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

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.

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

• 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.

1. 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]
2. 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]).
3. 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."
4. 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]
5. 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.
6. 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.
7. Circuit dysfunction. Impaired synaptic plasticity and excitatory synapse maintenance in hippocampal and cortical circuits lead to defective learning and memory circuit development. [inferred]
8. 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

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

Curation cautions for the KB entry

1. Single-proband disease. Every phenotype is n = 1, so state frequencies as 1/1 or omit them. Consider a KNOWLEDGE_GAP discussion on replication.
2. Evidence-source classification:
3. Hamdan co-IP and neuron experiments: IN_VITRO.
4. Proband phenotype: HUMAN_CLINICAL.
5. Mouse papers: MODEL_ORGANISM.
6. Split Hamdan into separate evidence items for each source.
7. 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.
8. 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.
9. 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.

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.

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.