
  • Neural-specific deletion. Nestin-Cre conditional deletion causes premature differentiation of neural progenitors (second-hand, see section 6).
  • Zebrafish. A trrap knockout shows craniofacial phenotypes (PMC8692476, Sci Rep 2021; I did not read it directly).
  • Fidelity. Null models test haploinsufficiency, which the human genetics argue is not the disease mechanism. Missense knock-in models of the clustered variants were not found.
  • Yeast. Tra1 deletion data are cited by Cogné et al. from prior literature.
  • Natural disease in other species (OMIA). Not checked.

Curation notes for the entry

  1. Evidence snippets must be exact substrings. Run just fetch-reference PMID:30827496, then quote from the cached abstract or full text. I did not quote the paper verbatim here, because the fetch tool would not return long verbatim text.
  2. Decide how to relate this entry to MONDO:0100465 and the ClinGen assertion (see section 1).
  3. Look up every CURIE listed above before writing it into YAML.
  4. The gene-disease validity row cannot go on this entry unless the two terms are judged the same.
  5. Create a claim issue first: Curate developmental delay with or without dysmorphic facies and autism (MONDO:0032760).
  6. Delete the stub and add a history record in the curation PR.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 3
Resolved 3
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 3
On topic 2
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 21
Resolved 20
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 0
Terms whose name was checked 10
Terms named correctly 8
Terms named as a different term 1
Terms whose name is worth a second look 1

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:

  • HP:0000077 (1 mention) - the report calls it "coarse; prefer a more specific term"; HP calls it Abnormality of the kidney

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0016573 (obsolete histone acetylation) (1 mention)

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:0016573 (1 mention) - the report calls it "histone acetylation"; GO calls it obsolete histone acetylation