Intellectual disability, autosomal dominant 48 (MRD48) is a syndromic neurodevelopmental disorder caused by heterozygous, de novo missense variants in RAC1, a Rho-family GTPase that cycles between GDP- and GTP-bound states and, when active, drives actin cytoskeleton remodelling through effectors such as PAK1 and the WAVE regulatory complex. All reported individuals have developmental delay and intellectual disability, usually with speech delay and brain malformations (corpus callosum and cerebellar vermis hypoplasia, polymicrogyria, white matter changes); hypotonia, feeding difficulties, behavioural problems, congenital heart defects, epilepsy, eczematous or ichthyosiform skin changes and a recognisable but evolving facial gestalt are common. The disorder splits by variant mechanism. Dominant-negative or presumed dominant-negative variants (for example p.Cys18Tyr, p.Asn39Ser and variants in the C-terminal part of switch II, P69-Q74) reduce RAC1 signalling and cause microcephaly; activating variants, mostly in the N-terminal part of switch II (Q61-R68) but also p.Ala159Thr in the G5 box, over-activate PAK and the WAVE regulatory complex and cause normocephaly or milder head-size changes; and two variants at Val51 cause macrocephaly by an unresolved mechanism. Head circumference across the reported variants spans about 10 standard deviations.
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Conditions with similar clinical presentations that must be differentiated from Intellectual Disability, Autosomal Dominant 48:
name: Intellectual Disability, Autosomal Dominant 48
creation_date: "2026-10-01T14:00:00Z"
category: Mendelian
synonyms:
- MRD48
- RAC1-related intellectual developmental disorder
- mental retardation, autosomal dominant 48
- autosomal dominant intellectual disability 48
- autosomal dominant mental retardation 48
description: >-
Intellectual disability, autosomal dominant 48 (MRD48) is a syndromic
neurodevelopmental disorder caused by heterozygous, de novo missense variants
in RAC1, a Rho-family GTPase that cycles between GDP- and GTP-bound states
and, when active, drives actin cytoskeleton remodelling through effectors such
as PAK1 and the WAVE regulatory complex. All reported individuals have
developmental delay and intellectual disability, usually with speech delay
and brain malformations (corpus callosum and cerebellar vermis hypoplasia,
polymicrogyria, white matter changes); hypotonia, feeding difficulties,
behavioural problems, congenital heart defects, epilepsy, eczematous or
ichthyosiform skin changes and a recognisable but evolving facial gestalt are
common. The disorder splits by variant mechanism. Dominant-negative or
presumed dominant-negative variants (for example p.Cys18Tyr, p.Asn39Ser and
variants in the C-terminal part of switch II, P69-Q74) reduce RAC1 signalling
and cause microcephaly; activating variants, mostly in the N-terminal part of
switch II (Q61-R68) but also p.Ala159Thr in the G5 box, over-activate PAK and
the WAVE regulatory complex and cause normocephaly or milder head-size
changes; and two variants at Val51 cause macrocephaly by an unresolved
mechanism. Head circumference across the reported variants spans about 10
standard deviations.
parents:
- hereditary disease
- intellectual disability
disease_term:
preferred_term: intellectual disability, autosomal dominant 48
term:
id: MONDO:0030913
label: intellectual disability, autosomal dominant 48
has_subtypes:
- name: Microcephalic
display_name: Microcephalic MRD48 (dominant-negative RAC1 variants)
description: >-
Microcephaly (about -2.5 to -5 SD) with dominant-negative or presumed
dominant-negative variants. p.Cys18Tyr, p.Asn39Ser, p.Glu31Gly and variants
in the C-terminal part of switch II (P69-Q74) are dominant-negative in
functional assays; p.Pro73Leu and p.Cys157Tyr showed at most a modest effect
in fibroblast assays and are grouped here by phenotype.
evidence:
- reference: PMID:42120539
reference_title: "Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "By contrast, individuals with variants in the C-terminal part of switch II exhibited microcephaly."
explanation: >-
Microcephaly in individuals with C-terminal switch II variants.
- name: Normocephalic
display_name: Normocephalic MRD48 (activating RAC1 variants)
description: >-
Normal head size, or milder micro- or macrocephaly, with activating
variants: those in the N-terminal part of switch II (Q61-R68), including
p.Tyr64Asp and p.Glu62Lys, and p.Ala159Thr in the G5 box.
evidence:
- reference: PMID:42120539
reference_title: "Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Consistent with our previous study, individuals with variants in the N-terminal part of switch II were normocephalic."
explanation: >-
Normocephaly in individuals with N-terminal switch II variants.
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we describe two additional individuals with previously unreported de novo missense variants in RAC1 and a NDD characterized by normal OFC, facial dysmorphisms, mild/moderate DD/ID and a variable range of additional signs"
explanation: >-
Normal head size with the activating p.Ala159Thr and p.Glu62Lys variants.
- name: Macrocephalic
display_name: Macrocephalic MRD48 (Val51 variants)
description: >-
Macrocephaly (+4.2 and +4.5 SD) in two individuals with p.Val51Met and
p.Val51Leu; the functional effect of these variants is unresolved.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD."
explanation: >-
Macrocephaly in both individuals with Val51 variants.
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A relatively homogenous presentation in the absence of any obvious genotype-phenotype correlation was apparent, except for macrocrania in two individuals carrying pathogenic variants involving the residue V51."
explanation: >-
Head size at Val51 is the one clear genotype-phenotype correlation in the 2023 review.
inheritance:
- name: Autosomal Dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Heterozygous missense variants, de novo in all reported individuals.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes."
explanation: >-
De novo heterozygous variants in the founding series.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Several dozen individuals have been reported across case series since
2017 (7 in the founding series, 8 with activating switch II variants, 15
further switch II individuals in 2026, and smaller reports); no
population prevalence estimate exists.
evidence:
- reference: PMID:42120539
reference_title: "Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report 15 new individuals with variants in switch II of RAC1."
explanation: >-
The largest single series to date.
pathophysiology:
- name: De Novo RAC1 Missense Variant Altering the GTPase Switch
biological_scale: MOLECULAR
description: >-
Heterozygous de novo missense variants cluster in and around the guanine
nucleotide-binding site and the switch I and switch II regions, which
control GDP/GTP exchange and effector binding. They act either as
dominant-negative alleles or as activating alleles, rather than by
haploinsufficiency; RAC1 is highly constrained against missense variation
and constitutive Rac1 knockout is embryonic lethal in mice.
genetic_context:
gene:
preferred_term: RAC1
term:
id: hgnc:9801
label: RAC1
variant_origin: GERMLINE
molecular_functions:
- preferred_term: RAC1 GTPase activity
term:
id: GO:0003924
label: GTPase activity
modifier: ABNORMAL
downstream:
- target: Reduced RAC1 Effector Signalling
causal_link_type: DIRECT
evidence:
- reference: PMID:42120539
reference_title: "Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Cell-based assays revealed that N- and C-terminal variants affect RAC1 function differently: N-terminal variants are activating, while C-terminal variants are dominant-negative."
explanation: >-
C-terminal switch II variants are dominant-negative in cell-based
assays.
- reference: PMID:39307291
reference_title: "Pathophysiological significance of the p.E31G variant in RAC1 responsible for a neurodevelopmental disorder with microcephaly."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In transient expression analyses using COS7 cells, RAC1-E31G exhibited minimal interaction with the downstream effector PAK1, even in its GTP-bound state."
explanation: >-
A microcephaly-associated variant fails to engage PAK1.
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: REFUTE
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Cells expressing p.Val51Met, p.Pro73Leu, and p.Cys157Tyr all showed a tendency toward increased filopodia and reduced lamellipodia but did not result in a significant change in circularity index relative to cells expressing wild-type Rac, suggesting at most a modest impact on Rac function in these assays"
explanation: >-
For the microcephaly-associated p.Pro73Leu and p.Cys157Tyr, a
dominant-negative effect was not clearly shown.
- target: RAC1 Over-Activation
causal_link_type: DIRECT
evidence:
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Collectively, these data suggest that all the patient variants studied here increase the proportion of cellular RAC1 in an active GTP-bound state, increase RAC1 activity in cellular conditions and alter cell morphology."
explanation: >-
N-terminal switch II variants raise active GTP-bound RAC1 in cells.
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we observed that RAC1E62K behaved as a weakly constitutively activated GTPase, while RAC1A159T showed a full CA behavior, similar to that characterizing RAC1A159V and RAC1G12V (Fig. 1D)"
explanation: >-
p.Glu62Lys and p.Ala159Thr are activating.
- target: Macrocephaly
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The Val51 variants are predicted to destabilise RAC1, but their effect on
signalling has not been resolved, so the route to macrocephaly is
unknown.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
directness: INDIRECT
evidence_source: COMPUTATIONAL
snippet: "Free energy calculations by FoldX (in the SNPeffect 4.0 server)29 revealed a reduction of protein stability for these two substitutions"
explanation: >-
The only functional prediction for the Val51 variants is reduced
protein stability; how this leads to macrocephaly is unknown.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "The genetic data and in silico modeling suggested that the phenotypes are unlikely to result from haploinsufficiency."
explanation: >-
The variants are thought to act by altered function rather than loss of
one copy.
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: BACKGROUND
snippet: "In mouse studies, Rac1 is required for the formation of three germ layers during gastrulation, with Rac1-knockout mice being embryonic lethal."
explanation: >-
Complete loss of Rac1 is incompatible with development.
- name: Reduced RAC1 Effector Signalling
biological_scale: CELLULAR
subtypes:
- Microcephalic
description: >-
Dominant-negative variants block activation of RAC1 effectors such as PAK1,
reducing actin polymerisation and lamellipodia formation. The p.Cys18Tyr
variant is predicted to occlude the GTP-binding pocket.
biological_processes:
- preferred_term: Rac protein signal transduction
term:
id: GO:0016601
label: Rac protein signal transduction
modifier: DECREASED
downstream:
- target: Reduced Neural Progenitor Proliferation
causal_link_type: DIRECT
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo."
explanation: >-
Expressing the dominant-negative variants in zebrafish reduces
neuronal proliferation and head size.
- target: Impaired Neuronal Morphogenesis and Synaptic Plasticity
causal_link_type: DIRECT
evidence:
- reference: PMID:39307291
reference_title: "Pathophysiological significance of the p.E31G variant in RAC1 responsible for a neurodevelopmental disorder with microcephaly."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Moreover, in vivo studies employing in utero electroporation revealed that acute expression of RAC1-E31G resulted in impairments in axonal elongation and dendritic arborization in the young adult stage."
explanation: >-
A dominant-negative variant impairs axon and dendrite growth in mouse
cortex.
- reference: PMID:30042656
reference_title: "An Intellectual Disability-Related Missense Mutation in Rac1 Prevents LTP Induction."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Indeed, we find that this de novo mutation prevents Rac1 function and results in a selective reduction in synaptic AMPA receptor function."
explanation: >-
p.Cys18Tyr reduces synaptic AMPA receptor function in rat hippocampal
slice cultures.
evidence:
- reference: PMID:30042656
reference_title: "An Intellectual Disability-Related Missense Mutation in Rac1 Prevents LTP Induction."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "Our modeling predicts that this mutation will strongly inhibit Rac1 activation by occluding Rac1's GTP binding pocket."
explanation: >-
Structural modelling of p.Cys18Tyr.
- reference: PMID:37328543
reference_title: "A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "RAC1-p.Tyr40His interacted minimally with PAK1, and did not enable PAK1 activation."
explanation: >-
A variant at the PAK1-binding site fails to activate PAK1.
- name: RAC1 Over-Activation
biological_scale: CELLULAR
subtypes:
- Normocephalic
description: >-
Activating variants raise the fraction of GTP-bound RAC1 and over-activate
PAK1/2/3 and the WAVE regulatory complex, which drives Arp2/3-dependent
actin branching.
biological_processes:
- preferred_term: Rac protein signal transduction
term:
id: GO:0016601
label: Rac protein signal transduction
modifier: INCREASED
downstream:
- target: Abnormal Neuronal Morphology from Excess Actin Branching
causal_link_type: DIRECT
evidence:
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Axons of neurons isolated from Drosophila embryos expressing the most common of the activating variants are significantly shorter, with an increased density of filopodial protrusions."
explanation: >-
An activating variant distorts axon morphology in Drosophila neurons.
evidence:
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Pulldown assays, NIH3T3 fibroblast spreading assays and staining for activated PAK1/2/3 and WAVE2 suggest that these variants increase RAC1 activity and over-activate downstream signalling targets."
explanation: >-
Activating variants over-activate PAK and WAVE2 in cells.
- name: Reduced Neural Progenitor Proliferation
biological_scale: CELLULAR
subtypes:
- Microcephalic
description: >-
Reduced proliferation of neural progenitors, the proposed basis of
microcephaly with dominant-negative variants. Shown in zebrafish expressing
patient variants and in forebrain-specific Rac1 knockout mice; not measured
in human tissue.
biological_processes:
- preferred_term: neural precursor cell proliferation
term:
id: GO:0061351
label: neural precursor cell proliferation
modifier: DECREASED
cell_types:
- preferred_term: neural progenitor cell
term:
id: CL:0011020
label: neural progenitor cell
downstream:
- target: Microcephaly
causal_link_type: DIRECT
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: BACKGROUND
snippet: "Conditional forebrain-specific Rac1-knockout mice display impaired neuronal migration, abnormal dendritic growth and remodelling, disruption of lamellipodia formation, reduced neuronal proliferation, premature differentiation, and microcephaly."
explanation: >-
Forebrain Rac1 loss reduces neuronal proliferation and causes
microcephaly in mice.
- name: Impaired Neuronal Morphogenesis and Synaptic Plasticity
biological_scale: CELLULAR
subtypes:
- Microcephalic
description: >-
Dominant-negative RAC1 impairs axon elongation and dendritic arborisation
and, for p.Cys18Tyr, prevents long-term potentiation by reducing synaptic
AMPA receptor function.
biological_processes:
- preferred_term: neuron projection morphogenesis
term:
id: GO:0048812
label: neuron projection morphogenesis
modifier: DECREASED
- preferred_term: long-term synaptic potentiation
term:
id: GO:0060291
label: long-term synaptic potentiation
modifier: DECREASED
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
downstream:
- target: Intellectual Disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed link from impaired synaptic plasticity to intellectual
disability; the authors argue for it but it is not directly shown.
evidence:
- reference: PMID:30042656
reference_title: "An Intellectual Disability-Related Missense Mutation in Rac1 Prevents LTP Induction."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "Together, our findings strongly suggest that this mutation contributes to the development of ID in this individual."
explanation: >-
The authors' inference from the synaptic findings to intellectual
disability.
evidence:
- reference: PMID:30042656
reference_title: "An Intellectual Disability-Related Missense Mutation in Rac1 Prevents LTP Induction."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Furthermore, this mutation prevents the induction of long-term potentiation (LTP), the cellular mechanism underlying learning and memory formation."
explanation: >-
p.Cys18Tyr blocks long-term potentiation in rat hippocampal slice
cultures.
- name: Abnormal Neuronal Morphology from Excess Actin Branching
biological_scale: CELLULAR
subtypes:
- Normocephalic
description: >-
Activating variants shorten axons, increase filopodia, disorganise axon
tracts and over-branch dendrites with loss of self-avoidance in Drosophila
neurons. Knocking down the WAVE regulatory complex component Cyfip rescues
these defects, implicating the WAVE/Arp2/3 pathway.
biological_processes:
- preferred_term: neuron projection morphogenesis
term:
id: GO:0048812
label: neuron projection morphogenesis
modifier: ABNORMAL
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
downstream:
- target: Intellectual Disability
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed link from abnormal neuronal morphology to intellectual
disability, inferred from Drosophila neurons.
evidence:
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: "Our findings reveal that these variants cause altered downstream signalling, resulting in abnormal neuronal morphology and reveal the WAVE regulatory complex/Arp2/3 pathway as a possible therapeutic target for activating RAC1 variants."
explanation: >-
Links the activating variants to abnormal neuronal morphology; the step
to cognition is inferred.
- target: Polymicrogyria
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Proposed: altered neuronal morphology and migration are a plausible
route to cortical malformation, but this has not been tested.
evidence:
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "RNAi knock down of the WAVE regulatory complex component Cyfip significantly rescues these morphological defects."
explanation: >-
Reducing WAVE regulatory complex activity rescues the defects, placing it
downstream of activated RAC1.
- reference: PMID:42120539
reference_title: "Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In a Drosophila model, we observe divergent effects on neuronal morphology, with switch II N-terminal variants increasing the complexity of dendritic arbors, while switch II C-terminal variants reduce dendritic complexity."
explanation: >-
Activating and dominant-negative switch II variants have opposite
effects on dendritic complexity.
- name: Disturbed Neural Crest-Derived Tissue Development
biological_scale: TISSUE
description: >-
Proposed explanation for the cardiac and craniofacial features: Rac1 loss
in neural crest cells disrupts craniofacial and cardiac outflow tract
development in conditional knockout mice. Not shown with patient variants,
and heart defects occur with both dominant-negative and activating
variants, so this node has no upstream edge from either signalling
branch.
cell_types:
- preferred_term: neural crest cell
term:
id: CL:0011012
label: neural crest cell
downstream:
- target: Congenital Heart Defects
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Inferred from neural crest-targeted Rac1 knockout mice.
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
directness: INDIRECT
evidence_source: MODEL_ORGANISM
quote_role: REVIEW_SYNTHESIS
snippet: "Notably, the perturbed development of neural crest cell (NCC)-derived tissues documented in NCC-targeted Rac1 conditional KO mice may explain both craniofacial and cardiac features recurring in affected individuals"
explanation: >-
The authors propose neural crest dysfunction as the route to the
cardiac and craniofacial features, citing mouse models.
phenotypes:
- category: Neurological
name: Intellectual Disability
description: >-
Intellectual disability in every reported individual, ranging from mild to
severe.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Overall, all subjects shared ID with speech delay (10/10 and 7/7, respectively), a wide array of brain abnormalities (8/8)"
explanation: >-
Intellectual disability in 10 of 10 reviewed individuals.
- reference: PMID:39838818
reference_title: "Diverse Clinical Presentation of RAC1-Related Intellectual Developmental Disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We present one case with typical phenotype and two cases with a mild phenotype."
explanation: >-
Mild presentations widen the spectrum.
- category: Neurological
name: Global Developmental Delay
description: >-
Developmental delay in all reported individuals, with delayed independent
walking in most of those with activating switch II variants.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Global developmental delay
term:
id: HP:0001263
label: Global developmental delay
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes."
explanation: >-
Developmental delay in all seven individuals of the founding series.
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Age of independent walking was delayed in five out of seven children for whom information on motor milestones was available."
explanation: >-
Delayed walking in 5 of 7 with activating variants.
- category: Neurological
name: Delayed Speech and Language Development
description: >-
Speech delay in all individuals assessed.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Delayed speech and language development
term:
id: HP:0000750
label: Delayed speech and language development
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Overall, all subjects shared ID with speech delay (10/10 and 7/7, respectively), a wide array of brain abnormalities (8/8)"
explanation: >-
Speech delay in 7 of 7 assessed.
- category: Neurological
name: Microcephaly
description: >-
Microcephaly of about -2.5 to -5 SD with dominant-negative variants;
acquired microcephaly with p.Glu31Gly.
subtype: Microcephalic
phenotype_term:
preferred_term: Microcephaly
term:
id: HP:0000252
label: Microcephaly
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between -2.5 to -5 SD."
explanation: >-
Microcephaly in four individuals in the founding series.
- category: Neurological
name: Macrocephaly
description: >-
Macrocephaly (+4.2 and +4.5 SD) with Val51 variants.
subtype: Macrocephalic
phenotype_term:
preferred_term: Macrocephaly
term:
id: HP:0000256
label: Macrocephaly
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD."
explanation: >-
Macrocephaly in both Val51 individuals.
- category: Neurological
name: Hypoplasia of the Corpus Callosum
description: >-
Corpus callosum hypoplasia, one of the most common MRI findings, especially
in microcephalic individuals. Brain anomalies of some kind were present in
all individuals imaged (8 of 8 in a review).
phenotype_term:
preferred_term: Hypoplasia of the corpus callosum
term:
id: HP:0002079
label: Hypoplasia of the corpus callosum
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hypoplasia of the corpus callosum and the cerebellar vermis were the commonest features observed on available magnetic resonance imaging (MRI) studies of individuals with microcephaly."
explanation: >-
Common MRI finding in microcephalic individuals.
- category: Neurological
name: Cerebellar Vermis Hypoplasia
description: >-
Cerebellar vermis hypoplasia or dysgenesis, mainly in microcephalic
individuals.
phenotype_term:
preferred_term: Cerebellar vermis hypoplasia
term:
id: HP:0001320
label: Cerebellar vermis hypoplasia
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hypoplasia of the corpus callosum and the cerebellar vermis were the commonest features observed on available magnetic resonance imaging (MRI) studies of individuals with microcephaly."
explanation: >-
Common MRI finding in microcephalic individuals.
- category: Neurological
name: Polymicrogyria
description: >-
Polymicrogyria, reported with activating p.Tyr64Cys and p.Tyr64Asp variants.
phenotype_term:
preferred_term: Polymicrogyria
term:
id: HP:0002126
label: Polymicrogyria
evidence:
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Brain MRI scans showed polymicrogyria in two patients, one with Y64C and one with the Y64D variant (Fig. 1C)."
explanation: >-
Polymicrogyria in two individuals with activating variants.
- category: Neurological
name: Periventricular White Matter Lesions
description: >-
Periventricular white matter lesions in both macrocephalic individuals.
subtype: Macrocephalic
phenotype_term:
preferred_term: Periventricular white matter lesions
term:
id: HP:0002518
label: Abnormal periventricular white matter morphology
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The two individuals with macrocephaly (individuals 6 and 7) showed periventricular white matter lesions (Table 1; Figure 2)."
explanation: >-
White matter lesions in both macrocephalic individuals.
- category: Behavioral
name: Behavioural Abnormalities
description: >-
Behavioural problems including autistic features, impulsivity,
compulsivity, anxiety and stereotypies.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Atypical behavior
term:
id: HP:0000708
label: Atypical behavior
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "behavioral abnormalities (5/6), hypotonia and neonatal/childhood feeding difficulties (5/7 and 5/8, respectively)"
explanation: >-
Behavioural abnormalities in 5 of 6 assessed.
- category: Neurological
name: Hypotonia
description: >-
Hypotonia in most individuals assessed.
frequency: FREQUENT
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "behavioral abnormalities (5/6), hypotonia and neonatal/childhood feeding difficulties (5/7 and 5/8, respectively)"
explanation: >-
Hypotonia in 5 of 7 assessed.
- category: Gastrointestinal
name: Feeding Difficulties
description: >-
Neonatal or childhood feeding difficulties.
frequency: FREQUENT
phenotype_term:
preferred_term: Feeding difficulties
term:
id: HP:0011968
label: Feeding difficulties
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "behavioral abnormalities (5/6), hypotonia and neonatal/childhood feeding difficulties (5/7 and 5/8, respectively)"
explanation: >-
Feeding difficulties in 5 of 8 assessed.
- category: Cardiovascular
name: Congenital Heart Defects
description: >-
Septal defects, patent ductus arteriosus, bicuspid aortic valve and
pulmonary valve stenosis, in about half of individuals.
frequency: FREQUENT
phenotype_term:
preferred_term: Congenital heart defect
term:
id: HP:0001627
label: Abnormal heart morphology
coarse_binding_basis: VARIABLE_SPECTRUM
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CHDs were also common (4/8), while epilepsy was reported in 3/8 subjects."
explanation: >-
Congenital heart defects in 4 of 8 assessed.
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cardiovascular anomalies, such as ventricular septal defects, atrial septal defects and patent ductus arteriosus, were noted in four of eight patients."
explanation: >-
The same frequency, and the defect types, in the activating-variant
cohort.
- category: Neurological
name: Seizures
description: >-
Epilepsy in a minority, reported mainly outside the activating switch II
group, in which none of eight individuals had epilepsy.
frequency: FREQUENT
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CHDs were also common (4/8), while epilepsy was reported in 3/8 subjects."
explanation: >-
Epilepsy in 3 of 8 assessed.
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: "None of the affected individuals were reported to have epilepsy."
explanation: >-
No epilepsy among eight individuals with activating switch II variants,
so seizures are not a consistent feature of that subtype.
- category: Dermatological
name: Eczematous and Ichthyosiform Skin Changes
description: >-
Eczematous rashes, with or without ichthyosiform changes.
frequency: FREQUENT
phenotype_term:
preferred_term: Eczematous dermatitis
term:
id: HP:0000964
label: Eczematoid dermatitis
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We also observed recurrent ectodermal anomalies, mainly represented by eczematous rashes, with or without ichthyosiform manifestations (4/10)"
explanation: >-
Skin changes in 4 of 10.
- category: Dermatological
name: Ichthyosis
description: >-
Ichthyosiform skin changes, reported in some individuals with or without
eczema.
phenotype_term:
preferred_term: Ichthyosiform skin changes
term:
id: HP:0008064
label: Ichthyosis
evidence:
- reference: PMID:34725860
reference_title: "Ichthyosiform changes in a patient with RAC1 mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In this report, we describe the first known case of a RAC1 mutation with ichthyosiform changes."
explanation: >-
Case report of ichthyosiform skin changes.
- category: Craniofacial
name: Prominent Nasolabial Folds
description: >-
Deep nasolabial folds in 8 of 9, tending to soften with age.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Prominent nasolabial fold
term:
id: HP:0005272
label: Prominent nasolabial fold
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "overhanging columella (6/9) with a bulbous nasal tip (6/9), a short philtrum (7/9), deep nasolabial folds (8/9), thin upper lip (7/9)"
explanation: >-
Deep nasolabial folds in 8 of 9.
- category: Craniofacial
name: Thin Upper Lip
description: >-
Thin upper lip in 7 of 9.
frequency: FREQUENT
phenotype_term:
preferred_term: Thin upper lip vermilion
term:
id: HP:0000219
label: Thin upper lip vermilion
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "overhanging columella (6/9) with a bulbous nasal tip (6/9), a short philtrum (7/9), deep nasolabial folds (8/9), thin upper lip (7/9)"
explanation: >-
Thin upper lip in 7 of 9.
- category: Craniofacial
name: Sparse Lateral Eyebrows
description: >-
Lateral sparseness of the eyebrows in 7 of 9.
frequency: FREQUENT
phenotype_term:
preferred_term: Sparse lateral eyebrow
term:
id: HP:0005338
label: Sparse lateral eyebrow
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Common features included a high anterior hairline (9/9), arched eyebrows (8/9) with tendency to lateral sparse (7/9) and mild synophrys (4/9), a prominent nasal bridge (7/9), mild widely spaced eyes (8/9)"
explanation: >-
Tendency to lateral eyebrow sparseness in 7 of 9.
- category: Craniofacial
name: Prominent Nasal Bridge
description: >-
Prominent nasal bridge in 7 of 9.
frequency: FREQUENT
phenotype_term:
preferred_term: Prominent nasal bridge
term:
id: HP:0000426
label: Prominent nasal bridge
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Common features included a high anterior hairline (9/9), arched eyebrows (8/9) with tendency to lateral sparse (7/9) and mild synophrys (4/9), a prominent nasal bridge (7/9), mild widely spaced eyes (8/9)"
explanation: >-
Prominent nasal bridge in 7 of 9.
- category: Craniofacial
name: Long Pointed Chin
description: >-
Long pointed chin in 7 of 9.
frequency: FREQUENT
phenotype_term:
preferred_term: Long pointed chin
term:
id: HP:0000307
label: Pointed chin
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "everted lips (both superior and inferior) (5/9), and a long pointed chin (7/9)"
explanation: >-
Long pointed chin in 7 of 9. HP has no combined long-and-pointed chin term, so the binding carries the pointed shape and preferred_term keeps the length.
- category: Craniofacial
name: Abnormally Spaced Teeth
description: >-
Abnormally spaced teeth, with or without diastema of the upper incisors, in
all 6 individuals assessed.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Widely spaced teeth
term:
id: HP:0000687
label: Widely spaced teeth
notes: >-
The source reports "abnormally spaced" teeth rather than widely spaced
teeth. HP:0000687 is bound because the accompanying upper-incisor diastema
indicates gaps between teeth; the source does not say the spacing is
uniformly increased.
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "abnormally spaced teeth with or without diastema of superior incisors (6/6)"
explanation: >-
Abnormally spaced teeth in 6 of 6.
- category: Renal
name: Hydronephrosis
description: >-
Hydronephrosis in 2 of 10 reviewed individuals.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Hydronephrosis
term:
id: HP:0000126
label: Hydronephrosis
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two showed hydronephrosis (subject 1 from the present report and subject K from [15])"
explanation: >-
Hydronephrosis in 2 of 10.
- category: Skeletal
name: Short Feet
description: >-
Small hands and feet in 3 of 10.
frequency: FREQUENT
phenotype_term:
preferred_term: Short foot
term:
id: HP:0001773
label: Short foot
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "and various skeletal anomalies (3/10), such as small hands and feet (3/10)"
explanation: >-
Small hands and feet in 3 of 10.
- category: Craniofacial
name: High Anterior Hairline
description: >-
The most consistent facial feature (9 of 9 reviewed photographs). Facial
features such as widely spaced eyes and prominent nasolabial folds soften
with age.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: High anterior hairline
term:
id: HP:0009890
label: High anterior hairline
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Common features included a high anterior hairline (9/9), arched eyebrows (8/9) with tendency to lateral sparse (7/9) and mild synophrys (4/9), a prominent nasal bridge (7/9), mild widely spaced eyes (8/9)"
explanation: >-
High anterior hairline in 9 of 9.
- category: Craniofacial
name: Highly Arched Eyebrows
description: >-
Arched eyebrows in 8 of 9.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Highly arched eyebrow
term:
id: HP:0002553
label: Highly arched eyebrow
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Common features included a high anterior hairline (9/9), arched eyebrows (8/9) with tendency to lateral sparse (7/9) and mild synophrys (4/9), a prominent nasal bridge (7/9), mild widely spaced eyes (8/9)"
explanation: >-
Arched eyebrows in 8 of 9.
- category: Craniofacial
name: Hypertelorism
description: >-
Mildly widely spaced eyes in 8 of 9, tending to soften with age.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Hypertelorism
term:
id: HP:0000316
label: Hypertelorism
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Common features included a high anterior hairline (9/9), arched eyebrows (8/9) with tendency to lateral sparse (7/9) and mild synophrys (4/9), a prominent nasal bridge (7/9), mild widely spaced eyes (8/9)"
explanation: >-
Widely spaced eyes in 8 of 9.
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Specifically, widely spaced eyes, bulbous nasal tip and prominent nasolabial folds tend to smoothen in adolescents and young adults."
explanation: >-
The facial gestalt changes with age.
- category: Craniofacial
name: Short Philtrum
description: >-
Short philtrum in 7 of 9.
frequency: FREQUENT
phenotype_term:
preferred_term: Short philtrum
term:
id: HP:0000322
label: Short philtrum
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "overhanging columella (6/9) with a bulbous nasal tip (6/9), a short philtrum (7/9), deep nasolabial folds (8/9), thin upper lip (7/9)"
explanation: >-
Short philtrum in 7 of 9.
- category: Skeletal
name: Small Hands
description: >-
Small hands and feet in 3 of 10, among various skeletal anomalies.
frequency: FREQUENT
phenotype_term:
preferred_term: Small hand
term:
id: HP:0200055
label: Small hand
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "and various skeletal anomalies (3/10), such as small hands and feet (3/10)"
explanation: >-
Small hands and feet in 3 of 10.
genetic:
- name: RAC1
gene_term:
preferred_term: RAC1
term:
id: hgnc:9801
label: RAC1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
association: >-
Heterozygous de novo missense variants cause MRD48. Dominant-negative and
activating variants produce overlapping but distinguishable phenotypes,
most clearly in head size.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Collectively, we observed an extraordinary spread of ∼10 SD of head circumferences orchestrated by distinct mutations in the same gene."
explanation: >-
Different variants in the same gene produce opposite head-size effects.
- reference: PMID:42120539
reference_title: "Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We conclude that variants affecting N- and C-terminal parts of RAC1 switch II cause phenotypically and mechanistically distinct disorders."
explanation: >-
The variant classes behave as distinct disorders.
variants:
- name: RAC1 p.Cys18Tyr
description: >-
c.53G>A (NM_006908), dominant-negative; microcephaly. Predicted to occlude
the GTP-binding pocket and blocks long-term potentiation in rat hippocampal
neurons.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo."
explanation: >-
Dominant-negative effect of p.Cys18Tyr.
- name: RAC1 p.Asn39Ser
description: >-
c.116A>G, in switch I; dominant-negative; microcephaly.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo."
explanation: >-
Dominant-negative effect of p.Asn39Ser.
- name: RAC1 p.Tyr64Asp
description: >-
c.190T>G, in switch II; constitutively active. Head size was +1 SD in the
founding report and +3.06 SD (mild macrocephaly) at 14 years in a later
report.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Conversely, the p.Tyr64Asp substitution is constitutively active."
explanation: >-
Activating effect of p.Tyr64Asp.
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "One boy with a Y64D variant had mild macrocephaly of +3.06 at 14 years of age."
explanation: >-
Head size with p.Tyr64Asp in adolescence.
- name: RAC1 p.Glu62Lys and p.Ala159Thr
description: >-
c.184G>A (switch II, weakly activating) and c.475G>A (G5 box, fully
activating); both de novo, with normal head size.
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "we observed that RAC1E62K behaved as a weakly constitutively activated GTPase, while RAC1A159T showed a full CA behavior, similar to that characterizing RAC1A159V and RAC1G12V (Fig. 1D)"
explanation: >-
Both variants are activating.
- name: RAC1 p.Val51Met and p.Val51Leu
description: >-
c.151G>A and c.151G>C; macrocephaly; mechanism unresolved.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of +4.16 and +4.5 SD."
explanation: >-
The Val51 variants and their phenotype.
- name: RAC1 p.Glu31Gly
description: >-
c.92A>G (NM_006908.5), dominant-negative toward PAK1 signalling; acquired
microcephaly.
evidence:
- reference: PMID:39307291
reference_title: "Pathophysiological significance of the p.E31G variant in RAC1 responsible for a neurodevelopmental disorder with microcephaly."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "These findings suggest that the p.E31G variant functions as a dominant-negative version in the PAK1-mediated signaling pathway and is responsible for the clinical features observed in the patient under investigation, namely microcephaly and intellectual disability."
explanation: >-
Dominant-negative effect of p.Glu31Gly.
- name: RAC1 p.Tyr40His
description: >-
c.118T>C (NM_018890.4), at the PAK1-binding site; fails to activate PAK1.
Reported in a single neonate with a VACTERL-like presentation including
tracheal agenesis, who died on the first day of life; no neurodevelopmental
assessment was possible, so it is weak support for the microcephalic
group's mechanism.
evidence:
- reference: PMID:37328543
reference_title: "A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He died of respiratory failure caused by tracheal agenesis type III (Fig. 1i,j) on the first day after delivery."
explanation: >-
The severe phenotype associated with this variant.
differential_diagnoses:
- name: RAC3-related neurodevelopmental disorder (NEDBAF)
description: >-
Activating variants in the paralog RAC3 cause a similar disorder, with more
frequent corpus callosum, brainstem and cerebellar malformations than
MRD48.
evidence:
- reference: PMID:37059841
reference_title: "Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, specific MRI anomalies (i.e., hypoplasia/aplasia of corpus callosum, brainstem and cerebellar hypo/dysplasia) seem much more frequent in NEDBAF with respect to MRD48"
explanation: >-
Imaging differences between the RAC3 and RAC1 disorders.
- name: TRIO-related neurodevelopmental disorder
description: >-
Variants in the RAC1 activator TRIO cause intellectual disability with
microcephaly (reduced RAC1 activation) or macrocephaly (increased RAC1
activation), mirroring the RAC1 head-size split. Curated separately as
TRIO-Related_Neurodevelopmental_Disorder; distinguished by sequencing.
evidence:
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "increased or decreased RAC1 activation has also been detected in neurodevelopmental disorders caused by variants in TRIO"
explanation: >-
TRIO disorders also involve altered RAC1 activation in either
direction.
diagnosis:
- name: Exome or genome sequencing
description: >-
Diagnosis is by exome or genome sequencing, ideally as a trio to confirm
de novo status. Variant position (switch I, switch II N- versus C-terminal,
nucleotide-binding site) helps predict mechanism and head-size phenotype.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Review of data from 4,293 families, who underwent trio whole-exome sequencing (WES) as part of the Deciphering Developmental Disorders study,3 led to identification of three individuals with de novo RAC1 (GenBank: NM_006908) missense mutations"
explanation: >-
Trio exome sequencing as the route to diagnosis.
animal_models:
- name: Zebrafish expressing dominant-negative RAC1 variants
species: Zebrafish
genotype: Overexpression of human RAC1 p.Cys18Tyr or p.Asn39Ser
publication: PMID:28886345
modeled_mechanisms:
- target: Reduced Neural Progenitor Proliferation
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: ORGANISM
description: >-
Expressing the variants reduces neuronal proliferation and causes
microcephaly and cerebellar abnormalities.
limitations: >-
Overexpression in zebrafish embryos rather than a heterozygous
endogenous allele in a mammal.
evidence:
- reference: PMID:28886345
reference_title: "RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo."
explanation: >-
The zebrafish phenotype.
- name: Drosophila expressing activating Rac1-Y64D
species: Fruit fly
genotype: UAS-Rac1-Y64D driven in neurons
publication: PMID:35139179
modeled_mechanisms:
- target: Abnormal Neuronal Morphology from Excess Actin Branching
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Shorter axons with excess filopodia, axon tract defects and dendrite
over-branching, rescued by Cyfip knockdown.
limitations: >-
Invertebrate neurons overexpressing fly Rac1 carrying the equivalent
substitution; cortical development cannot be modelled.
evidence:
- reference: PMID:35139179
reference_title: "Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "RNAi knock down of the WAVE regulatory complex component Cyfip significantly rescues these morphological defects."
explanation: >-
The model's key rescue result.
- name: Mouse cortex with in utero electroporation of RAC1-E31G
species: Mouse
genotype: In utero electroporation of RAC1 p.Glu31Gly
publication: PMID:39307291
modeled_mechanisms:
- target: Impaired Neuronal Morphogenesis and Synaptic Plasticity
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Acute expression impairs axon elongation and dendritic arborisation.
limitations: >-
Acute overexpression in a subset of cortical neurons rather than a
germline heterozygous allele.
evidence:
- reference: PMID:39307291
reference_title: "Pathophysiological significance of the p.E31G variant in RAC1 responsible for a neurodevelopmental disorder with microcephaly."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Moreover, in vivo studies employing in utero electroporation revealed that acute expression of RAC1-E31G resulted in impairments in axonal elongation and dendritic arborization in the young adult stage."
explanation: >-
The model's neuronal phenotype.
experimental_models:
- name: Rat hippocampal slice cultures expressing RAC1 p.Cys18Tyr
experimental_model_type: OTHER
description: >-
Organotypic rat hippocampal slice cultures with CA1 pyramidal neurons
biolistically transfected with wild-type or Cys18Tyr RAC1.
publication: PMID:30042656
organism:
preferred_term: rat
term:
id: NCBITaxon:10116
label: Rattus norvegicus
modeled_mechanisms:
- target: Impaired Neuronal Morphogenesis and Synaptic Plasticity
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
The variant reduces synaptic AMPA receptor function and prevents
long-term potentiation.
limitations: >-
Overexpression in single neurons alongside endogenous RAC1, in slice
culture.
evidence:
- reference: PMID:30042656
reference_title: "An Intellectual Disability-Related Missense Mutation in Rac1 Prevents LTP Induction."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Furthermore, this mutation prevents the induction of long-term potentiation (LTP), the cellular mechanism underlying learning and memory formation."
explanation: >-
The model's synaptic phenotype.
discussions:
- discussion_id: mrd48_variant_class_split
kind: KNOWLEDGE_GAP
attaches_to:
- has_subtypes#Microcephalic
- has_subtypes#Normocephalic
- has_subtypes#Macrocephalic
prompt: >-
How do dominant-negative and activating RAC1 variants converge on
intellectual disability, and why do Val51 variants cause macrocephaly?
rationale: >-
Opposite effects on RAC1 signalling produce microcephaly or normocephaly
yet similar intellectual disability, brain malformations and heart
defects. The Val51 variants have not been assigned a mechanism, although
the head-size split mirrors TRIO, where reduced RAC1 activation gives
microcephaly and increased activation gives macrocephaly. Functional
testing of the Val51 variants and knock-in models of each class would
show where the pathways diverge and converge.
- discussion_id: mrd48_wave_therapeutic_target
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Abnormal Neuronal Morphology from Excess Actin Branching
prompt: >-
Could inhibiting the WAVE regulatory complex or Arp2/3 treat MRD48 caused
by activating variants?
rationale: >-
Cyfip knockdown rescues neuronal defects from an activating variant in
Drosophila, and the authors propose the WAVE/Arp2/3 pathway as a
therapeutic target. No such approach has been tested in a vertebrate
model, and it would be expected to worsen the dominant-negative class.
notes: >-
One individual with sensorineural hearing loss in the 2023 review also
carried a paternally inherited pathogenic GRHL2 nonsense variant (DFNA28),
so hearing loss is not curated as a feature of MRD48.
The macrocephalic subtype rests on two individuals, both with Val51
variants. A severe, lethal VACTERL-like presentation has been reported
with p.Tyr40His in a single neonate and is recorded under variants rather
than as a general phenotype.
No GeneReviews chapter covers MRD48. No disease-specific treatment exists.
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.
Create: Intellectual_Disability_Autosomal_Dominant_48 · 2026-10-01T14:28:00Z · View source
New entry for MRD48 (MONDO:0030913, RAC1), requested by the user and claimed in issue #13319. Modelled as three head-size subtypes (Microcephalic: dominant-negative or presumed dominant-negative; Normocephalic: activating; Macrocephalic: Val51, mechanism unresolved), following the field's own head-circumference grouping (PMID:42120539) and the variant-class findings of PMID:28886345, 35139179 and 37059841; pathophysiology branches carry subtypes. RAC1 is placed on the root variant node carrying GO:0003924 GTPase activity, so the new gene-activity grounding gate passes. Deep research was requested from falcon; no Edison key was configured, so the run used dr_fallback and the report was produced by claude_code. Report validation: 9/9 references resolved; preflight-dr PASS. No GeneReviews chapter (check-genereviews --online: NO_CHAPTER). A fresh-context red-team review (2 critical, 7 important, several minor) led to these changes: the Normocephalic subtype was widened from N-terminal switch II only to activating variants including p.Ala159Thr (G5 box) and p.Glu62Lys, with a variant record and the 37059841 activation sentence; a Global developmental delay phenotype was added; the macrocephaly edge now cites the FoldX stability prediction (COMPUTATIONAL) rather than the 'weakly dominant negative or context dependent' sentence, and the V51 macrocrania sentence was added to that subtype; the Microcephalic subtype now says 'dominant-negative or presumed dominant-negative', with a REFUTE item recording that p.Pro73Leu and p.Cys157Tyr showed at most a modest effect; the neural crest cell term was corrected to CL:0011012 and its sentence regraded REVIEW_SYNTHESIS; prominent nasolabial folds, thin upper lip, widely spaced teeth, hydronephrosis, short feet and a separate ichthyosis phenotype were added from their stated frequencies; the Upadia 2025 mild cases were cited; p.Tyr40His is now described as a neonate with no neurodevelopmental assessment; the Y64D head-size change with age was recorded; the TRIO differential gained evidence; and an uncited DOI cache file was removed. The reviewer's suggestion to cite the fibroblast sentence on the variant records was not taken because the cited abstract sentence includes the zebrafish result those records also rely on. Validation: just validate 77/77 snippets; gene-activity grounding, entity-refs, causal-targets and duplicate-keys OK. Stub stubs/Intellectual_Disability_Autosomal_Dominant_48.yaml deleted.
Permissions block grep; I'll use Read.
Target: Intellectual Disability, Autosomal Dominant 48. MONDO:0030913 as given in the template; OMIM #617751. Report date: 2026-10-01
I read the nine primary references already cached in this worktree's references_cache/ (PMIDs 28886345, 30042656, 34725860, 35139179, 37059841, 37328543, 39307291, 39838818, 42120539). Five have full text and four have abstracts only. Every quoted snippet below was copied from those cached files.
runoak or the term caches before it is bound.Overview. MRD48 is a rare, highly variable neurodevelopmental disorder (NDD). It is caused by heterozygous, almost always de novo, missense variants in RAC1, a Rho-family small GTPase. The core features are: - developmental delay or intellectual disability (DD/ID) with speech delay; - structural brain anomalies; - hypotonia, feeding difficulties and behavioural problems; - a recognisable but subtle facial gestalt.
Its most striking feature is that head size depends on the variant. Occipitofrontal circumference ranges from about −5 SD to +4.5 SD, and this follows whether the variant is dominant-negative or activating.
Identifiers
| Resource | ID | Note |
|---|---|---|
| OMIM (phenotype) | 617751 | Quoted in PMID:37059841 and PMID:35139179 |
| OMIM (gene) | RAC1 602048 | PMID:37059841 |
| MONDO | MONDO:0030913 | From the template; check its label and status in cache/mondo/terms.csv (that file has uncommitted changes in this worktree) |
| HGNC | RAC1 = hgnc:9801 [verify] | Use the lowercase hgnc: prefix |
| Orphanet / ICD-10 / ICD-11 / MeSH | Not verified | No disease-specific Orphanet code was confirmed. Expect a generic ID code (for example ICD-10 F7x / Q-codes) rather than a specific one |
Synonyms: Intellectual developmental disorder, autosomal dominant 48; MRD48; RAC1-related neurodevelopmental disorder (RAC1-NDD, PMID:35139179); RAC1-related intellectual developmental disorder (PMID:39838818).
Basis of knowledge. Everything comes from individual-patient case series: about 7 patients in 2017, 8 in 2022, 2 in 2023, and further single cases from 2023 to 2025. The 2026 switch II paper reports 15 new individuals but gives clinical detail for only 6. No registry or EHR-level data exist.
Lump/split note for curation. The 2026 paper says "variants affecting N- and C-terminal parts of RAC1 switch II cause phenotypically and mechanistically distinct disorders" (PMID:42120539). Recommendation: keep one Disease entry anchored to OMIM 617751 / MONDO, and model functional-class strata as has_subtypes:
- dominant-negative / microcephalic;
- activating switch II N-terminal (Q61–R68) / normocephalic;
- macrocephalic (V51).
There are no separate MONDO terms for these strata.
Frequencies come from the 10-patient review in PMID:37059841. The denominator is the number of patients assessed for each feature:
"all subjects shared ID with speech delay (10/10 and 7/7, respectively), a wide array of brain abnormalities (8/8) … behavioral abnormalities (5/6), hypotonia and neonatal/childhood feeding difficulties (5/7 and 5/8, respectively). CHDs were also common (4/8), while epilepsy was reported in 3/8 subjects. We also observed recurrent ectodermal anomalies, mainly represented by eczematous rashes, with or without ichthyosiform manifestations (4/10), and various skeletal anomalies (3/10), such as small hands and feet (3/10)."
| Phenotype | Frequency | Onset / course | Suggested HPO [verify all] | Source |
|---|---|---|---|---|
| Intellectual disability (mild to severe; 5/10 mild–moderate) | 10/10 | Infancy/childhood; static. Regression was reported once (worsening from age 12) | HP:0001249 Intellectual disability | 37059841 |
| Global developmental delay | Near-universal | Infancy | HP:0001263 | 28886345, 35139179 |
| Speech delay | 7/7 | Childhood | HP:0000750 Delayed speech and language development | 37059841 |
| Brain anomalies (polymicrogyria/pachygyria, corpus callosum hypoplasia, cerebellar vermis hypoplasia/dysgenesis, enlarged ventricles, mega cisterna magna, thin brainstem, white matter lesions) | 8/8 | Congenital | HP:0002126 Polymicrogyria; HP:0001338 Partial agenesis of the corpus callosum or HP:0002079 Hypoplasia of the corpus callosum; HP:0001320 Cerebellar vermis hypoplasia | 37059841 table; 35139179 |
| Microcephaly (−2.5 to −5 SD) | DN variants (C18Y, N39S, P73L, C157Y; switch II C-terminal P69–Q74; E31G acquired) | Congenital or acquired | HP:0000252 Microcephaly | 28886345, 42120539, 39307291 |
| Macrocephaly (+4.16 / +4.5 SD) | V51M/V51L | Congenital | HP:0000256 Macrocephaly | 28886345 |
| Normocephaly | Activating switch II Q61–R68 variants | – | – | 35139179, 42120539 |
| Behavioural anomalies (ASD, impulsivity, compulsivity, anxiety, stereotypies) | 5/6 | Childhood/adolescence | HP:0000729 Autistic behavior; HP:0000708 Behavioral abnormality; HP:0000733 Motor stereotypy | 37059841 |
| Hypotonia | 5/7 | Neonatal/infantile | HP:0001252 Hypotonia | 37059841 |
| Feeding difficulties | 5/8 | Neonatal/childhood | HP:0011968 Feeding difficulties | 37059841 |
| Congenital heart defects (septal defects, BAV, pulmonary valve stenosis, PDA, PFO, outflow tract) | 4/8 (5/10 in the discussion) | Congenital | HP:0001627 Abnormal heart morphology; HP:0001631 Atrial septal defect; HP:0001629 Ventricular septal defect; HP:0001647 Bicuspid aortic valve | 37059841, 35139179 |
| Seizures | 3/8 | Childhood | HP:0001250 Seizure | 37059841 |
| Ectodermal anomalies: eczema, ichthyosiform skin | 4/10 | Childhood | HP:0000964 Eczema; HP:0008064 Ichthyosis | 37059841, 34725860 |
| Small hands/feet, skeletal anomalies | 3/10 | Congenital | HP:0200055 Small hand; HP:0001773 Short foot | 37059841 |
| Sensorineural deafness | 2/10 (one has an alternative GRHL2 explanation) | Congenital/childhood | HP:0000407 Sensorineural hearing impairment | 37059841 |
| Hydronephrosis | 2/10 | Congenital | HP:0000126 Hydronephrosis | 37059841 |
| Ocular findings (myopia, chorioretinal atrophy, congenital cataract, visual impairment) | Isolated | – | HP:0000545 Myopia; HP:0000519 Congenital cataract | 37059841 table |
| Facial gestalt (see below) | 6–9/9 per feature | Softens with age | Individual facial HPO terms | 37059841 |
Facial gestalt. From systematic review of photographs: "high anterior hairline (9/9), arched eyebrows (8/9) with tendency to lateral sparse (7/9) … mild widely spaced eyes (8/9), wave-shaped palpebral fissures (7/9), overhanging columella (6/9) … short philtrum (7/9), deep nasolabial folds (8/9), thin upper lip (7/9), abnormally spaced teeth … (6/6) … and a long pointed chin (7/9)." The same paper notes that "widely spaced eyes, bulbous nasal tip and prominent nasolabial folds tend to smoothen in adolescents and young adults" (PMID:37059841).
Some HPO terms to check for these features: HP:0000294 Low anterior hairline (do not use; the feature here is a high hairline), HP:0002668 Arched eyebrow, HP:0000316 Hypertelorism, HP:0000322 Short philtrum, HP:0000219 Thin upper lip vermilion, HP:0000687 Widely spaced teeth. [verify all]
Severe or atypical presentations. - p.Tyr40His (Seyama 2023, PMID:37328543): a VACTERL-like presentation with fatal tracheal aplasia. "the patient died of respiratory failure caused by tracheal aplasia type III." Other features were TAPVR, oesophageal atresia, scoliosis and polydactyly. - Mild cases: Upadia et al. 2025 (PMID:39838818) widen the mild end of the spectrum: "We present one case with typical phenotype and two cases with a mild phenotype."
Quality of life. No studies using standard instruments (EQ-5D, PedsQL) were found. The burden is inferred from ID, behavioural disorder and congenital heart disease.
Reported pathogenic variants and functional class
| Variant (NP_008839) | Region | Head size | Functional effect | Evidence |
|---|---|---|---|---|
| p.Cys18Tyr (c.53G>A) | P-loop/G1 vicinity | Microcephaly | Dominant-negative; blocks GTP-mediated activation and LTP | 28886345; 30042656 |
| p.Glu31Gly (c.92A>G) | Switch I | Acquired microcephaly | DN toward PAK1 | 39307291 |
| p.Asn39Ser (c.116A>G) | Switch I | Microcephaly | Dominant-negative | 28886345 |
| p.Tyr40His (c.118T>C) | PAK1-binding site, adjacent to switch I | Lethal, VACTERL-like | Inactivates PAK1 signalling | 37328543 |
| p.Val51Met / p.Val51Leu (c.151G>A/C) | β2–β3 | Macrocephaly | Context-dependent / unclear | 28886345 |
| p.Gln61–p.Arg68 (incl. p.Tyr64Asp c.190T>G, p.Glu62Lys c.184G>A) | Switch II N-terminal | Normocephaly | Activating / gain of function | 28886345, 35139179, 37059841, 42120539 |
| p.Pro69–p.Gln74 (incl. p.Pro73Leu c.218C>T) | Switch II C-terminal | Microcephaly | Dominant-negative | 28886345, 42120539 |
| p.Cys157Tyr (c.470G>A) | G5 box | Microcephaly | Weak DN / context-dependent | 28886345 |
| p.Ala159Thr (c.475G>A) | G5 nucleotide-binding pocket | Normocephaly | Constitutively active (like the oncogenic A159V) | 37059841 |
just list-gene-validity / clingen-list before filling gene_disease_validity, and do not assign a tier yourself.Suggested functional_impact_category values:
- DOMINANT_NEGATIVE for the C18Y, N39S, E31G and C-terminal switch II variants;
- GAIN_OF_FUNCTION (or HYPERMORPHIC) for Y64D, E62K, A159T and the other Q61–R68 variants.
Not applicable. No environmental, lifestyle or infectious contributors have been reported.
measure_type: CASES_IN_LITERATURE with prevalence_class: ULTRA_RARE or NOT_YET_DOCUMENTED.There is no disease-specific or approved therapy, and no clinical trials. Supportive, multidisciplinary management:
| Intervention | NCIT suggestion [verify] | therapeutic_modality |
|---|---|---|
| Early intervention / special education; speech therapy | Speech language therapy NCIT:C159273 | BEHAVIORAL |
| Physical / occupational therapy for hypotonia | NCIT:C15302 Physical Therapy; NCIT:C121351 Occupational Therapy | BEHAVIORAL |
| Antiseizure medication | NCIT:C15986 Pharmacotherapy (+ agent if one is named) | SMALL_MOLECULE |
| Cardiac surgery for CHD | NCIT:C15329 Surgical Procedure | SURGERY |
| Feeding support / nutrition | NCIT:C15433 Nutritional Support (review per case; do not tag mechanically) | – |
| Behavioural / psychiatric management | Behavioral counseling NCIT:C181743 | BEHAVIORAL |
| Hearing aids (if deaf) | Device; use a qualifier pattern per CLAUDE.md | DEVICE |
| Genetic counselling | NCIT:C15240 | – |
Experimental and preclinical leads only: - For activating alleles, the WAVE regulatory complex/Arp2/3 pathway has been proposed as a target: "reveal the WAVE regulatory complex/Arp2/3 pathway as a possible therapeutic target for activating RAC1 variants" (PMID:35139179). This rests on Drosophila Cyfip knockdown only. - RAC1 inhibitors (e.g., NSC23766, EHT1864) are research tools and have not been tested in patients. - Because the functional classes are opposite, any targeted therapy would need to be allele-class-specific.
| Model | Type | Findings | Fidelity / limits | PMID |
|---|---|---|---|---|
| Zebrafish embryo, overexpression of human C18Y and N39S | Transient overexpression | Microcephaly, reduced neuronal proliferation, cerebellar abnormalities | PARTIALLY_RECAPITULATES microcephaly. Overexpression is supraphysiological, and zebrafish lack cortical organisation | 28886345 |
| Drosophila Rac1-Y64D (UAS/Gal4: elav, ppk) | Transgenic | Short axons, more filopodia, fasciculation defects, dendrite over-branching; Cyfip RNAi rescue | Shows the GoF cellular mechanism; invertebrate, with no cortex or head-size readout | 35139179 |
| Drosophila switch II N- vs C-terminal variants | Transgenic | N-terminal: more dendritic complexity and locomotor hyperactivity; C-terminal: less complexity | Behavioural readout only in flies | 42120539 |
| Mouse in utero electroporation of RAC1-E31G | Acute cortical expression | Impaired axon elongation and dendritic arborisation | Overexpression, not knock-in | 39307291 |
| Rat/mouse hippocampal neurons (slice) with C18Y | Ex vivo / in vitro | Loss of AMPA receptor currents; LTP blocked | IN_VITRO; links to the learning mechanism | 30042656 |
| Mouse Rac1 KO and conditional KOs (forebrain, neural crest, second heart field) | Knockout | Germline KO is embryonic lethal; forebrain cKO causes microcephaly, migration and dendrite defects; neural crest and SHF cKO cause craniofacial and outflow tract/right ventricular defects | Null alleles, not the patient DN/GoF missense alleles | Reviewed in 28886345, 37059841 (Supplementary Table S5) |
| COS-1/COS7, HEK293T, NIH3T3 cells | Cell lines | GTP-loading, PAK binding, cell spreading/roundness | IN_VITRO | 37059841, 35139179, 37328543 |
Gap: no patient-allele knock-in mouse or iPSC/organoid model was identified. A HUMAN_MODEL_MISMATCH discussion would fit here: the microcephaly and neuron-morphology mechanisms rest on zebrafish and Drosophila overexpression rather than human cortical tissue.
| PMID | Citation | Evidence type |
|---|---|---|
| 28886345 | Reijnders MRF et al. RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes. Am J Hum Genet 2017. doi:10.1016/j.ajhg.2017.08.007 | Founding report; human clinical + MODEL_ORGANISM (zebrafish) + IN_VITRO |
| 30042656 | Tian C et al. An Intellectual Disability-Related Missense Mutation in Rac1 Prevents LTP Induction. Front Mol Neurosci 2018 | IN_VITRO / ex vivo |
| 34725860 | Haugh IM et al. Ichthyosiform changes in a patient with RAC1 mutation. Pediatr Dermatol 2021 | Case report |
| 35139179 | Banka S et al. Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology. Brain 2022 | Human clinical + Drosophila + IN_VITRO |
| 37059841 | Priolo M et al. Clinical profiling of MRD48 and functional characterization of two novel pathogenic RAC1 variants. Eur J Hum Genet 2023 | Clinical review with frequencies + IN_VITRO |
| 37328543 | Seyama R et al. A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association. Sci Rep 2023 | Case report + IN_VITRO |
| 39307291 | Nishikawa M et al. Pathophysiological significance of the p.E31G variant in RAC1… Biochim Biophys Acta Mol Basis Dis 2025 | Case report + mouse in utero electroporation |
| 39838818 | Upadia J et al. Diverse Clinical Presentation of RAC1-Related Intellectual Developmental Disorder. Am J Med Genet A 2025 | Case series (abstract only) |
| 42120539 | Althebaiti HO et al. Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1. Eur J Hum Genet 2026 | Human clinical + Drosophila + IN_VITRO (abstract only) |
evidence_source.Checked with linkml-reference-validator 0.3.0rc3.
| Outcome | Count |
|---|---|
| References checked | 9 |
| Resolved | 9 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 9 |
| On topic | 7 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 66 |
| Resolved | 66 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 0 |
| Terms whose name was checked | 15 |
| Terms named correctly | 9 |
| Terms named as a different term | 3 |
| Terms whose name is worth a second look | 3 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0030913 (3 mentions) - the report calls it "MONDO"; MONDO calls it intellectual disability, autosomal dominant 48HP:0001263 (1 mention) - the report calls it "Infancy"; HP calls it Global developmental delayGO:0030027 (1 mention) - the report calls it "Subcellular location: actin cytoskeleton / lamellipodium"; GO calls it lamellipodium**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:0003924 (1 mention) - the report calls it "Molecular function: GTPase activity"; GO calls it GTPase activity**, and lists "tubulin GTPase activity" among its other namesCL:0011020 (1 mention) - the report calls it "Cell types: neural progenitor cell"; CL calls it neural progenitor cell**NCIT:C15240 (1 mention) - the report calls it "Genetic counselling"; NCIT calls it Genetic Counseling