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Inheritance

1

Autosomal recessive HP:0000007

All four reported individuals carry biallelic TM2D3 variants, and three of them carry the recurrent c.503G>A (p.Gly168Asp) allele.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families with overlapping clinical presentations"

Biallelic variants in every affected individual, across four unrelated families.

◈

Mechanistic Hypotheses

1

Loss of TM2D3 reduces Notch receptor surface presentation and so Notch signaling during development

tm2d3_notch_surface_presentation EMERGING

Evidence balance 1 support

TM2D3 is the mammalian orthologue of Drosophila almondex, a neurogenic gene whose loss disrupts Notch-mediated lateral inhibition, and TM2D3 promotes surface expression of Notch1. Notch signaling is required for neural, cardiac and renal development, so reduced Notch signaling is a plausible contributor to the multi-organ malformations. The support comes entirely from fly genetics and mouse cultured cells. Notch activity has not been measured in patient cells, and the defining clinical report attributes the disease to ER dysfunction instead. Edges in this group opt in via hypothesis_groups.

Pathograph links

TM2D3 Biallelic Loss of Function -> Reduced Notch Receptor Surface Presentation DIRECT

Show evidence (1 reference)

PMID:38016980 SUPPORT In Vitro

"These results indicate that TM2D3 is an element involved in Notch signaling through the surface presentation."

The authors' conclusion tying TM2D3 to Notch signaling through receptor surface presentation.

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Discussions and Knowledge Gaps

1

Do the malformations of neurocardiorenal malformation syndrome arise from the ER-stress defect seen in patient fibroblasts, from reduced Notch signaling, or from both?

KNOWLEDGE GAP OPEN ncrms_er_versus_notch_mechanism

Attached to

pathophysiology#Dysregulated Endoplasmic Reticulum Stress Response pathophysiology#Reduced Notch Receptor Surface Presentation

The two literatures on TM2D3 have not met. The disease report measured ER stress, ultrastructure and transcription in patient fibroblasts and does not report Notch activity in its abstract. The Notch work used mouse null cells and flies and has no patient material. Notch receptors are themselves transmembrane proteins that pass through the ER, so the two explanations may be one, with reduced surface presentation a consequence of the ER defect, but that has not been tested. For this reason each phenotype is linked only to the TM2D3 genotype, with unknown intermediate steps, and not to either mechanism.

Proposed experiments

Notch surface presentation and target-gene expression in patient cells

ncrms_patient_cell_notch_surface

Measure surface Notch1 and Notch2 and HES/HEY target expression in p.Gly168Asp patient fibroblasts or iPSC-derived neural progenitors against parental controls, with and without ER-stress induction.

Readouts

Surface Notch1 in patient cells

pathophysiology#Reduced Notch Receptor Surface Presentation

Direction: DECREASED

Interpretation: A reduction in patient cells would carry the mouse finding into the human disease; no change would argue that the ER defect acts through other cargo.

⚙

Pathophysiology

6

TM2D3 Biallelic Loss of Function

Biallelic TM2D3 variants, including the recurrent missense allele c.503G>A (p.Gly168Asp). TM2D3 is a transmembrane protein expressed in many tissues and most abundant in the central nervous system, and in SNB75 cells it localizes to the endoplasmic reticulum. Loss of function is inferred from the similarity of patient fibroblasts to TM2D3-knockout cells. The missense alleles may be hypomorphic rather than null; that distinction is not resolved in the abstract. The bound molecular function, Notch binding, is the only activity shown experimentally for TM2D3: the wild-type protein physically associates with Notch1. That the disease alleles reduce it is inferred from the node, not measured. GO's other function annotation for TM2D3, G protein-coupled receptor activity, rests on phylogenetic inference alone and is not bound.

Loss of TM2D3 reduces Notch receptor surface presentation and so Notch signaling during development

TM2D3 hgnc:24128

Genetic context TM2D3 hgnc:24128 allele_type: missense, nonsense, frameshift and intragenic deletion alleles in trans variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Notch1 binding GO:0005112 ↓ DECREASED

endoplasmic reticulum GO:0005783

Downstream

Dysregulated Endoplasmic Reticulum Stress Response

Altered Extracellular Matrix Gene Expression

Microcephaly Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this feature; which mechanism produces it is not established.

Severe global developmental delay Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this feature; which mechanism produces it is not established.

Absent speech Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this feature; which mechanism produces it is not established.

Autistic features Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this feature; which mechanism produces it is not established.

Heart malformation Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this feature; which mechanism produces it is not established.

Dysmorphic facial features Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this feature; which mechanism produces it is not established.

Reduced Notch Receptor Surface Presentation

Show evidence (3 references)

PMID:40449487 SUPPORT In Vitro

"Here, by using chemical and genetically encoded probes in SNB75 cells, we show that TM2D3 is an endoplasmic reticulum (ER) protein."

Places the protein in the ER, the compartment whose dysfunction the downstream nodes describe.

PMID:38016980 SUPPORT INDIRECT In Vitro

"TM2D3 physically associates with Notch1 at the region distinct from the ligand-binding domain and enhances expression of Notch1 on the cell surface."

Source for the Notch binding activity bound on this node. INDIRECT because it shows the wild-type protein binds Notch1, not that the disease alleles lose that binding.

PMID:40449487 SUPPORT BACKGROUND Other

"TM2D3 encodes a transmembrane protein present in many tissues, with a higher abundance in the central nervous system"

Tissue distribution, consistent with a multi-organ syndrome dominated by neurodevelopmental features. BACKGROUND because the paper restates known expression data rather than reporting a new measurement.

Dysregulated Endoplasmic Reticulum Stress Response

TM2D3-knockout cells and fibroblasts from individuals carrying p.Gly168Asp show dysregulated expression of the ER-stress and unfolded-protein-response genes ATF4, HSPA5 (BiP) and DDIT3 (CHOP). The authors summarize this as exacerbated sensitivity to ER stress.

skin fibroblast CL:0002620

response to endoplasmic reticulum stress GO:0034976 ↕ DYSREGULATED

Downstream

Endoplasmic Reticulum Swelling

Show evidence (1 reference)

PMID:40449487 SUPPORT In Vitro

"revealed an impact of TM2D3 on ER-stress response, with dysregulated expression of ATF4, HSPA5, and DDIT3"

The ER-stress readouts measured in knockout and patient cells.

Endoplasmic Reticulum Swelling

Transmission electron microscopy shows swollen ER. The ordering between the stress response and the structural change is not established, so the edge from the stress node carries an UNKNOWN link type.

skin fibroblast CL:0002620

endoplasmic reticulum organization GO:0007029 ⚠ ABNORMAL

Downstream

Secondary Mitochondrial Ultrastructural Alterations

Show evidence (1 reference)

PMID:40449487 SUPPORT In Vitro

"Transmission electron microscopy highlighted ER swelling"

The ultrastructural ER finding.

Secondary Mitochondrial Ultrastructural Alterations

Elongated mitochondria with widened cristae and increased ER-mitochondria distance. These changes are described as secondary to the ER defect, and their functional consequence is not stated in the abstract.

skin fibroblast CL:0002620

mitochondrion organization GO:0007005 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:40449487 SUPPORT In Vitro

"unexpected secondary mitochondrial alterations including increased length, cristae width, and ER-mitochondria distance"

The specific mitochondrial changes observed.

Altered Extracellular Matrix Gene Expression

RNA sequencing of fibroblasts from the three p.Gly168Asp individuals against four parents found 21 differentially expressed genes, including extracellular matrix genes involved in the migration of neuronal precursors. This is a transcriptional signal in fibroblasts. It has not been shown in neural tissue, and the connection to the neurodevelopmental phenotype is the authors' interpretation rather than a tested step, so no edge to a phenotype is drawn.

skin fibroblast CL:0002620

extracellular matrix GO:0031012

Show evidence (1 reference)

PMID:40449487 SUPPORT In Vitro

"disclosed 21 differentially expressed genes, including genes coding for extracellular matrix components involved in the migration of neuronal precursors"

The transcriptomic finding in patient fibroblasts.

Reduced Notch Receptor Surface Presentation

TM2D3 binds Notch1 outside its ligand-binding domain and increases Notch1 at the cell surface, which is a prerequisite for ligand-induced endocytosis and activating cleavage. Tm2d3-null mouse embryonic fibroblasts show less full-length and S1-processed Notch1 and less surface Notch1 and Notch2. In Drosophila, loss of the orthologue almondex impairs endocytosis of the Notch extracellular domain and Delta in early embryos. None of this has been examined in patient cells.

embryonic fibroblast CL:2000042

protein localization to plasma membrane GO:0072659 ↓ DECREASED Notch signaling pathway GO:0007219 ↓ DECREASED

Animal models

almondex loss-of-function Drosophila Drosophila melanogaster partially recapitulates The neurogenic phenotype and impaired Notch extracellular domain and Delta endocytosis read out the Notch defect directly.

Show evidence (3 references)

PMID:38016980 SUPPORT In Vitro

"TM2D3 physically associates with Notch1 at the region distinct from the ligand-binding domain and enhances expression of Notch1 on the cell surface."

The molecular interaction and its effect on surface Notch1.

PMID:38016980 SUPPORT Model Organism

"Finally, amx-deficient Drosophila early embryos exhibit impaired endocytosis of NECD and Delta ligand, for which surface presentation of Notch is required."

In vivo counterpart in the fly embryo.

PMID:34905536 SUPPORT Model Organism

"We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect."

The neurogenic phenotype is the classical readout of failed Notch-mediated lateral inhibition, and all three TM2D genes share it.

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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

6

Cardiovascular 1

Heart malformation Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"

Heart malformation is a shared feature; the abstract does not name the lesion.

Head and Neck 2

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"

Listed among the shared features of the four affected individuals.

Dysmorphic facial features Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"

Dysmorphic facial features are a shared feature.

Nervous System 3

Severe global developmental delay HP:0011344

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"

Severe global developmental delay is a shared feature.

Absent speech HP:0001344

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"severe global developmental delay with absent speech"

Absent speech accompanies the developmental delay.

Autistic features Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"

Autistic features are a shared feature.

🧬

Genetic Associations

1

TM2D3

Gene: TM2D3 hgnc:24128 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"these clinical and experimental data show that bi-allelic TM2D3 variants underlie a severe syndromic neurodevelopmental disorder"

The gene-disease conclusion of the defining report.

Variants (1)

c.503G>A (p.Gly168Asp) recurrent variant

Gene: TM2D3 hgnc:24128 missense variant

Missense allele carried by three of the four reported individuals, and the allele whose patient fibroblasts were used for the ER-stress, ultrastructure and RNA-sequencing work. The abstract does not give its clinical-significance classification, so none is recorded.

Show evidence (1 reference)

PMID:40449487 SUPPORT In Vitro

"skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele"

Names the variant and states that it recurs across affected individuals. Graded IN_VITRO because the abstract mentions the allele only within its description of the fibroblast experiments, and the same sentence is graded that way elsewhere in this entry.

🗃️

External Assertions

1

OMIM neurocardiorenal malformation syndrome record

OMIM disease record OMIM:621379

The OMIM phenotype record cross-referenced by MONDO:0980704. Its MedGen definition describes an autosomal recessive severe neurodevelopmental disorder with microcephaly, distinctive facial features, and cardiac and renal malformations, citing Gabillard-Lefort et al. (2025).

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"these clinical and experimental data show that bi-allelic TM2D3 variants underlie a severe syndromic neurodevelopmental disorder"

The report on which the OMIM record rests.

🔬

Diagnosis

1

Exome sequencing

All four families were diagnosed by exome sequencing in the setting of a severe syndromic neurodevelopmental disorder.

exome sequencing NCIT:C101295

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families"

The diagnostic method used for every reported case.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Four individuals from four unrelated families in a single 2025 report; no rate exists.

Show evidence (1 reference)

PMID:40449487 SUPPORT Human Clinical

"We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families"

The whole published case series.

🐁

Animal Models

1

almondex loss-of-function Drosophila

Embryos from amx-null mothers have the maternal-effect neurogenic phenotype of failed Notch signaling. Adult amx loss shortens lifespan, with progressive motor and electrophysiological defects.

Species

Drosophila melanogaster

Genotype

amx null (and triple TM2D knockout)

Publication

PMID:34905536

Pathograph links

Reduced Notch Receptor Surface Presentation partially recapitulates fidelity: low observes: cellular The neurogenic phenotype and impaired Notch extracellular domain and Delta endocytosis read out the Notch defect directly.

Limitations: The fly phenotype is maternal-effect, arising in the early embryo, which has no counterpart in a recessive human disorder caused by zygotic loss. The model is a null, whereas the recurrent human allele is missense. PMID:34905536 reports no fly phenotype corresponding to the human cardiac or renal malformations or to microcephaly, and does not examine the ER and mitochondrial findings of the human disease.

Show evidence (1 reference)

PMID:34905536 SUPPORT Model Organism

"We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect."

The loss-of-function fly shows the neurogenic phenotype that reads out failed Notch signaling, which is what this link claims.

{ }

Source YAML

click to show

name: Neurocardiorenal Malformation Syndrome
category: Mendelian
creation_date: "2026-10-14T17:36:29Z"
synonyms:
- NCRMS
- TM2D3-related neurodevelopmental disorder
description: >-
  Neurocardiorenal malformation syndrome is an autosomal recessive syndromic
  neurodevelopmental disorder caused by biallelic variants in TM2D3, which encodes a
  transmembrane protein of the conserved TM2 domain family. The defining report describes
  four affected individuals from four unrelated families with microcephaly, severe global
  developmental delay with absent speech, autistic features, heart malformation and
  dysmorphic facial features. The OMIM synopsis of the same report adds renal
  malformations, which is where the name comes from.

  Two mechanistic strands are recorded, and they rest on different kinds of evidence. The
  one demonstrated in patient material is endoplasmic reticulum (ER) dysfunction: TM2D3 is an
  ER protein, and patient fibroblasts and TM2D3-knockout cells show a dysregulated ER-stress
  response, ER swelling, secondary mitochondrial ultrastructural changes, and altered
  expression of extracellular matrix genes. The second strand is Notch signaling. The fly
  orthologue almondex is a classical maternal-effect neurogenic gene required for Notch
  signaling, and Tm2d3-deficient mouse cells present less Notch1 and Notch2 at the cell
  surface. Whether reduced Notch signaling contributes to the human malformations has not
  been tested in patients, so it is carried as an emerging hypothesis rather than as the
  disease mechanism.
disease_term:
  preferred_term: neurocardiorenal malformation syndrome
  term:
    id: MONDO:0980704
    label: neurocardiorenal malformation syndrome
references:
- reference: PMID:40449487
  title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
- reference: PMID:38016980
  title: "TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors."
- reference: PMID:34905536
  title: "TM2D genes regulate Notch signaling and neuronal function in Drosophila."
- reference: PMID:27764101
  title: "Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease."
inheritance:
- name: Autosomal recessive
  description: >-
    All four reported individuals carry biallelic TM2D3 variants, and three of them carry the
    recurrent c.503G>A (p.Gly168Asp) allele.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families with overlapping clinical presentations"
    explanation: Biallelic variants in every affected individual, across four unrelated families.
mechanistic_hypotheses:
- hypothesis_group_id: tm2d3_notch_surface_presentation
  hypothesis_label: >-
    Loss of TM2D3 reduces Notch receptor surface presentation and so Notch signaling during
    development
  status: EMERGING
  description: >-
    TM2D3 is the mammalian orthologue of Drosophila almondex, a neurogenic gene whose loss
    disrupts Notch-mediated lateral inhibition, and TM2D3 promotes surface expression of
    Notch1. Notch signaling is required for neural, cardiac and renal development, so reduced
    Notch signaling is a plausible contributor to the multi-organ malformations. The support
    comes entirely from fly genetics and mouse cultured cells. Notch activity has not been
    measured in patient cells, and the defining clinical report attributes the disease to ER
    dysfunction instead. Edges in this group opt in via hypothesis_groups.
  evidence:
  - reference: PMID:38016980
    reference_title: "TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results indicate that TM2D3 is an element involved in Notch signaling through the surface presentation."
    explanation: The authors' conclusion tying TM2D3 to Notch signaling through receptor surface presentation.
pathophysiology:
- name: TM2D3 Biallelic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic TM2D3 variants, including the recurrent missense allele c.503G>A
    (p.Gly168Asp). TM2D3 is a transmembrane protein expressed in many tissues and most
    abundant in the central nervous system, and in SNB75 cells it localizes to the
    endoplasmic reticulum. Loss of function is inferred from the similarity of patient
    fibroblasts to TM2D3-knockout cells. The missense alleles may be hypomorphic rather than
    null; that distinction is not resolved in the abstract.

    The bound molecular function, Notch binding, is the only activity shown experimentally
    for TM2D3: the wild-type protein physically associates with Notch1. That the disease
    alleles reduce it is inferred from the node, not measured. GO's other function
    annotation for TM2D3, G protein-coupled receptor activity, rests on phylogenetic
    inference alone and is not bound.
  genes:
  - preferred_term: TM2D3
    term:
      id: hgnc:24128
      label: TM2D3
  genetic_context:
    genes:
    - preferred_term: TM2D3
      term:
        id: hgnc:24128
        label: TM2D3
    allele_type: missense, nonsense, frameshift and intragenic deletion alleles in trans
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: Notch1 binding
    modifier: DECREASED
    term:
      id: GO:0005112
      label: Notch binding
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, by using chemical and genetically encoded probes in SNB75 cells, we show that TM2D3 is an endoplasmic reticulum (ER) protein."
    explanation: Places the protein in the ER, the compartment whose dysfunction the downstream nodes describe.
  - reference: PMID:38016980
    reference_title: "TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "TM2D3 physically associates with Notch1 at the region distinct from the ligand-binding domain and enhances expression of Notch1 on the cell surface."
    explanation: >-
      Source for the Notch binding activity bound on this node. INDIRECT because it shows the
      wild-type protein binds Notch1, not that the disease alleles lose that binding.
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "TM2D3 encodes a transmembrane protein present in many tissues, with a higher abundance in the central nervous system"
    explanation: >-
      Tissue distribution, consistent with a multi-organ syndrome dominated by
      neurodevelopmental features. BACKGROUND because the paper restates known expression
      data rather than reporting a new measurement.
  downstream:
  - target: Dysregulated Endoplasmic Reticulum Stress Response
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Further analysis on SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele revealed an impact of TM2D3 on ER-stress response, with dysregulated expression of ATF4, HSPA5, and DDIT3."
      explanation: Knockout cells and patient cells both show the ER-stress defect, which links loss of TM2D3 to this node.
  - target: Altered Extracellular Matrix Gene Expression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we performed RNA sequencing from the fibroblasts of the three individuals harboring the p.Gly168Asp variant and four available parents and disclosed 21 differentially expressed genes, including genes coding for extracellular matrix components involved in the migration of neuronal precursors"
      explanation: >-
        The expression change was found by comparing patient fibroblasts with their parents,
        so it is attributed to the TM2D3 genotype. The route from the gene to these
        transcripts is not described.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this
      feature; which mechanism produces it is not established.
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
      explanation: >-
        Biallelic TM2D3 variants were found in four unrelated families sharing this feature,
        which supports the genotype causing it without naming the intermediate steps.
  - target: Severe global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this
      feature; which mechanism produces it is not established.
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
      explanation: >-
        Biallelic TM2D3 variants were found in four unrelated families sharing this feature,
        which supports the genotype causing it without naming the intermediate steps.
  - target: Absent speech
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this
      feature; which mechanism produces it is not established.
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
      explanation: >-
        Biallelic TM2D3 variants were found in four unrelated families sharing this feature,
        which supports the genotype causing it without naming the intermediate steps.
  - target: Autistic features
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this
      feature; which mechanism produces it is not established.
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
      explanation: >-
        Biallelic TM2D3 variants were found in four unrelated families sharing this feature,
        which supports the genotype causing it without naming the intermediate steps.
  - target: Heart malformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this
      feature; which mechanism produces it is not established.
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
      explanation: >-
        Biallelic TM2D3 variants were found in four unrelated families sharing this feature,
        which supports the genotype causing it without naming the intermediate steps.
  - target: Dysmorphic facial features
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Genotype-to-phenotype link only. The case series ties biallelic TM2D3 variants to this
      feature; which mechanism produces it is not established.
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
      explanation: >-
        Biallelic TM2D3 variants were found in four unrelated families sharing this feature,
        which supports the genotype causing it without naming the intermediate steps.
  - target: Reduced Notch Receptor Surface Presentation
    causal_link_type: DIRECT
    hypothesis_groups:
    - tm2d3_notch_surface_presentation
    evidence:
    - reference: PMID:38016980
      reference_title: "TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Furthermore, cell surface expression of Notch1 and Notch2 is reduced in Tm2d3-deficient cells."
      explanation: >-
        Loss of Tm2d3 reduces surface Notch in mouse embryonic fibroblasts. INDIRECT because
        it is a null mouse cell, not a patient allele or a patient cell.
- name: Dysregulated Endoplasmic Reticulum Stress Response
  biological_scale: CELLULAR
  description: >-
    TM2D3-knockout cells and fibroblasts from individuals carrying p.Gly168Asp show
    dysregulated expression of the ER-stress and unfolded-protein-response genes ATF4, HSPA5
    (BiP) and DDIT3 (CHOP). The authors summarize this as exacerbated sensitivity to ER
    stress.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    modifier: DYSREGULATED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "revealed an impact of TM2D3 on ER-stress response, with dysregulated expression of ATF4, HSPA5, and DDIT3"
    explanation: The ER-stress readouts measured in knockout and patient cells.
  downstream:
  - target: Endoplasmic Reticulum Swelling
    causal_link_type: UNKNOWN
- name: Endoplasmic Reticulum Swelling
  biological_scale: CELLULAR
  description: >-
    Transmission electron microscopy shows swollen ER. The ordering between the stress
    response and the structural change is not established, so the edge from the stress node
    carries an UNKNOWN link type.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: endoplasmic reticulum organization
    modifier: ABNORMAL
    term:
      id: GO:0007029
      label: endoplasmic reticulum organization
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transmission electron microscopy highlighted ER swelling"
    explanation: The ultrastructural ER finding.
  downstream:
  - target: Secondary Mitochondrial Ultrastructural Alterations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Transmission electron microscopy highlighted ER swelling as well as unexpected secondary mitochondrial alterations including increased length, cristae width, and ER-mitochondria distance."
      explanation: >-
        The authors call the mitochondrial changes secondary, placing them downstream of the
        primary ER defect, and the increased ER-mitochondria distance is the contact between
        the two. How the ER defect reaches the mitochondria is not described.
- name: Secondary Mitochondrial Ultrastructural Alterations
  biological_scale: CELLULAR
  description: >-
    Elongated mitochondria with widened cristae and increased ER-mitochondria distance. These
    changes are described as secondary to the ER defect, and their functional consequence is
    not stated in the abstract.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: mitochondrion organization
    modifier: ABNORMAL
    term:
      id: GO:0007005
      label: mitochondrion organization
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "unexpected secondary mitochondrial alterations including increased length, cristae width, and ER-mitochondria distance"
    explanation: The specific mitochondrial changes observed.
- name: Altered Extracellular Matrix Gene Expression
  biological_scale: CELLULAR
  description: >-
    RNA sequencing of fibroblasts from the three p.Gly168Asp individuals against four parents
    found 21 differentially expressed genes, including extracellular matrix genes involved in
    the migration of neuronal precursors. This is a transcriptional signal in fibroblasts. It
    has not been shown in neural tissue, and the connection to the neurodevelopmental
    phenotype is the authors' interpretation rather than a tested step, so no edge to a
    phenotype is drawn.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  cellular_components:
  - preferred_term: extracellular matrix
    term:
      id: GO:0031012
      label: extracellular matrix
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "disclosed 21 differentially expressed genes, including genes coding for extracellular matrix components involved in the migration of neuronal precursors"
    explanation: The transcriptomic finding in patient fibroblasts.
- name: Reduced Notch Receptor Surface Presentation
  biological_scale: CELLULAR
  description: >-
    TM2D3 binds Notch1 outside its ligand-binding domain and increases Notch1 at the cell
    surface, which is a prerequisite for ligand-induced endocytosis and activating cleavage.
    Tm2d3-null mouse embryonic fibroblasts show less full-length and S1-processed Notch1 and
    less surface Notch1 and Notch2. In Drosophila, loss of the orthologue almondex impairs
    endocytosis of the Notch extracellular domain and Delta in early embryos. None of this
    has been examined in patient cells.
  cell_types:
  - preferred_term: embryonic fibroblast
    term:
      id: CL:2000042
      label: embryonic fibroblast
  biological_processes:
  - preferred_term: protein localization to plasma membrane
    modifier: DECREASED
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
  - preferred_term: Notch signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007219
      label: Notch signaling pathway
  evidence:
  - reference: PMID:38016980
    reference_title: "TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TM2D3 physically associates with Notch1 at the region distinct from the ligand-binding domain and enhances expression of Notch1 on the cell surface."
    explanation: The molecular interaction and its effect on surface Notch1.
  - reference: PMID:38016980
    reference_title: "TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Finally, amx-deficient Drosophila early embryos exhibit impaired endocytosis of NECD and Delta ligand, for which surface presentation of Notch is required."
    explanation: In vivo counterpart in the fly embryo.
  - reference: PMID:34905536
    reference_title: "TM2D genes regulate Notch signaling and neuronal function in Drosophila."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect."
    explanation: >-
      The neurogenic phenotype is the classical readout of failed Notch-mediated lateral
      inhibition, and all three TM2D genes share it.
phenotypes:
- name: Microcephaly
  category: Neurological
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
    explanation: Listed among the shared features of the four affected individuals.
- name: Severe global developmental delay
  category: Neurological
  phenotype_term:
    preferred_term: Severe global developmental delay
    term:
      id: HP:0011344
      label: Severe global developmental delay
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
    explanation: Severe global developmental delay is a shared feature.
- name: Absent speech
  category: Neurological
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe global developmental delay with absent speech"
    explanation: Absent speech accompanies the developmental delay.
- name: Autistic features
  category: Behavioral
  phenotype_term:
    preferred_term: Autistic features
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
    explanation: Autistic features are a shared feature.
- name: Heart malformation
  category: Cardiovascular
  description: >-
    The abstract reports heart malformation without naming the lesion, so the binding is the
    general heart-morphology term. The specific lesions reported in the full text are listed
    in the entry notes.
  phenotype_term:
    preferred_term: Heart malformation
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
    explanation: Heart malformation is a shared feature; the abstract does not name the lesion.
- name: Dysmorphic facial features
  category: Craniofacial
  phenotype_term:
    preferred_term: Dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
    explanation: Dysmorphic facial features are a shared feature.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: Four individuals from four unrelated families in a single 2025 report; no rate exists.
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families"
    explanation: The whole published case series.
genetic:
- name: TM2D3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: TM2D3
    term:
      id: hgnc:24128
      label: TM2D3
  features: >-
    TM2D3 encodes a TM2 domain transmembrane protein, the orthologue of Drosophila almondex.
    The recurrent disease allele is c.503G>A (p.Gly168Asp), carried by three of the four
    reported individuals.
  variants:
  - name: c.503G>A (p.Gly168Asp) recurrent variant
    description: >-
      Missense allele carried by three of the four reported individuals, and the allele whose
      patient fibroblasts were used for the ER-stress, ultrastructure and RNA-sequencing work.
      The abstract does not give its clinical-significance classification, so none is
      recorded.
    gene:
      preferred_term: TM2D3
      term:
        id: hgnc:24128
        label: TM2D3
    type: missense_variant
    evidence:
    - reference: PMID:40449487
      reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele"
      explanation: >-
        Names the variant and states that it recurs across affected individuals. Graded
        IN_VITRO because the abstract mentions the allele only within its description of the
        fibroblast experiments, and the same sentence is graded that way elsewhere in this
        entry.
  notes: >-
    A different TM2D3 missense variant, p.Pro155Leu, is a reported risk allele for late-onset
    Alzheimer disease. That is a separate, susceptibility-type relationship with adult onset
    and is not part of this entry (PMID:27764101).
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these clinical and experimental data show that bi-allelic TM2D3 variants underlie a severe syndromic neurodevelopmental disorder"
    explanation: The gene-disease conclusion of the defining report.
diagnosis:
- name: Exome sequencing
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    All four families were diagnosed by exome sequencing in the setting of a severe
    syndromic neurodevelopmental disorder.
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families"
    explanation: The diagnostic method used for every reported case.
animal_models:
- name: almondex loss-of-function Drosophila
  species: Drosophila melanogaster
  genotype: amx null (and triple TM2D knockout)
  publication: PMID:34905536
  description: >-
    Embryos from amx-null mothers have the maternal-effect neurogenic phenotype of failed
    Notch signaling. Adult amx loss shortens lifespan, with progressive motor and
    electrophysiological defects.
  modeled_mechanisms:
  - target: Reduced Notch Receptor Surface Presentation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      The neurogenic phenotype and impaired Notch extracellular domain and Delta endocytosis
      read out the Notch defect directly.
    limitations: >-
      The fly phenotype is maternal-effect, arising in the early embryo, which has no
      counterpart in a recessive human disorder caused by zygotic loss. The model is a null,
      whereas the recurrent human allele is missense. PMID:34905536 reports no fly phenotype
      corresponding to the human cardiac or renal malformations or to microcephaly, and does
      not examine the ER and mitochondrial findings of the human disease.
    evidence:
    - reference: PMID:34905536
      reference_title: "TM2D genes regulate Notch signaling and neuronal function in Drosophila."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect."
      explanation: >-
        The loss-of-function fly shows the neurogenic phenotype that reads out failed Notch
        signaling, which is what this link claims.
discussions:
- discussion_id: ncrms_er_versus_notch_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - "pathophysiology#Dysregulated Endoplasmic Reticulum Stress Response"
  - "pathophysiology#Reduced Notch Receptor Surface Presentation"
  prompt: >-
    Do the malformations of neurocardiorenal malformation syndrome arise from the ER-stress
    defect seen in patient fibroblasts, from reduced Notch signaling, or from both?
  rationale: >-
    The two literatures on TM2D3 have not met. The disease report measured ER stress,
    ultrastructure and transcription in patient fibroblasts and does not report Notch activity
    in its abstract. The Notch work used mouse null cells and flies and has no patient
    material. Notch receptors are themselves transmembrane proteins that pass through the ER,
    so the two explanations may be one, with reduced surface presentation a consequence of
    the ER defect, but that has not been tested. For this reason each phenotype is linked
    only to the TM2D3 genotype, with unknown intermediate steps, and not to either
    mechanism.
  proposed_experiments:
  - experiment_id: ncrms_patient_cell_notch_surface
    name: Notch surface presentation and target-gene expression in patient cells
    description: >-
      Measure surface Notch1 and Notch2 and HES/HEY target expression in p.Gly168Asp
      patient fibroblasts or iPSC-derived neural progenitors against parental controls, with
      and without ER-stress induction.
    readouts:
    - name: Surface Notch1 in patient cells
      target: "pathophysiology#Reduced Notch Receptor Surface Presentation"
      direction: DECREASED
      interpretation: >-
        A reduction in patient cells would carry the mouse finding into the human disease;
        no change would argue that the ER defect acts through other cargo.
external_assertions:
- name: OMIM neurocardiorenal malformation syndrome record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:621379
  url: https://omim.org/entry/621379
  description: >-
    The OMIM phenotype record cross-referenced by MONDO:0980704. Its MedGen definition
    describes an autosomal recessive severe neurodevelopmental disorder with microcephaly,
    distinctive facial features, and cardiac and renal malformations, citing Gabillard-Lefort
    et al. (2025).
  evidence:
  - reference: PMID:40449487
    reference_title: "Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these clinical and experimental data show that bi-allelic TM2D3 variants underlie a severe syndromic neurodevelopmental disorder"
    explanation: The report on which the OMIM record rests.
notes: >-
  Scope: curated as a DISEASE. One gene, one reported series, and no MONDO descendants.

  Several clinical findings are deliberately left out of phenotypes. The defining paper
  (PMID:40449487) is not open access, and both the PubMed and DOI routes return only its
  abstract, so nothing beyond the abstract can carry a verified snippet. The full text is
  readable at PMC12256896 but is not open access, so the fetcher cannot cache it. The
  deep-research report (research/Neurocardiorenal_Malformation_Syndrome-deep-research-claude_code.md)
  read the full-text Table 1 and reports the following.
  These figures are unverified here and recorded only so a curator with full-text access
  knows what to add: renal anomaly in 3 of 4 (horseshoe kidney in 2, mild pyelocaliceal
  dilatation in 1); congenital heart defect in 4 of 4 (ventricular septal defect in 3,
  patent ductus arteriosus with patent foramen ovale, polyvalvular dysplasia, and a duplicated
  vena cava); ocular findings in 3 of 4 (hypermetropia, strabismus, legal blindness in one);
  seizures in 2
  of 4; structural brain anomalies on MRI in 3 of 4 (frontal hypoplasia, abnormal gyration,
  cerebellar vermis hypoplasia); genital anomalies in both males; and prenatal growth
  restriction or polyhydramnios. The renal component, despite giving the disease its name,
  is not in the abstract; MedGen's definition of OMIM:621379 states it.

  For the same reason no frequency is given on any phenotype: the abstract lists shared
  features without saying how many of the four individuals had each.

📚

References & Deep Research

References

4

PMID:40449487

Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities.

No top-level findings curated for this source.

PMID:38016980

TM2D3, a mammalian homologue of Drosophila neurogenic gene product Almondex, regulates surface presentation of Notch receptors.

No top-level findings curated for this source.

PMID:34905536

TM2D genes regulate Notch signaling and neuronal function in Drosophila.

No top-level findings curated for this source.

PMID:27764101

Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

Scope: curated as a DISEASE. One gene, one reported series, and no MONDO descendants. Several clinical findings are deliberately left out of phenotypes. The defining paper (PMID:40449487) is not open access, and both the PubMed and DOI routes return only its abstract, so nothing beyond the abstract can carry a verified snippet. The full text is readable at PMC12256896 but is not open access, so the fetcher cannot cache it. The deep-research report (research/Neurocardiorenal_Malformation_Syndrome-deep-research-claude_code.md) read the full-text Table 1 and reports the following. These figures are unverified here and recorded only so a curator with full-text access knows what to add: renal anomaly in 3 of 4 (horseshoe kidney in 2, mild pyelocaliceal dilatation in 1); congenital heart defect in 4 of 4 (ventricular septal defect in 3, patent ductus arteriosus with patent foramen ovale, polyvalvular dysplasia, and a duplicated vena cava); ocular findings in 3 of 4 (hypermetropia, strabismus, legal blindness in one); seizures in 2 of 4; structural brain anomalies on MRI in 3 of 4 (frontal hypoplasia, abnormal gyration, cerebellar vermis hypoplasia); genital anomalies in both males; and prenatal growth restriction or polyhydramnios. The renal component, despite giving the disease its name, is not in the abstract; MedGen's definition of OMIM:621379 states it. For the same reason no frequency is given on any phenotype: the abstract lists shared features without saying how many of the four individuals had each.

Create: Neurocardiorenal_Malformation_Syndrome · 2026-10-14T17:49:26Z · View source

New entry for MONDO:0980704 (TM2D3, OMIM:621379), claimed in #14166. Falcon was the default deep-research provider but returned a 503 authentication failure, which the client classes as retryable so --fallback did not hand over; the claude_code provider was run directly instead and its report is committed (8/8 references and 71/71 CURIEs resolved; just preflight-dr confirmed TM2D3 is the subject). Evidence comes from three primary papers: PMID:40449487 (defining case series and ER/mitochondrial work), PMID:38016980 (Notch surface presentation in Tm2d3-null mouse cells and fly embryos) and PMID:34905536 (Drosophila TM2D genes), plus PMID:27764101 for the separate Alzheimer-risk allele. The defining paper is not open access; PubMed and DOI routes both return the abstract only, so the full-text findings the report quotes (renal anomalies, specific heart lesions, seizures, MRI findings) are recorded in notes as unverified rather than curated as phenotypes. Notch is carried as an EMERGING hypothesis group because it is not tested in patients. Validated with just validate, count-verified-snippets (27/27), check-entity-refs, check-causal-targets, check-coarse-phenotypes, check-snippet-grading and check-genereviews (no chapter). A pre-PR self-review then narrowed the cell-type bindings to CL:0002620 skin fibroblast and CL:2000042 embryonic fibroblast, regraded the tissue-expression quote to OTHER, replaced the fly model's overexpression snippet with its loss-of-function result, dropped the off-claim Alzheimer evidence item, dropped GO:0042407 (cristae width was measured, not cristae assembly), and added NCIT:C101295 as the diagnosis term.

Claude Code ▸

Neurocardiorenal Malformation Syndrome (NCRMS; TM2D3-related): Research Report

claude-haiku-5-5, claude-opus-5-5 10 citations 2026-10-14T13:41:29.991046

Neurocardiorenal Malformation Syndrome (NCRMS; TM2D3-related): Research Report

Prepared: 2026-10-14 · MONDO: MONDO:0980704 · OMIM phenotype: #621379 · Gene: TM2D3 (OMIM *610014, 15q26.3)

About the CURIEs in this report. Identifiers below that were read from a source in this session are marked ✅. Ontology terms marked 🔎 are suggestions to look up with runoak / just validate-terms before binding. Under the repository's CURIE rule they are leads, not checked bindings.

1. Disease Information

Overview. NCRMS is an autosomal recessive syndrome that is mainly a severe neurodevelopmental disorder, with structural heart and kidney malformations. MedGen gives the OMIM-derived definition: "Neurocardiorenal malformation syndrome (NCRMS) is an autosomal recessive severe neurodevelopmental disorder associated with microcephaly, distinctive facial features, and multiorgan involvement including cardiac and renal malformations" (MedGen C6024737).

The syndrome was defined by one report: Gabillard-Lefort et al. 2025, Am J Hum Genet 112(7):1711–1721, PMID:40449487 ✅ (PMC12256896, free in Europe PMC; abstract cached at references_cache/PMID_40449487.md). Abstract quote:

"We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features."

Identifiers

System	ID	Status
MONDO	MONDO:0980704	✅ MedGen xref
OMIM (phenotype)	621379	✅ MedGen, PanelApp
OMIM (gene)	610014 (TM2D3)	✅ PanelApp
MedGen	C6024737 (UID 1887965)	✅
Orphanet	none found	MedGen lists no ORPHA code
ICD-10 / ICD-11 / MeSH	no specific code	would fall under generic "multiple congenital anomalies" codes
Ensembl	ENSG00000184277	✅ PanelApp

Synonyms: NCRMS. GeneCards also lists "severe neurodevelopmental disorder with facial dysmorphism, cerebral-renal-cardiac anomalies" (GeneCards TM2D3).

Data provenance: all clinical data come from individual patients in a single case series (n = 4, four families). There is no registry or EHR cohort.

Lump/split note for curation. TM2D3 is also linked to late-onset Alzheimer disease risk through the heterozygous p.Pro155Leu variant (PMID:27764101 ✅). That is a separate, susceptibility-type association. It should not be merged into this entry, though it is worth a sentence in notes or genetic[].notes.

2. Etiology

Cause: biallelic germline loss-of-function or hypomorphic variants in TM2D3. In all four families the parents were heterozygous carriers, and two healthy sisters of Individual 2 were also heterozygous (PMID:40449487 full text).
Genetic risk factors: none beyond the causal genotype. The recurrent c.503G>A (p.Gly168Asp) allele was found in 3 of the 4 families (France ×2, Italy). These were non-consanguineous families of different origins, which fits a recurrent allele rather than a confirmed founder effect; no haplotype analysis was reported.
Environmental, protective, and gene–environment factors: none reported. The mechanism study used tunicamycin as an experimental ER stressor. The authors' "exacerbated ER-stress sensitivity" framing raises the idea that physiological stress could modify severity, but this has not been tested in patients and should not be curated as an environmental factor.

3. Phenotypes

The cohort is n = 4, so the frequencies below are counts, not population estimates. Sources: the PMID:40449487 full text (Table 1) and the HPO annotation list in MedGen, which includes 87 HPO features.

Phenotype	Freq.	Detail	Suggested HP 🔎
Microcephaly, postnatal/progressive	4/4	OFC −5, −3.6, −2.5, −4 SD	HP:0000252 Microcephaly; HP:0000253 Progressive microcephaly; HP:0005484 Secondary microcephaly
Severe global developmental delay	4/4	1 never walked; others walked at 2–4 y, with support or wide-based gait	HP:0011344
Absent or severely limited speech	4/4	Ind. 3 used bisyllabic words	HP:0001344 Absent speech
Autistic features	several	—	HP:0000729 Autistic behavior
Anxiety, agitation, self-injury, aggression, stereotypies	several	—	HP:0000739; HP:0000713; HP:0100716; HP:0000718; HP:0000733
Seizures	2/4	Ind. 2: focal, onset 22 mo. Ind. 3: onset 2 mo, with episodes of alternating hemiplegia	HP:0001250; HP:0007359 Focal-onset seizure; "Episodic hemiplegia" per MedGen
Structural brain anomalies	3/4 on MRI	small frontal lobes (2), abnormal gyration (2), thick corpus callosum (1), vermis hypoplasia (1); Ind. 4 had a pineal cyst on CT	HP:0007333 Hypoplasia of the frontal lobes; HP:0002536 Abnormal cortical gyration; HP:0001320 Cerebellar vermis hypoplasia; HP:0007074 Thick corpus callosum
Congenital heart defect	4/4	VSD (3/4, three VSDs in Ind. 3); PDA + PFO (Ind. 1); polyvalvular dysplasia (Ind. 2); duplicated vena cava (Ind. 3)	HP:0001629 VSD; HP:0001643 PDA; HP:0001655 PFO; "Bilateral superior vena cava" per MedGen
Renal anomaly	3/4	horseshoe kidney (2/4); mild pyelocaliceal dilatation (1/4); Ind. 4 normal	HP:0000085 Horseshoe kidney; "Dilatation of renal calices" per MedGen
Genital anomalies (males)	2/2	scrotal hypoplasia (2), cryptorchidism (1)	HP:0000046 Small scrotum; HP:0000028 Cryptorchidism
Prenatal findings	4/4	IUGR and/or polyhydramnios; decreased fetal movement	HP:0001511; HP:0001561; HP:0001558
Short stature	2/4	−3 and −3.3 SD (Ind. 1, 2)	HP:0004322
Ocular	3/4	hypermetropia (2), strabismus (2), legal blindness (1), optic disc drusen	HP:0000540; HP:0000486; HP:0000618
Facial dysmorphism	4/4	mild coarse features, convex nasal ridge, low columella, pinched or narrow mouth, sparse eyebrows, thin upper lip, low-set or posteriorly rotated ears, micrognathia	HP:0000444 Convex nasal ridge; HP:0000160 Narrow mouth; HP:0000347 Micrognathia
Hand and foot	some	2–3 toe syndactyly, 3–4 finger cutaneous syndactyly, single transverse palmar crease	per MedGen
Tone and motor	some	axial hypotonia, limb hypertonia, dystonia, gait ataxia	HP:0008936; HP:0002509; HP:0001332; HP:0002066
Other	isolated	laryngomalacia, recurrent pneumonia, sleep apnea, feeding difficulties, constipation, syringomyelia, Horner syndrome, scoliosis, dental anomalies (microdontia, delayed eruption)	per MedGen

Course: onset is congenital or prenatal, and microcephaly is postnatal and progressive. The authors note no regression in any patient. The oldest patient was 26 years old at last exam, so survival into adulthood occurs.

Quality of life: no formal measure (EQ-5D, PROMIS) has been reported. The impact is inferred from profound intellectual and motor disability and absent speech, with lifelong dependence.

4. Genetic / Molecular Information

Gene: TM2D3 (TM2 domain containing 3; also BLP2, β-amyloid peptide binding protein-like 2). It encodes a protein with a signal peptide and two transmembrane domains joined by a conserved intracellular DRF motif (PMID:34905536 ✅). It has two splice isoforms (v1 and v2), which differ by 26 residues near the signal peptide (PMID:38016980 ✅). HGNC ID 🔎 should be looked up; use the lowercase hgnc: form.

Reported variants (PMID:40449487 Table 2; ClinVar SCV005387825–SCV005387828)

Variant	Type	Families / zygosity	gnomAD AF	In silico
c.503G>A p.(Gly168Asp)	missense (first base of exon 5; no splice effect on cDNA)	Ind. 3 homozygous; Ind. 1 and 2 compound het	1×10⁻⁵	CADD 36; AlphaMissense 0.987; PolyPhen-2 1
c.7G>T p.(Gly3*)	nonsense (NMD predicted)	Ind. 1, in trans with Gly168Asp	~5×10⁻⁶	—
c.153dup p.(Val52Serfs*9)	frameshift	Ind. 2, in trans with Gly168Asp	absent	—
c.677C>T p.(Thr226Met)	missense	Ind. 4	1.05×10⁻⁵	CADD 30; REVEL 0.72
del15q26.3 (~33 kb, exons 1–6; chr15:102182681–102215940, GRCh37)	intragenic deletion	Ind. 4, in trans with Thr226Met	—	—

Classification: the paper's figure legend calls Gly168Asp "likely pathogenic". Formal ACMG calls per variant are not in the main text.
Functional class: every genotype pairs a predicted-null allele with a missense allele, or has homozygous missense. No patient had two null alleles, which fits IMPC complete preweaning lethality in Tm2d3 homozygous knockout mice (see §15). The authors suggest the missense alleles are hypomorphic. Gly168Asp restored basal GRP78 in rescue experiments but showed a trend toward abnormal accumulation under stress (p = 0.09), which they read as partial loss of function. The functional_impact_category options are LOSS_OF_FUNCTION for the null alleles and PARTIAL_LOSS_OF_FUNCTION for Gly168Asp, the latter only if a curator accepts that inference.
Gene–disease validity: ClinGen has not assessed it. Gene2Phenotype rates it moderate. Genomics England PanelApp rates it Amber on the Severe Microcephaly panel and it is tagged for promotion to Green in Q1 2026 (PanelApp). Under the repo rule, do not populate gene_disease_validity, because no ClinGen record exists.
Chromosomal context: TM2D3 sits in distal 15q26.3. Terminal 15q26 deletions and ring 15 include it (e.g., PMID:27160288, PMID:18194513, PMID:29223476). These are hemizygous and contiguous-gene events, so they are not NCRMS.
Modifier genes and epigenetics: none reported.

5. Environmental Information

Not applicable. No environmental, lifestyle, or infectious factors have been reported. Leave the environmental: section empty rather than inventing one.

6. Mechanism / Pathophysiology

Ordered causal chain

Biallelic TM2D3 variants (one null plus one hypomorphic missense, or homozygous missense) lead to reduced TM2D3 function. Demonstrated for null alleles by the variant class. Partially demonstrated for Gly168Asp by rescue assays (PMID:40449487).
Loss of TM2D3, an ER-resident transmembrane protein, results in a dysregulated ER unfolded-protein response. KO SNB75 cells showed mildly decreased ATF4, HSPA5 and DDIT3 at baseline and a dramatic increase after tunicamycin. Patient fibroblasts showed decreased HSPA5 at baseline and a strong HSPA5 rise under stress. TEM showed ER luminal swelling. Demonstrated in vitro (PMID:40449487).
Quote (abstract): "revealed an impact of TM2D3 on ER-stress response, with dysregulated expression of ATF4, HSPA5, and DDIT3."
ER dysfunction leads to secondary mitochondrial changes: longer mitochondria, wider cristae, a larger ER–mitochondria distance, and higher OPA1. Respiratory-chain activity and oxygen consumption were normal, so this is structural, not bioenergetic. The authors propose disturbed DNM1L-mediated fission at ER–mitochondria contacts. Morphology demonstrated; fission mechanism inferred.
Branch A, ECM / neuronal migration (inferred). Fibroblast RNA-seq found 21 DEGs: up EYA2, DPT, COMP, TNC, LRRC20; down TLR4, EBF2, KRT19, LGR4, among others. The ECM genes TNC, DPT and COMP are implicated in neuronal-precursor migration. This is a transcriptional association in a non-neural cell type, and the causal role is not shown.
Branch B, Notch signaling (inferred for the human disease). TM2D3 promotes cell-surface presentation of NOTCH1 and NOTCH2, and Tm2d3⁻/⁻ mouse embryonic fibroblasts show lower surface Notch (PMID:38016980 ✅). Fly orthologs (almondex, amaretto, biscotti) are required for Notch signaling at the γ-secretase step (PMID:34905536 ✅). Quote: "cell surface expression of Notch1 and Notch2 is reduced in Tm2d3-deficient cells." The NCRMS paper did not test Notch and found no Notch signature among its DEGs. Notch dysfunction is a plausible link to the heart, kidney and neurogenesis phenotypes, but it is not demonstrated in patients. Model it as an EMERGING hypothesis group.
Neural progenitor depletion or mis-migration (inferred) leads to postnatal microcephaly, frontal hypoplasia and gyral anomalies, which result in severe developmental delay, absent speech, autism and seizures.
Disrupted organogenesis (mechanism unknown; Notch suggested) results in VSD/PDA/valve dysplasia and horseshoe kidney. No direct evidence.

Suggested ontology terms 🔎

GO: GO:0030968 endoplasmic reticulum unfolded protein response; GO:0034976 response to endoplasmic reticulum stress; GO:0007219 Notch signaling pathway; GO:0045747 positive regulation of Notch signaling pathway; GO:0007005 mitochondrion organization; GO:0000266 mitochondrial fission; GO:0001764 neuron migration; GO:0007405 neuroblast proliferation; GO:0007507 heart development; GO:0001822 kidney development.
GO cellular component: GO:0005783 endoplasmic reticulum; GO:0044233 mitochondria-associated ER membrane contact site.
CL: CL:0000057 fibroblast (assay system); CL:0011020 neural progenitor cell; CL:0000540 neuron.
Proteins: ATF4, HSPA5/GRP78, DDIT3/CHOP, OPA1, NOTCH1, NOTCH2.
Biological scale tags: step 2 = CELLULAR; step 3 = CELLULAR; steps 6–7 = TISSUE.

Molecular profiling: fibroblast bulk RNA-seq (3 patients vs 4 parents). No single-cell, proteomics, metabolomics, or GEO accession was reported, so do not add datasets: without an accession.

7. Anatomical Structures Affected 🔎

Brain UBERON:0000955: frontal lobe (UBERON:0016525), cerebral cortex (UBERON:0000956), cerebellar vermis (UBERON:0004720), corpus callosum (UBERON:0002336).
Heart UBERON:0000948: interventricular septum (UBERON:0002094), ductus arteriosus (UBERON:0004145), cardiac valves.
Kidney UBERON:0002113 (horseshoe fusion; collecting system dilatation).
Male genitalia: scrotum, testis.
Eye.
Subcellular: ER (primary site); mitochondria (secondary).
Laterality: the malformations are midline or fusion defects. No lateralization is reported.

8. Temporal Development

Onset: prenatal (IUGR, polyhydramnios, structural defects present at birth), with postnatal progressive microcephaly. Seizure onset ranged from 2 months to 22 months.
Course: a static neurodevelopmental encephalopathy with no regression. Microcephaly progresses in relative terms. The disease is lifelong.
Stages: none defined. Ages at last exam were 5½–26 y; the text says "5–24 y", one of several internal inconsistencies in the paper.

9. Inheritance and Population

Inheritance: autosomal recessive (HP:0000007 🔎). Penetrance appears complete in biallelic individuals; heterozygous carriers are unaffected.
Expressivity: variable. Renal involvement is 3/4, seizures 2/4, and growth failure 2/4.
Epidemiology: 4 reported cases worldwide (France ×2, Italy, USA). Prevalence is unknown. Suggested record: measure_type: CASES_IN_LITERATURE, prevalence_class: BELOW_1_IN_1000000 or ULTRA_RARE, with evidence PMID:40449487.
Sex: 2 M, 2 F.
Consanguinity: none in the 4 families.
Carrier frequency: the variants are each ~10⁻⁵ in gnomAD. No aggregate carrier frequency has been published.

10. Diagnostics

Genetic: exome sequencing was the diagnostic route in all four families. CNV calling, or CMA/genome sequencing, is needed because one allele was a 33 kb intragenic deletion. TM2D3 is on the PanelApp Severe Microcephaly, Intellectual Disability and DDG2P panels.
Supportive clinical work-up: echocardiography (VSD/PDA), renal ultrasound (horseshoe kidney), brain MRI (frontal hypoplasia, gyral anomalies, vermis hypoplasia), EEG, ophthalmologic exam.
Biomarkers: none are validated. Raised HSPA5/GRP78 after ER-stress challenge in fibroblasts is a research assay only.
Differential diagnosis (suggested from phenotype overlap; not from the paper): TMEM260 structural heart defects and renal anomalies syndrome (OMIM #617478), whose neurodevelopmental, cardiac and renal triad overlaps; 15q26 terminal deletion and ring 15; and primary microcephaly genes with congenital heart disease. Use any of these only with a citation.
Screening: no newborn screening. Cascade carrier testing and prenatal or PGT-M testing are possible once familial variants are known.

11. Outcome / Prognosis

No survival data exist. One patient reached 26 years.
Expect severe lifelong intellectual and motor disability and dependence, plus legal blindness in one patient.
Complications: seizures, recurrent pneumonia or bronchitis, sleep apnea, feeding difficulties, scoliosis.
No prognostic factors or biomarkers are known.

12. Treatment

No disease-specific therapy exists. Management is supportive and symptomatic (NCIT suggestions 🔎; these must sit under NCIT:C25218):

Intervention	NCIT 🔎
Antiseizure pharmacotherapy	NCIT:C15986 Pharmacotherapy (no specific agents reported)
Cardiac surgical repair of VSD/PDA, as indicated	NCIT:C15329 Surgical Procedure
Physical, occupational and speech therapy	NCIT:C15302; NCIT:C121351; NCIT:C159273
Genetic counseling	NCIT:C15240
Supportive care (feeding, respiratory)	NCIT:C15747

No ER-stress-modulating drugs (e.g., chemical chaperones such as 4-PBA or TUDCA) have been tested. Mention them only as a knowledge gap. There are no clinical trials (no NCT or ICTRP entries found).

13. Prevention

Primary prevention is not applicable.
Genetic counseling covers 25% recurrence risk for carrier parents, carrier testing of siblings, and prenatal diagnosis or PGT-M.
Tertiary prevention: cardiac and renal surveillance, seizure management, ophthalmology follow-up.

14. Other Species / Natural Disease

No naturally occurring animal disease has been reported (OMIA not checked in this session). TM2D3 is conserved across metazoans; the Drosophila ortholog is almondex (amx). Human TM2D3 provides about 50% of fly Amx activity in rescue assays (PMID:34905536).

15. Model Organisms

Model	Findings	Relevance to NCRMS	Ref
*Mouse Tm2d3^em1(IMPC)J* (IMPC)	Homozygous: preweaning lethality, complete penetrance; E15.5 edema and hemorrhage. Heterozygous: increased anxiety-related response, decreased lean mass, decreased grip strength	The null is lethal, which fits patients carrying ≥1 hypomorphic allele. Embryonic edema and hemorrhage may reflect a cardiovascular defect (not established)	IMPC genotype-phenotype API (mousephenotype.org); cited in PMID:40449487 discussion
*Mouse Tm2d3⁻/⁻ MEFs* (CRISPR exon-5 deletion)	~40% lower Notch1 full-length protein; reduced surface NOTCH1 and NOTCH2; mRNA unchanged	Mechanistic, in vitro	PMID:38016980 ✅
Drosophila amx, amrt, bisc nulls	Maternal-effect neurogenic phenotype (loss of Notch lateral inhibition); act at γ-secretase S3 cleavage; shortened lifespan; progressive motor and electrophysiological decline	Notch link; neuronal maintenance; not a malformation model	PMID:34905536 ✅
Drosophila amx embryo	Impaired endocytosis of the Notch extracellular domain and Delta	Mechanism of surface presentation	PMID:38016980 ✅
SNB75 TM2D3-KO cells; patient fibroblasts	ER localization, ER stress, mitochondrial morphology	Main disease-mechanism evidence	PMID:40449487 ✅

Limitations: no model recapitulates the human malformation spectrum. The fly phenotypes are maternal-effect and Notch-centric. The mouse null is lethal, and no hypomorphic (Gly168Asp knock-in) model exists. This is a good candidate for a HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP discussion.
evidence_source: MODEL_ORGANISM for the fly and IMPC data; IN_VITRO for the MEF, SNB75 and fibroblast data.

Key evidence quotes for curation

Claim	Reference	Exact abstract quote
Core phenotype, AR biallelic	PMID:40449487	"bi-allelic variants in TM2D3 in four affected individuals from four unrelated families with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features"
ER localization	PMID:40449487	"we show that TM2D3 is an endoplasmic reticulum (ER) protein"
ER-stress dysregulation	PMID:40449487	"revealed an impact of TM2D3 on ER-stress response, with dysregulated expression of ATF4, HSPA5, and DDIT3"
Mitochondrial alterations	PMID:40449487	"Transmission electron microscopy highlighted ER swelling as well as unexpected secondary mitochondrial alterations including increased length, cristae width, and ER-mitochondria distance"
ECM DEGs	PMID:40449487	"disclosed 21 differentially expressed genes, including genes coding for extracellular matrix components involved in the migration of neuronal precursors"
Notch surface presentation	PMID:38016980	"cell surface expression of Notch1 and Notch2 is reduced in Tm2d3-deficient cells"
Fly Notch / γ-secretase	PMID:34905536	"Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step."

Caveats for snippet validation

The PMID:40449487 cache is abstract-only. The counts "kidney malformation (2/4: horseshoe kidney)" and "heart malformation (4/4: …)" come from the full text. They will not validate against the current cache unless full text is fetched; otherwise attach those phenotype claims to an abstract quote or leave them unquoted.
The abstract does not mention renal anomalies. The renal component rests on the full-text table and the OMIM/MedGen synopsis.

Sources

Gabillard-Lefort C et al. Am J Hum Genet 2025;112:1711–1721. PMID:40449487; PMC12256896; FLORE record
Masuda W et al. Sci Rep 2023. PMID:38016980
Salazar JL et al. PLoS Genet 2021. PMID:34905536
Jakobsdottir J et al. PLoS Genet 2016. PMID:27764101 (Alzheimer-risk association; distinct entity)
MedGen C6024737 – NCRMS
Genomics England PanelApp – TM2D3
GeneCards – TM2D3
IMPC – Tm2d3 genotype–phenotype records
MedGen search (TMEM260 differential)
Jakobsdottir 2016 coverage: DOAJ, Technology Networks

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	4
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	71
Resolved	71
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	8
Terms named correctly	1
Terms named as a different term	6
Terms whose name is worth a second look	1

Terms the report names something else

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

MONDO:0980704 (2 mentions) - the report calls it "MONDO"; MONDO calls it neurocardiorenal malformation syndrome
HP:0011344 (1 mention) - the report calls it "1 never walked; others walked at 2–4 y, with support or wide-based gait"; HP calls it Severe global developmental delay
HP:0004322 (1 mention) - the report calls it "−3 and −3.3 SD (Ind. 1, 2)"; HP calls it Short stature
UBERON:0000955 (1 mention) - the report calls it "frontal lobe"; UBERON calls it brain
UBERON:0000948 (1 mention) - the report calls it "interventricular septum"; UBERON calls it heart
UBERON:0002113 (1 mention) - the report calls it "horseshoe fusion; collecting system dilatation"; UBERON calls it kidney

Terms whose name is worth a second look

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

NCIT:C15747 (1 mention) - the report calls it "Supportive care (feeding, respiratory)"; NCIT calls it Supportive Care

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References & Deep Research

References

Deep Research

Neurocardiorenal Malformation Syndrome (NCRMS; TM2D3-related): Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

7. Anatomical Structures Affected 🔎

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key evidence quotes for curation

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look