👪

Inheritance

1

Autosomal Dominant HP:0000006

The only reported variant arose de novo in a heterozygous patient with unaffected parents; transmission has not been observed.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:21376300 SUPPORT Human Clinical

"De novo missense mutations were identified in KIF1A (c.296C>T/p.Thr99Met), GRIN1 (c.1984G>A/p.Glu662Lys), EPB41L1 (c.2560C>T/p.Pro854Ser), and CACNG2 (c.427G>C/p.Val143Leu) (Table 2)."

The EPB41L1 variant arose de novo, consistent with a dominant effect of a single heterozygous allele.

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Discussions and Knowledge Gaps

2

Do de novo EPB41L1 variants cause intellectual disability, or was the single reported variant incidental?

KNOWLEDGE GAP mrd11_single_patient

Attached to

genetic#EPB41L1

The association rests on one de novo missense variant found in a candidate-gene screen of 95 patients, supported by cell-culture assays. A targeted screen of 50 further patients found no second de novo EPB41L1 variant, and no replication has been published in PubMed since 2011. Additional patients with de novo EPB41L1 variants from large exome cohorts, ideally with a shared phenotype, would confirm or refute the association.

Why do rodent studies disagree on whether 4.1N is needed for glutamatergic synapse function, and does the patient's C-terminal variant act through the same route?

HUMAN MODEL MISMATCH mrd11_rodent_synapse_mismatch

Attached to

pathophysiology#Impaired Glutamatergic Synapse Function and Plasticity

Acute 4.1N knockdown in 6-week-old mice impairs the maintenance of long-term potentiation, yet 3-week-old mice with 4.1N at 22% of normal have normal transmission and long-term potentiation; the authors of the knockdown study attribute the difference to age and to developmental compensation that acute knockdown avoids. The CA1 null results may also reflect very low 4.1N expression in CA1 pyramidal neurons. In rat dentate gyrus granule neurons, 4.1N knockdown reduces synapses, but the C-terminal domain is dispensable and the FERM domain is needed for synaptic AMPA receptors. If the C-terminal domain is dispensable for the synaptic role, a C-terminal missense variant may act through another 4.1N partner or not be pathogenic. A knock-in model of the patient variant, examined in dentate gyrus as well as CA1, would resolve this.

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Pathophysiology

4

De Novo EPB41L1 p.Pro854Ser Variant

A heterozygous de novo missense variant, c.2560C>T p.(Pro854Ser), at a conserved residue in the C-terminal domain of protein 4.1N, the domain that binds AMPA receptor subunits. Whether the variant acts by partial loss of function or by interfering with the normal allele has not been tested.

Genetic context EPB41L1 hgnc:3378 variant_origin: GERMLINE

ionotropic glutamate receptor binding GO:0035255 ↓ DECREASED

Downstream

Reduced 4.1N Binding to GluA1

Show evidence (1 reference)

PMID:21376300 SUPPORT BACKGROUND In Vitro

"EPB41L1 encodes a neuronal cytoskeletal protein known as 4.1N, which binds to AMPAR subunits through its C-terminal domain and regulates their expression at the synaptic membrane."

Places the variant's domain in the AMPA-receptor-binding region of 4.1N.

Reduced 4.1N Binding to GluA1

Protein 4.1N binds a membrane-proximal region of the GluA1 C-terminus through a consensus sequence in its own C-terminal domain, and associates with GluA1 at excitatory synapses. The patient's variant reduces this binding by about half in transfected cells.

Downstream

Reduced Surface GluA1 AMPA Receptors

Show evidence (1 reference)

PMID:11050113 SUPPORT PRIMARY RESULT Model Organism

"Protein 4.1N also associates with GluR1 in vivo and colocalizes with AMPA receptors in excitatory synapses."

Co-immunoprecipitation from rat brain establishes the normal 4.1N-GluA1 interaction that the variant weakens.

Reduced Surface GluA1 AMPA Receptors

4.1N is required for activity-dependent extrasynaptic insertion of GluA1 into the neuronal plasma membrane, a step that depends on PKC phosphorylation of GluA1 Ser816 and Ser818. Weaker 4.1N binding is expected to lower surface and synaptic GluA1. The patient's variant lowers steady-state surface GluA1 in cultured neurons; its effect on insertion events was not measured.

hippocampal neuron CL:0002608

GluA1 AMPA receptor transport to the neuronal surface GO:0098877 ↓ DECREASED

Experimental models

Hippocampal neurons expressing the patient variant PRIMARY CELL CULTURE Neurons expressing the variant 4.1N insert less GluA1 at the surface.

Downstream

Impaired Glutamatergic Synapse Function and Plasticity Acute 4.1N knockdown in mouse CA1 impairs the maintenance of long-term potentiation with basal transmission unchanged, but this has not been shown for the patient's variant. A 4.1N-hypomorphic mouse has normal long-term potentiation, and in dentate gyrus neurons the C-terminal domain carrying the variant is dispensable for 4.1N's synaptic role.

Show evidence (2 references)

PMID:19503082 SUPPORT In Vitro

"we found that the protein 4.1N was required for activity-dependent GluR1 insertion"

4.1N is required for activity-dependent GluA1 insertion in rodent neurons.

PMID:11050113 SUPPORT PRIMARY RESULT In Vitro

"Disruption of the interaction of GluR1 with 4.1N or disruption of actin filaments decreased the surface expression of GluR1 in heterologous cells."

Breaking the 4.1N-GluA1 interaction lowers surface GluA1.

Impaired Glutamatergic Synapse Function and Plasticity

Impaired maintenance of long-term potentiation at excitatory synapses, the proposed basis for the cognitive phenotype; basal transmission is normal when 4.1N is knocked down in CA1. Separately, 4.1N knockdown reduces synapse number and function in dentate gyrus granule neurons, where the C-terminal domain is dispensable and the FERM domain is needed for synaptic AMPA receptors. A mouse lacking 4.1G with 4.1N at 22% of normal has normal basal transmission and long-term potentiation at 3 weeks.

glutamatergic neuron CL:0000679 dentate gyrus granule cell CL:2000089

long-term synaptic potentiation GO:0060291 ↓ DECREASED

Animal models

4.1G-null 4.1N-hypomorphic mouse Mouse fails to recapitulate Hippocampal glutamatergic transmission and long-term potentiation are normal despite severe loss of 4.1N and 4.1G.

Downstream

Severe Intellectual Disability Proposed link. The step from altered AMPA receptor trafficking to intellectual disability rests on one patient and on cell-culture experiments, and the authors call for replication in larger cohorts.

Show evidence (1 reference)

PMID:37845032 SUPPORT INDIRECT In Vitro

"We discover that reducing 4.1N expression in rat DG granule neurons of either sex results in a significant reduction in glutamatergic synapse function that is caused by a decrease in the number of glutamatergic synapses."

4.1N knockdown in organotypic rat hippocampal slice cultures reduces glutamatergic synapses in dentate gyrus granule neurons.

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Pathograph

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

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Phenotypes

1

Severe Intellectual Disability Neurological HP:0010864

Show evidence (2 references)

PMID:21376300 SUPPORT Human Clinical

"The p.Pro854Ser in EPB41L1 was found in a male with severe ID (Table 3)."

Severe intellectual disability in the single reported patient.

PMID:21376300 SUPPORT Human Clinical

"(2) absence of specific dysmorphic features, as assessed by an experienced clinical geneticist, (3) birth weight and postnatal growth within normal limits, (4) normal head circumference at birth"

Cohort inclusion criteria, which define the phenotype as nonsyndromic.

🧬

Genetic Associations

1

EPB41L1 (Provisional. A single de novo heterozygous missense variant in one patient, with functional effects shown only in cell culture. No second patient has been published, and the authors state that larger cohorts are needed.)

Gene: EPB41L1 hgnc:3378 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:21376300 SUPPORT In Vitro

"Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic."

The functional basis for the association, stated as possible rather than established pathogenicity.

PMID:21376300 SUPPORT Human Clinical

"Although sequencing these genes in larger cohorts is needed to further ascertain their involvement in NSID, genetic and functional evidence argue in favor of this possibility."

The authors' own statement that the association needs replication.

🔬

Variants

1

EPB41L1 c.2560C>T p.(Pro854Ser)

De novo heterozygous missense variant at a conserved residue in the 4.1N C-terminal domain (rat equivalent Pro852). The only published variant.

Show evidence (1 reference)

PMID:21376300 SUPPORT Human Clinical

"Because p.Pro854Ser affects a highly conserved residue in this C-terminal domain, we tested whether it disrupts the interaction of 4.1N with the AMPAR subunit GluR1 in transfected HEK293 cells."

Location of the variant in the conserved C-terminal domain.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

One PubMed-indexed patient, identified among 95 sporadic nonsyndromic intellectual disability cases screened for de novo variants in 197 glutamate-receptor-complex genes; sequencing EPB41L1 in 50 further cases found no second de novo variant.

Show evidence (1 reference)

PMID:21376300 SUPPORT Human Clinical

"The p.Pro854Ser in EPB41L1 was found in a male with severe ID (Table 3)."

The single reported patient.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Intellectual Disability, Autosomal Dominant 11:

20q11.2 microdeletion syndrome

Overlapping Features Proximal 20q11.2 deletions that include EPB41L1 cause a contiguous-gene syndrome with developmental delay, growth retardation, feeding difficulties and facial dysmorphism. EPB41L1 lay in the originally proposed critical region, but a 2024 refinement named GDF5 as the primary candidate gene, so the deletion syndrome does not establish EPB41L1 dosage sensitivity. Chromosomal microarray distinguishes it.

Show evidence (2 references)

PMID:38511524 SUPPORT Human Clinical

"A 1.62 Mb minimal critical region at 20q11.2, encompassing three genes GDF5, EPB41L1, and SAMHD1, is proposed to be responsible for this syndrome."

EPB41L1 lies in the originally proposed critical region.

PMID:38511524 SUPPORT Human Clinical

"We propose GDF5 to be the primary candidate gene generating the phenotype of patients with 20q11.2 deletions."

The refined analysis points to GDF5 rather than EPB41L1.

Other de novo glutamatergic synaptic gene disorders

Overlapping Features Nonsyndromic intellectual disability from de novo variants in other glutamate-receptor-complex genes found in the same screen, including SYNGAP1, STXBP1, SHANK3, GRIN1, CACNG2 and KIF1A. Exome or genome sequencing distinguishes them.

Show evidence (1 reference)

PMID:21376300 SUPPORT Human Clinical

"De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic."

Clinically similar disorders identified in the same cohort.

🧫

Experimental Models

1

Hippocampal neurons expressing the patient variant PRIMARY_CELL_CULTURE

Cultured rat hippocampal neurons co-transfected with GFP-GluA1 and wild-type or Pro852Ser 4.1N (the rat equivalent of human Pro854Ser), with surface GluA1 measured under non-permeabilizing conditions.

Organism

rat NCBITaxon:10116

Publication

PMID:21376300

Pathograph links

Reduced Surface GluA1 AMPA Receptors recapitulates fidelity: moderate observes: cellular Neurons expressing the variant 4.1N insert less GluA1 at the surface.

Limitations: Overexpression in rat neurons in culture, on a background of endogenous wild-type 4.1N; no synaptic physiology was measured.

Show evidence (1 reference)

PMID:21376300 SUPPORT In Vitro

"Moreover, insertion of the AMPAR subunit GluR1 at the synaptic membrane was significantly decreased in transfected hippocampal neurons producing mutant 4.1N when compared to cells producing wild-type 4.1N (Figure 3B)."

The variant's effect measured in the model.

🐁

Animal Models

2

4.1G-null 4.1N-hypomorphic mouse

Mice lacking 4.1G and expressing 4.1N at 22% of wild-type levels, with combined hippocampal 4.1G and 4.1N at 12% of normal.

Species

Mouse

Genotype

Epb41l2 null; Epb41l1 hypomorph (4.1N at 22% of wild type)

Publication

PMID:19225127

Pathograph links

Impaired Glutamatergic Synapse Function and Plasticity fails to recapitulate fidelity: low observes: tissue Hippocampal glutamatergic transmission and long-term potentiation are normal despite severe loss of 4.1N and 4.1G.

Limitations: The mouse reduces total 4.1N rather than carrying the patient's C-terminal missense variant, removes 4.1G as well, and was tested in hippocampal CA1 rather than in dentate gyrus granule neurons, where 4.1N knockdown does affect synapses.

Show evidence (1 reference)

PMID:19225127 SUPPORT Model Organism

"Our study indicates that 4.1G and 4.1N do not have a crucial role in glutamatergic synaptic transmission and the induction and maintenance of long-term plastic changes in synaptic efficacy."

The authors' conclusion that 4.1N and 4.1G are not required for glutamatergic transmission or long-term potentiation.

4.1N knockout mouse

Complete 4.1N knockout mice are born below the expected Mendelian ratio, many die at 3-5 weeks, survivors are small, and they have gonadal atrophy with reduced pituitary secretory granules and loss of GnRH from hypothalamic axons. Cognition was not reported, and the homozygous null genotype does not correspond to the heterozygous patient.

Species

Mouse

Genotype

Epb41l1 -/-

Publication

PMID:33046791

Show evidence (1 reference)

PMID:33046791 SUPPORT Model Organism

"We show that 4.1N-/- mice were born at a significantly reduced Mendelian ratio and exhibited high mortality between 3 to 5 weeks of age."

The whole-animal phenotype of complete 4.1N loss.

{ }

Source YAML

click to show

name: Intellectual Disability, Autosomal Dominant 11
creation_date: "2026-09-28T17:30:00Z"
category: Mendelian
synonyms:
- MRD11
- mental retardation, autosomal dominant 11
- autosomal dominant intellectual disability 11
- autosomal dominant mental retardation 11
- mental retardation, autosomal dominant type 11
- autosomal dominant non-syndromic intellectual disability 11
- EPB41L1 autosomal dominant non-syndromic intellectual disability
- autosomal dominant non-syndromic intellectual disability caused by mutation in EPB41L1
description: >-
  Intellectual disability, autosomal dominant 11 (MRD11) is a provisional
  gene-disease association resting on a single patient: a boy with severe
  nonsyndromic intellectual disability who carries a de novo heterozygous
  missense variant, p.Pro854Ser, in EPB41L1. EPB41L1 encodes protein 4.1N, a
  neuron-enriched FERM-domain adaptor that links membrane receptors to the
  spectrin-actin cytoskeleton and binds the AMPA receptor subunit GluA1
  (GluR1) through its C-terminal domain. In cultured cells the variant halves
  4.1N binding to GluA1 and lowers surface GluA1 in neurons, and acute 4.1N
  knockdown in mouse hippocampus impairs the maintenance of long-term
  potentiation without changing basal transmission. The rodent evidence is not
  consistent, however: 3-week-old mice with 4.1N reduced to about a fifth of
  normal (and no 4.1G) have normal glutamatergic transmission and long-term
  potentiation, and in rat dentate gyrus granule neurons the C-terminal domain
  carrying the patient's variant was dispensable for 4.1N's synaptic role,
  whereas the FERM domain was needed for synaptic AMPA receptors. No second
  patient has been published, so both the gene-disease link and the mechanism
  remain unconfirmed.
parents:
- hereditary disease
- intellectual disability
disease_term:
  preferred_term: intellectual disability, autosomal dominant 11
  term:
    id: MONDO:0013658
    label: intellectual disability, autosomal dominant 11
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The only reported variant arose de novo in a heterozygous patient with
    unaffected parents; transmission has not been observed.
  evidence:
  - reference: PMID:21376300
    reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "De novo missense mutations were identified in KIF1A (c.296C>T/p.Thr99Met), GRIN1 (c.1984G>A/p.Glu662Lys), EPB41L1 (c.2560C>T/p.Pro854Ser), and CACNG2 (c.427G>C/p.Val143Leu) (Table 2)."
    explanation: >-
      The EPB41L1 variant arose de novo, consistent with a dominant effect of
      a single heterozygous allele.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    One PubMed-indexed patient, identified among 95 sporadic nonsyndromic
    intellectual disability cases screened for de novo variants in 197
    glutamate-receptor-complex genes; sequencing EPB41L1 in 50 further cases
    found no second de novo variant.
  evidence:
  - reference: PMID:21376300
    reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.Pro854Ser in EPB41L1 was found in a male with severe ID (Table 3)."
    explanation: >-
      The single reported patient.
pathophysiology:
- name: De Novo EPB41L1 p.Pro854Ser Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous de novo missense variant, c.2560C>T p.(Pro854Ser), at a
    conserved residue in the C-terminal domain of protein 4.1N, the domain
    that binds AMPA receptor subunits. Whether the variant acts by partial
    loss of function or by interfering with the normal allele has not been
    tested.
  genetic_context:
    gene:
      preferred_term: EPB41L1
      term:
        id: hgnc:3378
        label: EPB41L1
    variant_origin: GERMLINE
  molecular_functions:
  - preferred_term: ionotropic glutamate receptor binding
    term:
      id: GO:0035255
      label: ionotropic glutamate receptor binding
    modifier: DECREASED
  downstream:
  - target: Reduced 4.1N Binding to GluA1
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21376300
      reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Coimmunoprecipitation (coIP) studies showed that p.Pro854Ser reduces the binding of 4.1N to GluR1 by 50% in these cells (Figure 3A)."
      explanation: >-
        Co-immunoprecipitation in transfected HEK293 cells shows the variant
        halves 4.1N binding to GluA1.
  evidence:
  - reference: PMID:21376300
    reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "EPB41L1 encodes a neuronal cytoskeletal protein known as 4.1N, which binds to AMPAR subunits through its C-terminal domain and regulates their expression at the synaptic membrane."
    explanation: >-
      Places the variant's domain in the AMPA-receptor-binding region of 4.1N.
- name: Reduced 4.1N Binding to GluA1
  biological_scale: MOLECULAR
  description: >-
    Protein 4.1N binds a membrane-proximal region of the GluA1 C-terminus
    through a consensus sequence in its own C-terminal domain, and associates
    with GluA1 at excitatory synapses. The patient's variant reduces this
    binding by about half in transfected cells.
  downstream:
  - target: Reduced Surface GluA1 AMPA Receptors
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21376300
      reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Moreover, insertion of the AMPAR subunit GluR1 at the synaptic membrane was significantly decreased in transfected hippocampal neurons producing mutant 4.1N when compared to cells producing wild-type 4.1N (Figure 3B)."
      explanation: >-
        In cultured hippocampal neurons expressing the variant, steady-state
        surface GluA1 is reduced.
  evidence:
  - reference: PMID:11050113
    reference_title: "Regulation of AMPA receptor GluR1 subunit surface expression by a 4. 1N-linked actin cytoskeletal association."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Protein 4.1N also associates with GluR1 in vivo and colocalizes with AMPA receptors in excitatory synapses."
    explanation: >-
      Co-immunoprecipitation from rat brain establishes the normal 4.1N-GluA1
      interaction that the variant weakens.
- name: Reduced Surface GluA1 AMPA Receptors
  biological_scale: CELLULAR
  description: >-
    4.1N is required for activity-dependent extrasynaptic insertion of GluA1
    into the neuronal plasma membrane, a step that depends on PKC phosphorylation of
    GluA1 Ser816 and Ser818. Weaker 4.1N binding is expected to lower surface
    and synaptic GluA1. The patient's variant lowers steady-state surface
    GluA1 in cultured neurons; its effect on insertion events was not
    measured.
  biological_processes:
  - preferred_term: GluA1 AMPA receptor transport to the neuronal surface
    term:
      id: GO:0098877
      label: neurotransmitter receptor transport to plasma membrane
    modifier: DECREASED
  cell_types:
  - preferred_term: hippocampal neuron
    term:
      id: CL:0002608
      label: hippocampal neuron
  downstream:
  - target: Impaired Glutamatergic Synapse Function and Plasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acute 4.1N knockdown in mouse CA1 impairs the maintenance of long-term
      potentiation with basal transmission unchanged, but this has not been
      shown for the patient's variant. A 4.1N-hypomorphic mouse has normal
      long-term potentiation, and in dentate gyrus neurons the C-terminal
      domain carrying the variant is dispensable for 4.1N's synaptic role.
    evidence:
    - reference: PMID:19503082
      reference_title: "Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, knocking down 4.1N significantly reduced LTP expression 50–60 minutes after induction (Fig. 8d), without affecting the initial phase (up to 30 minutes after induction) of LTP expression."
      explanation: >-
        Lentiviral 4.1N knockdown in mouse hippocampus impairs the late,
        maintenance phase of long-term potentiation. Indirect because the
        manipulation removes 4.1N rather than introducing the patient variant.
    - reference: PMID:19225127
      reference_title: "The function of glutamatergic synapses is not perturbed by severe knockdown of 4.1N and 4.1G expression."
      supports: REFUTE
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "They show a moderate reduction in synaptosomal expression levels of the AMPA receptor subunit GluR1 at 3 weeks of age, but no change in basic glutamatergic synaptic transmission and long-term potentiation in the hippocampus."
      explanation: >-
        Mice with severely reduced 4.1N and no 4.1G have lower synaptosomal
        GluA1 but normal hippocampal transmission and long-term potentiation
        at 3 weeks, arguing that reduced 4.1N does not by itself impair
        synapse function. Indirect because the mouse is a hypomorph, not the
        patient variant.
    - reference: PMID:37845032
      reference_title: "Protein 4.1N Plays a Cell Type-Specific Role in Hippocampal Glutamatergic Synapse Regulation."
      supports: REFUTE
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "We also find 4.1N's C-terminal domain (CTD) to be nonessential to its role in the regulation of glutamatergic synapses of DG granule neurons."
      explanation: >-
        The patient's variant lies in the C-terminal domain, which this study
        found dispensable for basal synapse function in dentate gyrus granule
        neurons. The study did not test long-term potentiation or GluA1
        insertion.
  evidence:
  - reference: PMID:19503082
    reference_title: "Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found that the protein 4.1N was required for activity-dependent GluR1 insertion"
    explanation: >-
      4.1N is required for activity-dependent GluA1 insertion in rodent
      neurons.
  - reference: PMID:11050113
    reference_title: "Regulation of AMPA receptor GluR1 subunit surface expression by a 4. 1N-linked actin cytoskeletal association."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Disruption of the interaction of GluR1 with 4.1N or disruption of actin filaments decreased the surface expression of GluR1 in heterologous cells."
    explanation: >-
      Breaking the 4.1N-GluA1 interaction lowers surface GluA1.
- name: Impaired Glutamatergic Synapse Function and Plasticity
  biological_scale: CELLULAR
  description: >-
    Impaired maintenance of long-term potentiation at excitatory synapses, the
    proposed basis for the cognitive phenotype; basal transmission is normal
    when 4.1N is knocked down in CA1. Separately, 4.1N knockdown reduces
    synapse number and function in dentate gyrus granule neurons, where the
    C-terminal domain is dispensable and the FERM domain is needed for
    synaptic AMPA receptors. A mouse lacking 4.1G with 4.1N at 22% of normal
    has normal basal transmission and long-term potentiation at 3 weeks.
  biological_processes:
  - preferred_term: long-term synaptic potentiation
    term:
      id: GO:0060291
      label: long-term synaptic potentiation
    modifier: DECREASED
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  - preferred_term: dentate gyrus granule cell
    term:
      id: CL:2000089
      label: dentate gyrus granule cell
  downstream:
  - target: Severe Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed link. The step from altered AMPA receptor trafficking to
      intellectual disability rests on one patient and on cell-culture
      experiments, and the authors call for replication in larger cohorts.
    evidence:
    - reference: PMID:21376300
      reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Abnormal AMPAR trafficking and/or activity has been linked to ID, as outlined below, suggesting a possible mechanism for the potential pathogenicity of these DNMs."
      explanation: >-
        The authors propose AMPA receptor trafficking as the mechanism while
        describing the variants' pathogenicity as potential.
  evidence:
  - reference: PMID:37845032
    reference_title: "Protein 4.1N Plays a Cell Type-Specific Role in Hippocampal Glutamatergic Synapse Regulation."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "We discover that reducing 4.1N expression in rat DG granule neurons of either sex results in a significant reduction in glutamatergic synapse function that is caused by a decrease in the number of glutamatergic synapses."
    explanation: >-
      4.1N knockdown in organotypic rat hippocampal slice cultures reduces
      glutamatergic synapses in dentate gyrus granule neurons.
phenotypes:
- category: Neurological
  name: Severe Intellectual Disability
  description: >-
    Severe intellectual disability without specific dysmorphic features,
    growth abnormality or abnormal head circumference at birth, which were
    exclusion criteria for the cohort. Only one patient is known, so no
    frequency is given.
  phenotype_term:
    preferred_term: Severe intellectual disability
    term:
      id: HP:0010864
      label: Severe intellectual disability
  evidence:
  - reference: PMID:21376300
    reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The p.Pro854Ser in EPB41L1 was found in a male with severe ID (Table 3)."
    explanation: >-
      Severe intellectual disability in the single reported patient.
  - reference: PMID:21376300
    reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(2) absence of specific dysmorphic features, as assessed by an experienced clinical geneticist, (3) birth weight and postnatal growth within normal limits, (4) normal head circumference at birth"
    explanation: >-
      Cohort inclusion criteria, which define the phenotype as nonsyndromic.
genetic:
- name: EPB41L1
  gene_term:
    preferred_term: EPB41L1
    term:
      id: hgnc:3378
      label: EPB41L1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Provisional. A single de novo heterozygous missense variant in one patient,
    with functional effects shown only in cell culture. No second patient has
    been published, and the authors state that larger cohorts are needed.
  evidence:
  - reference: PMID:21376300
    reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic."
    explanation: >-
      The functional basis for the association, stated as possible rather
      than established pathogenicity.
  - reference: PMID:21376300
    reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although sequencing these genes in larger cohorts is needed to further ascertain their involvement in NSID, genetic and functional evidence argue in favor of this possibility."
    explanation: >-
      The authors' own statement that the association needs replication.
variants:
- name: EPB41L1 c.2560C>T p.(Pro854Ser)
  description: >-
    De novo heterozygous missense variant at a conserved residue in the 4.1N
    C-terminal domain (rat equivalent Pro852). The only published variant.
  evidence:
  - reference: PMID:21376300
    reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because p.Pro854Ser affects a highly conserved residue in this C-terminal domain, we tested whether it disrupts the interaction of 4.1N with the AMPAR subunit GluR1 in transfected HEK293 cells."
    explanation: >-
      Location of the variant in the conserved C-terminal domain.
differential_diagnoses:
- name: 20q11.2 microdeletion syndrome
  description: >-
    Proximal 20q11.2 deletions that include EPB41L1 cause a contiguous-gene
    syndrome with developmental delay, growth retardation, feeding
    difficulties and facial dysmorphism. EPB41L1 lay in the originally
    proposed critical region, but a 2024 refinement named GDF5 as the primary
    candidate gene, so the deletion syndrome does not establish EPB41L1
    dosage sensitivity. Chromosomal microarray distinguishes it.
  evidence:
  - reference: PMID:38511524
    reference_title: "Clinical and molecular cytogenetic studies of five new patients with 20q11q12 deletion and review of the literature: Proposition of two critical regions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 1.62 Mb minimal critical region at 20q11.2, encompassing three genes GDF5, EPB41L1, and SAMHD1, is proposed to be responsible for this syndrome."
    explanation: >-
      EPB41L1 lies in the originally proposed critical region.
  - reference: PMID:38511524
    reference_title: "Clinical and molecular cytogenetic studies of five new patients with 20q11q12 deletion and review of the literature: Proposition of two critical regions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose GDF5 to be the primary candidate gene generating the phenotype of patients with 20q11.2 deletions."
    explanation: >-
      The refined analysis points to GDF5 rather than EPB41L1.
- name: Other de novo glutamatergic synaptic gene disorders
  description: >-
    Nonsyndromic intellectual disability from de novo variants in other
    glutamate-receptor-complex genes found in the same screen, including
    SYNGAP1, STXBP1, SHANK3, GRIN1, CACNG2 and KIF1A. Exome or genome
    sequencing distinguishes them.
  evidence:
  - reference: PMID:21376300
    reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic."
    explanation: >-
      Clinically similar disorders identified in the same cohort.
animal_models:
- name: 4.1G-null 4.1N-hypomorphic mouse
  species: Mouse
  genotype: Epb41l2 null; Epb41l1 hypomorph (4.1N at 22% of wild type)
  publication: PMID:19225127
  description: >-
    Mice lacking 4.1G and expressing 4.1N at 22% of wild-type levels, with
    combined hippocampal 4.1G and 4.1N at 12% of normal.
  modeled_mechanisms:
  - target: Impaired Glutamatergic Synapse Function and Plasticity
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Hippocampal glutamatergic transmission and long-term potentiation are
      normal despite severe loss of 4.1N and 4.1G.
    limitations: >-
      The mouse reduces total 4.1N rather than carrying the patient's
      C-terminal missense variant, removes 4.1G as well, and was tested in
      hippocampal CA1 rather than in dentate gyrus granule neurons, where
      4.1N knockdown does affect synapses.
    evidence:
    - reference: PMID:19225127
      reference_title: "The function of glutamatergic synapses is not perturbed by severe knockdown of 4.1N and 4.1G expression."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our study indicates that 4.1G and 4.1N do not have a crucial role in glutamatergic synaptic transmission and the induction and maintenance of long-term plastic changes in synaptic efficacy."
      explanation: >-
        The authors' conclusion that 4.1N and 4.1G are not required for
        glutamatergic transmission or long-term potentiation.
- name: 4.1N knockout mouse
  species: Mouse
  genotype: Epb41l1 -/-
  publication: PMID:33046791
  description: >-
    Complete 4.1N knockout mice are born below the expected Mendelian ratio,
    many die at 3-5 weeks, survivors are small, and they have gonadal atrophy
    with reduced pituitary secretory granules and loss of GnRH from
    hypothalamic axons. Cognition was not reported, and the homozygous null
    genotype does not correspond to the heterozygous patient.
  evidence:
  - reference: PMID:33046791
    reference_title: "Selective effects of protein 4.1N deficiency on neuroendocrine and reproductive systems."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We show that 4.1N-/- mice were born at a significantly reduced Mendelian ratio and exhibited high mortality between 3 to 5 weeks of age."
    explanation: >-
      The whole-animal phenotype of complete 4.1N loss.
experimental_models:
- name: Hippocampal neurons expressing the patient variant
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Cultured rat hippocampal neurons co-transfected with GFP-GluA1 and wild-type
    or Pro852Ser 4.1N (the rat equivalent of human Pro854Ser), with surface
    GluA1 measured under non-permeabilizing conditions.
  publication: PMID:21376300
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  modeled_mechanisms:
  - target: Reduced Surface GluA1 AMPA Receptors
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Neurons expressing the variant 4.1N insert less GluA1 at the surface.
    limitations: >-
      Overexpression in rat neurons in culture, on a background of endogenous
      wild-type 4.1N; no synaptic physiology was measured.
    evidence:
    - reference: PMID:21376300
      reference_title: "Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Moreover, insertion of the AMPAR subunit GluR1 at the synaptic membrane was significantly decreased in transfected hippocampal neurons producing mutant 4.1N when compared to cells producing wild-type 4.1N (Figure 3B)."
      explanation: >-
        The variant's effect measured in the model.
discussions:
- discussion_id: mrd11_single_patient
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#EPB41L1
  prompt: >-
    Do de novo EPB41L1 variants cause intellectual disability, or was the
    single reported variant incidental?
  rationale: >-
    The association rests on one de novo missense variant found in a
    candidate-gene screen of 95 patients, supported by cell-culture assays.
    A targeted screen of 50 further patients found no second de novo EPB41L1
    variant, and no replication has been published in PubMed since 2011. Additional
    patients with de novo EPB41L1 variants from large exome cohorts, ideally
    with a shared phenotype, would confirm or refute the association.
- discussion_id: mrd11_rodent_synapse_mismatch
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Impaired Glutamatergic Synapse Function and Plasticity
  prompt: >-
    Why do rodent studies disagree on whether 4.1N is needed for glutamatergic
    synapse function, and does the patient's C-terminal variant act through
    the same route?
  rationale: >-
    Acute 4.1N knockdown in 6-week-old mice impairs the maintenance of
    long-term potentiation, yet 3-week-old mice with 4.1N at 22% of normal
    have normal transmission and long-term potentiation; the authors of the
    knockdown study attribute the difference to age and to developmental
    compensation that acute knockdown avoids. The CA1 null results may also
    reflect very low 4.1N expression in CA1 pyramidal neurons. In rat dentate gyrus
    granule neurons, 4.1N knockdown reduces synapses, but the C-terminal
    domain is dispensable and the FERM domain is needed for synaptic AMPA
    receptors. If the C-terminal domain is
    dispensable for the synaptic role, a C-terminal missense variant may act
    through another 4.1N partner or not be pathogenic. A knock-in model of
    the patient variant, examined in dentate gyrus as well as CA1, would
    resolve this.
notes: >-
  The gene-disease association is weak. The phenotype rests on one published
  patient (PMID:21376300). As of September 2026, GenCC submitters classify the
  EPB41L1 relationship as Limited (ClinGen gene page, HGNC:3378), and the
  Genomics England PanelApp intellectual disability panel lists the phenotype
  as "?Mental retardation, autosomal dominant 11 614257", using OMIM's
  question-mark notation for a provisional gene-phenotype relationship.

  Hypotonia, absence of seizures and a normal brain MRI are reported for the
  patient in OMIM 602879 but are not stated in the text of the primary paper,
  so they are not curated here. A second de novo missense variant
  (p.Glu619Asp) is reported in a pediatric nephrology case report that is not
  indexed in PubMed; it is unverified and not included.

  No GeneReviews chapter covers MRD11. No disease-specific treatment exists.

📚

References & Deep Research

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: Intellectual_Disability_Autosomal_Dominant_11 · 2026-09-28T17:38:30Z · View source

New entry for MRD11 (MONDO:0013658, EPB41L1), requested by the user and claimed in issue #13094. The association is deliberately curated as provisional: it rests on one patient with a de novo EPB41L1 p.(Pro854Ser) variant (PMID:21376300), GenCC submitters rate it Limited, and PanelApp carries the OMIM '?' provisional notation (both checked on the live sites in September 2026 and recorded in notes with their source). 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: 12/13 identifiers resolved; PMID:25572454 failed to resolve (it exists in PubMed, so this looks like a transport error, but it is not cited), and the report's quote from PMID:11050113 was a paraphrase, so the actual source sentence was used instead. preflight-dr returned WARN only because the report cites the gene MIM 602879 alongside the phenotype MIM 614257 that MONDO cross-references; EPB41L1 dominates the gene mentions (26). Only severe intellectual disability is curated as a phenotype; hypotonia, no seizures and normal MRI are in OMIM but not in the primary paper's text. check-genereviews --online (with synonyms): NO_CHAPTER. A fresh-context red-team review (7 important, 7 minor, no critical findings) led to these changes: the 19503082 LTP evidence was regraded MODEL_ORGANISM (in vivo lentiviral knockdown) and restated as impaired LTP maintenance with basal transmission unchanged, using the late-phase sentence; the synapse node description was narrowed accordingly; the 19225127 and 37845032 REFUTE items were moved from the synapse node onto the surface-GluA1-to-synapse edge, with directness INDIRECT and a note that 37845032 tested basal DG synapses only; the rodent-mismatch discussion now gives the authors' own explanations (age and developmental compensation; very low 4.1N in CA1); the FERM/CTD wording was corrected (CTD dispensable, FERM needed for synaptic AMPA receptors); CL terms were changed to CL:0002608 hippocampal neuron, CL:0000679 glutamatergic neuron and CL:2000089 dentate gyrus granule cell; GO:0072659 was replaced by GO:0098877 neurotransmitter receptor transport to plasma membrane; the variant data are now described as reduced surface GluA1 rather than insertion; the 11050113 in vivo co-IP was regraded MODEL_ORGANISM and its heterologous-disruption sentence added on the surface node; two background sentences were given quote_role BACKGROUND; 'no second variant' became 'no second de novo variant'; and the notes now attribute the GenCC and PanelApp facts to their source and date, with process narration removed and the pLI remark dropped. The reviewer's suggestion to add supportive-care treatments was not taken because no citable source describes care for this patient. Validation: just validate 24/24 snippets; check-entity-refs, check-causal-targets and check-duplicate-keys OK. Stub stubs/Intellectual_Disability_Autosomal_Dominant_11.yaml deleted.

Claude Code ▸

Intellectual Disability, Autosomal Dominant 11 (MRD11; EPB41L1-related): research report

claude-haiku-4-5-20251001, claude-opus-5-5 8 citations 2026-09-28T12:59:01.165950

I've read the cached sources; now I'm pulling the patient phenotype table and checking for any later EPB41L1 case reports.

Found a ClinGen assertion in the local cache; reading it, then writing the report.

Intellectual Disability, Autosomal Dominant 11 (MRD11; EPB41L1-related): research report

Target: Intellectual disability, autosomal dominant 11 · MONDO:0013658 · Mendelian Report date: 2026-09-28

Sourcing. Quotes marked [cached] were read from the full texts or abstracts already fetched into this worktree's references_cache/. Items marked [web] came from search-result snippets that I could not open in full and need checking against the primary source. Ontology CURIEs in this report were not looked up. Treat them as leads and resolve each one with runoak or the term cache before binding it, as the repo's term contract requires.

Summary

The disease rests on one patient. MRD11 is defined by a single de novo missense variant, EPB41L1 c.2560C>T / p.Pro854Ser, found in one boy with severe nonsyndromic intellectual disability (ID) in a candidate-gene screen (Hamdan et al., 2011, PMID:21376300).
The mechanism is inferred from cell culture. The variant halves 4.1N binding to the AMPA receptor subunit GluR1 and lowers GluR1 at the neuronal surface. That fits established 4.1N biology in AMPA receptor trafficking (PMID:11050113, PMID:19503082).
Mouse data point in different directions:
A combined 4.1N/4.1G hypomorph showed no defect in glutamatergic transmission or LTP (PMID:19225127).
Knocking down 4.1N in rat dentate gyrus granule neurons did reduce synapse number and function (PMID:37845032).
The complete 4.1N knockout mouse has a hypothalamic–pituitary–gonadal phenotype and not a reported cognitive one (PMID:33046791).
The gene–disease link is weak. It should be curated as a single-case, limited-evidence association. The one PubMed-indexed human report is the original one. A second de novo missense (p.Glu619Asp), described in a pediatric nephrology report, is not in PubMed and could not be verified.

1. Disease information

Overview. MRD11 is an autosomal dominant, nonsyndromic intellectual developmental disorder caused by a heterozygous (de novo) variant in EPB41L1. EPB41L1 encodes protein 4.1N, a neuron-enriched FERM-domain scaffold that links membrane receptors to the spectrin–actin cytoskeleton.

The index case is described in PMID:21376300 [cached]: "The p.Pro854Ser in EPB41L1 was found in a male with severe ID (Table 3). EPB41L1 encodes a neuronal cytoskeletal protein known as 4.1N, which binds to AMPAR subunits through its C-terminal domain and regulates their expression at the synaptic membrane."

Identifiers

Resource	ID	Note
MONDO	MONDO:0013658	label "intellectual disability, autosomal dominant 11" (confirmed in `cache/mondo/terms.csv`)
OMIM phenotype	614257 (MRD11)	from memory; verify
OMIM gene	602879 (EPB41L1)	Hamdan 2011 cites "EPB4L1 (MIM 602879)" [cached]
Gene locus	20q11.23 [web: OMIM/GeneCards]
Orphanet	No disorder-specific entry is known. MRD11 probably sits under ORPHA:178469 "Autosomal dominant non-syndromic intellectual disability"	verify; a grouping-level class, not an exact match
ICD-10 / ICD-11	F79 / 6A00 (nonspecific ID codes only)	no disease-specific code
MeSH	Intellectual Disability (D008607)	nonspecific

Synonyms: mental retardation, autosomal dominant 11; intellectual developmental disorder, autosomal dominant 11; EPB41L1-related intellectual disability.

Data provenance: a single published proband from a research cohort (French-Canadian nonsyndromic ID cohort, Montreal). No EHR or registry data exist.

2. Etiology

Cause: a heterozygous germline de novo missense variant in EPB41L1. It is the only published variant in PubMed.
The screen that found it [cached, PMID:21376300]: "we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs … De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic."
The authors' own caveat [cached]: "Although sequencing these genes in larger cohorts is needed to further ascertain their involvement in NSID, genetic and functional evidence argue in favor of this possibility." This is the key evidentiary limit for the entry.
Cohort exclusions. The cohort excluded dysmorphic features, abnormal growth, abnormal head circumference at birth, and perinatal or teratogenic risk factors. By design, the phenotype is "pure" ID.
Environmental, protective, and gene–environment factors: none known. Record as not applicable.
Copy-number context. EPB41L1 lies inside the proposed 1.62 Mb minimal critical region of the 20q11.2 microdeletion syndrome, together with GDF5 and SAMHD1 (Jedraszak 2015, PMID:25572454; Bensaid 2024, PMID:38511524). That syndrome is a separate, contiguous-gene disorder (ID, skeletal/brachydactyly and facial features). Its ID has been attributed to EPB41L1 haploinsufficiency as a candidate, not proven. Keep it distinct from MRD11, or cite it only as indirect support for dosage sensitivity.

3. Phenotypes

Only one proband is described, so every frequency is 1/1. Use SOURCE_UNSPECIFIED caution and do not state population frequencies.

Phenotype	Details	Source	HPO lead (verify)
Severe intellectual disability	male; "severe ID"	PMID:21376300 [cached]	HP:0010864 Intellectual disability, severe
Global developmental delay	implied by the childhood ID diagnosis made on standardized tests	PMID:21376300 (cohort definition)	HP:0001263
Hypotonia	reported in the OMIM clinical synopsis	[web: OMIM 602879] "The patient had hypotonia, no evidence of epilepsy, and normal brain imaging by MRI"	HP:0001252 Hypotonia
Absent seizures	negative finding	[web: OMIM]	record in `notes`, do not add as a phenotype
Normal brain MRI	negative finding	[web: OMIM]	as above
Nonsyndromic: no dysmorphism, normal growth, normal OFC at birth	cohort inclusion criteria	PMID:21376300 [cached]	n/a

Ages. OMIM describes the patient as a 6-year-old boy [web].

Caution about the MRI footnote. The Hamdan Table 3 footnotes "Mild atrophy of the vermian region of the cerebellum on the MRI" and the "ADOS not suggestive of autism at 15 years" refer to other probands in that table. The EPB41L1 patient was about 6 years old with a normal MRI. Do not attach those footnotes to MRD11.

Onset and course: onset in infancy or childhood (developmental); non-progressive, as expected for a neurodevelopmental disorder; lifelong. No quality-of-life data exist.

4. Genetic and molecular information

Gene: EPB41L1 (erythrocyte membrane protein band 4.1 like 1); protein 4.1N (UniProt Q9H4G0). The HGNC ID is believed to be hgnc:3378; verify against cache/hgnc/terms.csv and use the lowercase hgnc: prefix.
Protein structure: "The 879 amino acid protein shares 70, 36, and 46% identity with 4.1R in the defined membrane-binding, spectrin-actin-binding, and C-terminal domains" (PMID:10414974 [cached]). The domains are FERM, SAB (spectrin-actin-binding) and CTD (C-terminal domain), separated by the unique regions U1–U3 (PMID:34589518 [cached]).

Pathogenic variant

Field	Value
Variant	c.2560C>T / p.Pro854Ser, in the C-terminal domain. Transcript not stated in the paper; OMIM uses NM_012156
Origin	germline, de novo, heterozygous
Type	missense
Classification	functionally damaging in vitro; no ClinVar or ClinGen classification verified here
Predicted effect	reduced GluR1 binding, i.e. hypomorphic / partial loss of function; dominant negative has not been tested

Primary finding [cached, PMID:21376300]: "Coimmunoprecipitation (coIP) studies showed that p.Pro854Ser reduces the binding of 4.1N to GluR1 by 50% in these cells … insertion of the AMPAR subunit GluR1 at the synaptic membrane was significantly decreased in transfected hippocampal neurons producing mutant 4.1N."
Other variants:
p.Glu619Asp (c.1857G>C, NM_012156.2), de novo, is reported in an Asian Journal of Pediatric Nephrology case, "Kidney Involvement in EPB41L1-associated MRD11" (about 2024). It is not PubMed-indexed and the full text is paywalled (HTTP 402). Unverified; do not cite until fetched.
No population allele frequency for p.Pro854Ser is reported in the source.
Gene–disease validity: not confirmed. No ClinGen CGGV: assertion for EPB41L1 exists in the local cache (a grep hit turned out to be RAB7A). With one proband, a curation would most plausibly be Limited.
Modifier genes, epigenetics, chromosomal abnormalities: none known, apart from the 20q11.2 deletion context described in section 2.

5. Environmental information

None known: no environmental, lifestyle or infectious factors. Not applicable.

6. Mechanism and pathophysiology

Ordered causal chain. Steps 1–3 are shown for the variant in vitro; steps 4–6 are inferred.

Initiating lesion. A heterozygous de novo EPB41L1 p.Pro854Ser variant changes a conserved residue in the 4.1N C-terminal domain. [human genetic; PMID:21376300]
Loss of GluR1 binding. This roughly halves 4.1N binding to the AMPA receptor GluR1 C-terminus. [in vitro, HEK293 co-IP; PMID:21376300] In normal biology, the 4.1N CTD binds a membrane-proximal region of the GluR1 C-terminus and links AMPA receptors to actin: "4.1N can associate with GluR1 in vivo and colocalizes with AMPA receptors at excitatory synapses. Disruption of the interaction … decreased the surface expression of GluR1" (PMID:11050113 [cached]).
Reduced surface GluR1. Impaired binding reduces activity-dependent insertion of GluR1 into the plasma membrane, lowering surface and synaptic GluR1. [in vitro, cultured hippocampal neurons; PMID:21376300] The normal step, from PMID:19503082 [cached]: "the protein 4.1N was required for activity-dependent GluR1 insertion. Protein kinase C (PKC) phosphorylation of the serine 816 (S816) and S818 residues of GluR1 enhanced 4.1N binding to GluR1 … disrupting 4.1N-dependent GluR1 insertion decreased surface expression of GluR1 and the expression of long-term potentiation."
Weaker excitatory transmission and plasticity. This leads to weakened AMPA-receptor-mediated excitatory transmission and impaired LTP. [inferred for the variant; shown for 4.1N disruption in rodent neurons]
Branch, cell-type specificity: "reducing 4.1N expression in rat DG granule neurons … results in a significant reduction in glutamatergic synapse function that is caused by a decrease in the number of glutamatergic synapses … reduction of 4.1N expression in hippocampal CA1 pyramidal neurons has no impact on basal glutamatergic neurotransmission." The FERM domain, not the CTD, was essential there (PMID:37845032 [cached]). This partly conflicts with the CTD-centred variant model, so record it as a caveat.
Contrary evidence: mice lacking 4.1G with 4.1N at 22% of wild type showed "no change in basic glutamatergic synaptic transmission and long-term potentiation in the hippocampus" (PMID:19225127 [cached]). Record this as a REFUTE or HUMAN_MODEL_MISMATCH discussion.
Circuit dysfunction. Impaired synaptic plasticity and excitatory synapse maintenance in hippocampal and cortical circuits lead to defective learning and memory circuit development. [inferred]
Clinical outcome: severe intellectual disability and developmental delay. [human, single case]

Other 4.1N partners that could contribute (speculative). The review PMID:34589518 [cached] lists GluK1–3 kainate receptors, mGluR8, KCC2, IP3R1, D2/D3 receptors, CASK, βII-spectrin and others. None is linked to the variant.

Mechanistic leads (GO and CL terms need lookup) - AMPA receptor trafficking / neurotransmitter receptor localization to the postsynaptic membrane: search GO "neurotransmitter receptor transport to postsynaptic membrane" and "regulation of AMPA receptor activity". - Long-term synaptic potentiation (GO:0060291). - Actin cytoskeleton organization (GO:0030036). - Protein localization to plasma membrane (GO:0072659). - Cell types: excitatory neuron / hippocampal neuron; dentate gyrus granule cell (search CL "granule cell"); CL:0000540 neuron. - Suggested biological_scale tags: MOLECULAR for the binding loss, CELLULAR for the trafficking defect, TISSUE/ORGANISM for circuit and cognition. - Candidate module: check just list-modules synap for an existing glutamatergic synaptopathy module before creating one.

Omics: no transcriptomic, proteomic, metabolomic or single-cell data specific to MRD11.

7. Anatomical structures

Organ and system: brain; central nervous system (UBERON:0000955 brain).
Regions: hippocampus, especially dentate gyrus (UBERON:0001885, verify) and cerebral cortex, based on 4.1N expression and function, not human pathology.
Normal expression [cached, PMID:10414974]: "4.1N is expressed in almost all central and peripheral neurons … detected in embryonic neurons at the earliest stage of postmitotic differentiation." It shows punctate synaptic staining in cerebellar and dentate granule layers.
Subcellular: postsynaptic density and postsynaptic membrane of excitatory synapses; cortical actin cytoskeleton. It colocalizes with PSD-95 and GluR1 (PMID:10414974). GO CC leads: postsynaptic density (GO:0014069), cortical actin cytoskeleton (GO:0030864).
Kidney involvement: raised only by the unverified AJPN report. Do not curate without the source.

8. Temporal development

Onset: congenital or neurodevelopmental, recognised in early childhood.
Course: static and lifelong. No stages, remission, natural-history or critical-period data exist.

9. Inheritance and population

Inheritance: autosomal dominant (HP:0000006), de novo in the reported case. Recurrence risk is low apart from germline mosaicism, which has not been assessed.
Penetrance and expressivity: unknown, since n = 1.
Prevalence: unknown. Use measure_type: CASES_IN_LITERATURE, roughly 1 in PubMed, or 2 if the AJPN case is verified.
Sex: the index case is male. No founder effect, anticipation or ethnic predilection is known; the index cohort was mostly French-Canadian.

10. Diagnostics

Genetic testing: exome or genome sequencing, or an ID gene panel, with trio analysis to establish de novo status. EPB41L1 is on some ID panels (see GTR gene 2036).
Chromosomal microarray: first tier, to exclude 20q11.2 deletions that include EPB41L1.
Other tests: no biomarkers or specific laboratory, imaging or EEG findings. The index MRI and seizure history were normal [web: OMIM].
Differential diagnosis: other glutamatergic nonsyndromic ID genes from the same screen (SYNGAP1, GRIN1, CACNG2/MRD10, SHANK3, STXBP1, KIF1A); the 20q11.2 microdeletion syndrome; EPB41L3-related disorders, which are biallelic with seizures and myelination defects (Brain 2024, doi:10.1093/brain/awae299). The last are a paralog disorder, not the same disease.
Screening: none.

11. Outcome and prognosis

No data on survival, life expectancy or complications. Expected lifelong severe cognitive disability; the index case had no epilepsy.

12. Treatment

No disease-specific or experimental therapy, and no clinical trials (none found on ClinicalTrials.gov). Care is supportive. NCIT leads to verify: - Supportive Care (NCIT:C15747) - Rehabilitation (NCIT:C15315) - Physical Therapy (NCIT:C15302), for hypotonia - Speech Language Therapy (NCIT:C159273) - Occupational Therapy (NCIT:C121351) - Genetic Counseling (NCIT:C15240)

These are all generic; mark therapeutic_modality: BEHAVIORAL where appropriate.

13. Prevention

No primary prevention. Genetic counseling is the main measure: for a de novo case, low recurrence risk with a small mosaicism caveat. Prenatal or preimplantation testing is possible once a familial variant is known. No screening programs exist.

14. Other species

No naturally occurring disease is recorded in OMIA. The EPB41L1 ortholog is conserved in vertebrates, including mouse Epb41l1 (MGI) and rat.

15. Model organisms

Model	Key finding	Recapitulation	Source
4.1N⁻/⁻ mouse (Epb41l1 KO)	"born at a significantly reduced Mendelian ratio and exhibited high mortality between 3 to 5 weeks of age"; small; gonadal atrophy; reduced pituitary secretory granules; GnRH absent from hypothalamic axons	Does not model ID: homozygous null, cognition not reported. Suggested link: `FAILS_TO_RECAPITULATE` or `PARTIALLY_RECAPITULATES` with `SPECIES_MISMATCH` and `POPULATION_MISMATCH` (null vs heterozygous missense) caveats	PMID:33046791 [cached]
4.1G-null / 4.1N-hypomorph mouse (22% 4.1N)	Moderate reduction in synaptosomal GluR1 at 3 weeks; normal basal transmission and LTP	Negative for the synaptic mechanism; candidate `HUMAN_MODEL_MISMATCH`	PMID:19225127 [cached]
Rat DG granule neuron 4.1N knockdown	Fewer glutamatergic synapses and weaker AMPA receptor function; CA1 unaffected	Partial support for the mechanism (`PERTURBS`, CELLULAR scale)	PMID:37845032 [cached]
Cultured hippocampal neurons, rat 4.1N-P852S (equivalent to human P854S)	Reduced surface GluR1	Direct variant model (IN_VITRO)	PMID:21376300 [cached]
Hippocampal neurons, 4.1N disruption	Required for activity-dependent GluR1 insertion and LTP	Mechanistic (IN_VITRO / ex vivo)	PMID:19503082 [cached]

No knock-in mouse carrying the patient variant has been reported. Only generic resources apply (MGI, IMPC).

Curation cautions for the KB entry

Single-proband disease. Every phenotype is n = 1, so state frequencies as 1/1 or omit them. Consider a KNOWLEDGE_GAP discussion on replication.
Evidence-source classification:
Hamdan co-IP and neuron experiments: IN_VITRO.
Proband phenotype: HUMAN_CLINICAL.
Mouse papers: MODEL_ORGANISM.
Split Hamdan into separate evidence items for each source.
Conflicting mouse evidence. The PMID:19225127 negative result and the PMID:37845032 finding that the FERM domain, not the CTD, is essential in dentate gyrus neurons should be recorded, not dropped.
Hypotonia, normal MRI and no seizures currently rest on OMIM, not a quotable abstract. Look for the text in Hamdan Table 3 (the table body is not in the cache) before binding HP:0001252.
Do not cite the p.Glu619Asp nephrology report until its full text has been obtained.

Sources

Hamdan FF et al. Am J Hum Genet 2011. PMID:21376300. https://doi.org/10.1016/j.ajhg.2011.02.001
Walensky LD et al. J Neurosci 1999. PMID:10414974
Shen L et al. J Neurosci 2000. PMID:11050113
Lin DT et al. Nat Neurosci 2009. PMID:19503082
Wozny C et al. J Cell Sci 2009. PMID:19225127
Wang H et al. Sci Rep 2020. PMID:33046791
Yang Q et al. Front Mol Biosci 2021 (review). PMID:34589518
Pushkin AN et al. J Neurosci 2023. PMID:37845032
Jedraszak G et al. Am J Med Genet A 2015. PMID:25572454
Bensaid S et al. Am J Med Genet A 2024. PMID:38511524
OMIM 602879 – EPB41L1
MalaCards – MRD11
GeneCards – EPB41L1
NCBI GTR – EPB41L1
Kidney involvement in EPB41L1-associated MRD11 (AJPN; unverified, paywalled)
Biallelic EPB41L3 variants, Brain 2024 (paralog differential)
ClinGen gene-validity search

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	13
Resolved	12
Unresolved (possible confabulation)	1
Unverifiable	0
Quoted claims checked	3
Quoted claims found in source	2
Quoted claims not found in source	1
References weighed for topical relevance	12
On topic	8
Off topic	0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

PMID:25572454 (2 mentions) - Identifier did not resolve to a record

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

PMID:11050113: "4.1N can associate with GluR1 in vivo and colocalizes with AMPA receptors at excitatory synapses. Disruption of the interaction … decreased the surface expression of GluR1"
closest text in source: "Protein 4.1N also associates with GluR1 in vivo and colocalizes with AMPA receptors in excitatory synapses"

Term Validation

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

Outcome	Count
Terms checked	20
Resolved	19
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	11
Terms named correctly	10
Terms named as a different term	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:

MONDO:0013658 (2 mentions) - the report calls it "MONDO"; MONDO calls it intellectual disability, autosomal dominant 11

Prefixes with no resolver

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

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Inheritance

Discussions and Knowledge Gaps

Pathophysiology

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Phenotypes

Genetic Associations

Variants

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

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References & Deep Research

Deep Research

Intellectual Disability, Autosomal Dominant 11 (MRD11; EPB41L1-related): research report

Summary

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species

15. Model organisms

Curation cautions for the KB entry

Sources

Reference Validation

Unresolved references

Quotes not found in the cited source

Term Validation

Terms the report names something else

Prefixes with no resolver