Temtamy Syndrome

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

autosomal recessive inheritance

Show evidence (1 reference)

PMID:24798461 SUPPORT Human Clinical

"Homozygous and compound heterozygous mutations in C12orf57 have recently been described to cause an autosomal recessive syndromic form of intellectual disability"

The report explicitly classifies C12orf57-related disease as autosomal recessive.

⚙

Pathophysiology

4

C12orf57 Loss of Function

Biallelic loss-of-function variants in C12orf57 (GRCC10) — most commonly an ancestral start-loss founder mutation (c.1A>G; p.M1?) and other truncating or missense changes — abolish or severely reduce function of a small, poorly annotated 126-amino-acid protein that is ubiquitously expressed and tightly conserved across evolution. The protein is required for normal development of the human corpus callosum and is expressed in tissues including the eye and brain, linking its loss to the combined forebrain commissural and ocular developmental phenotype.

neuron CL:0000540

C12orf57 hgnc:29521

corpus callosum development GO:0022038 ⚠ ABNORMAL eye development GO:0001654 ⚠ ABNORMAL nervous system development GO:0007399 ⚠ ABNORMAL

Downstream

Impaired Corpus Callosum and Forebrain Commissural Development Loss of the conserved C12orf57 protein impairs midline forebrain commissural development, producing agenesis, hypoplasia, or dysgenesis of the corpus callosum.

Impaired Ocular Development C12orf57 expression in the developing eye and its association with colobomatous microphthalmia implicate its loss in defective ocular morphogenesis.

Disrupted Synaptic AMPA-Receptor Homeostasis Beyond its developmental role, loss of C12orf57/GRCC10 disrupts activity dependent synaptic homeostatic downscaling in excitatory neurons, providing a candidate mechanism for the epilepsy and intellectual disability of the syndrome.

Show evidence (2 references)

PMID:23453666 SUPPORT Human Clinical

"C12orf57 is ubiquitously expressed and encodes a poorly annotated 126 amino acid protein of unknown function. This protein is without significant paralogs but has been tightly conserved across evolution. Our data suggest that this conserved gene is required for development of the human corpus callosum."

The whole-exome study identifies C12orf57 as a conserved gene required for corpus callosum development, establishing the primary developmental defect.

PMID:23453665 SUPPORT Human Clinical

"Little is known about C12orf57 but we show that it is expressed in several mouse tissues, including the eye and brain."

Expression in eye and brain links loss of C12orf57 to the combined ocular and CNS developmental phenotype.

Impaired Corpus Callosum and Forebrain Commissural Development

Defective midline commissural development produces a spectrum of corpus callosum abnormalities ranging from complete agenesis to hypoplasia or dysgenesis, often accompanied by cerebral white matter abnormalities.

neuron CL:0000540

corpus callosum development GO:0022038 ⚠ ABNORMAL commissural neuron axon guidance GO:0071679 ⚠ ABNORMAL

corpus callosum UBERON:0002336

Downstream

Corpus callosum abnormality Defective commissural development manifests as agenesis, hypoplasia, or dysgenesis of the corpus callosum on neuroimaging.

Cerebral white matter abnormality Brain white matter abnormalities accompany the commissural defect in a substantial fraction of patients.

Show evidence (1 reference)

PMID:29383837 SUPPORT Human Clinical

"63% (34/54) had corpus callosal abnormalities"

The combined cohort quantifies corpus callosal abnormalities as a frequent feature of the syndrome.

Impaired Ocular Development

Disrupted ocular morphogenesis produces a spectrum of eye malformations, including coloboma (iris, chorioretinal, optic disc) and microphthalmia, that defined the original colobomatous-microphthalmia presentation.

neuron CL:0000540

eye development GO:0001654 ⚠ ABNORMAL

eye UBERON:0000970

Downstream

Coloboma Ocular maldevelopment manifests as coloboma affecting the iris, retina, or optic disc.

Microphthalmia Ocular maldevelopment can produce microphthalmia, the original defining ocular feature of the syndrome.

Show evidence (1 reference)

PMID:23453665 SUPPORT Human Clinical

"colobomatous microphthalmia is associated with profound global developmental delay, intractable seizures, and corpus callosum abnormalities"

The founding paper documents colobomatous microphthalmia as the defining ocular phenotype.

Disrupted Synaptic AMPA-Receptor Homeostasis

Loss of C12orf57/GRCC10 disrupts the homeostatic downscaling of synaptic AMPA receptors that normally accompanies elevated neuronal activity. In a Grcc10 knockout mouse, hippocampal neurons show increased AMPA receptor expression and larger miniature excitatory postsynaptic currents, with increased epileptiform activity, via modulation of CAMK4 and downstream CREB and ARC expression.

glutamatergic neuron CL:0000679 hippocampal neuron CL:0002608

CAMK4 hgnc:1464

regulation of AMPA receptor activity GO:2000311 ⚠ ABNORMAL regulation of synaptic plasticity GO:0048167 ⚠ ABNORMAL

Downstream

Seizure Disrupted AMPA-receptor downscaling increases excitatory drive and seizure susceptibility, recapitulated as increased epileptiform activity in the knockout model.

Show evidence (2 references)

PMID:39974932 SUPPORT Model Organism

"hippocampal neurons in these mice exhibited significantly increased AMPA receptor expression levels and higher amplitude of miniature excitatory postsynaptic currents (mEPSCs)"

The knockout mouse model demonstrates the AMPA-receptor and synaptic current abnormalities downstream of Grcc10/C12orf57 loss.

PMID:39974932 SUPPORT Model Organism

"deletion of Grcc10 disrupts the characteristic synaptic AMPA receptor downscaling that accompanies increased activity in glutamatergic neurons"

The study identifies disrupted AMPA-receptor homeostatic downscaling as the core synaptic mechanism.

⬡

Pathograph

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

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Phenotypes

12

Cardiovascular 1

Congenital heart disease FREQUENT Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:29383837 SUPPORT Human Clinical

"a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50)"

The combined cohort reports congenital heart disease in 51.4% of patients, supporting a FREQUENT frequency band.

Eye 3

Coloboma OCCASIONAL Coloboma HP:0000589

Show evidence (1 reference)

PMID:29383837 SUPPORT Human Clinical

"14.5% (8/55) had coloboma"

The delineation cohort quantifies coloboma in 14.5% of patients, supporting an OCCASIONAL frequency band.

Chorioretinal coloboma Chorioretinal coloboma HP:0000567

Show evidence (1 reference)

PMID:24798461 SUPPORT Human Clinical

"two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures"

The report documents chorioretinal coloboma in two affected siblings.

Microphthalmia OCCASIONAL Microphthalmia HP:0000568

Show evidence (1 reference)

PMID:29383837 SUPPORT Human Clinical

"16.4% (9/55) had microphthalmia"

The delineation cohort quantifies microphthalmia in 16.4% of patients, supporting an OCCASIONAL frequency band.

Head and Neck 1

Facial dysmorphism Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:31853307 SUPPORT Human Clinical

"C12orf57 pathogenic variants are mainly associated with global developmental delay, epilepsy and dysmorphic facial appearances"

The literature-review case report identifies dysmorphic facial appearance as a main associated feature.

Nervous System 7

Intellectual disability OBLIGATE Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:29383837 SUPPORT Human Clinical

"While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable"

The combined cohort of 56 patients reports intellectual disability in all affected individuals.

Global developmental delay VERY_FREQUENT Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:23453665 SUPPORT Human Clinical

"colobomatous microphthalmia is associated with profound global developmental delay, intractable seizures, and corpus callosum abnormalities"

The founding report documents profound global developmental delay in affected patients.

Seizure FREQUENT Seizure HP:0001250

Show evidence (2 references)

PMID:29383837 SUPPORT Human Clinical

"73.2% (41/56) had epilepsy"

The delineation cohort quantifies epilepsy/seizures in 73.2% of patients, supporting a FREQUENT frequency band.

PMID:24798461 SUPPORT Human Clinical

"including agenesis/hypoplasia of the corpus callosum, optic coloboma, and intractable seizures"

The report documents intractable seizures as part of the syndrome.

Corpus callosum abnormality FREQUENT Hypoplasia of the corpus callosum HP:0002079

Show evidence (2 references)

PMID:29383837 SUPPORT Human Clinical

"63% (34/54) had corpus callosal abnormalities"

The delineation cohort quantifies corpus callosal abnormalities in 63% of patients, supporting a FREQUENT frequency band.

PMID:24798461 SUPPORT Human Clinical

"including agenesis/hypoplasia of the corpus callosum, optic coloboma, and intractable seizures"

The report documents agenesis/hypoplasia of the corpus callosum as part of the syndrome.

Agenesis of corpus callosum Agenesis of corpus callosum HP:0001274

Show evidence (1 reference)

PMID:35791610 SUPPORT Human Clinical

"Temtamy syndrome, an extremely rare disorder characterized by intellectual disability, seizures, facial dysmorphism and agenesis of corpus callosum"

This case report lists agenesis of the corpus callosum among the defining features of the syndrome.

Cerebral white matter abnormality FREQUENT Abnormal cerebral white matter morphology HP:0002500

Show evidence (1 reference)

PMID:29383837 SUPPORT Human Clinical

"brain white matter abnormalities (38%, 19/50)"

The delineation cohort documents brain white matter abnormalities in 38% of patients, supporting a FREQUENT frequency band.

Autistic behavior Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:37451886 SUPPORT Human Clinical

"Temtamy syndrome is a rare syndromic intellectual developmental disorder that presents with global developmental delay, autism, seizures, and agenesis/dysgenesis of the corpus callosum"

The case report describes autism as part of the Temtamy syndrome phenotype.

🧬

Genetic Associations

1

C12orf57 (Pathogenic Variants)

Gene: C12orf57 hgnc:29521

Autosomal recessive inheritance

Show evidence (3 references)

PMID:23453666 SUPPORT Human Clinical

"Exome sequence analysis identified C12orf57 mutations at the initiator methionine codon in four different families."

The founding study identifies recurrent C12orf57 start-loss mutations in multiple families with the syndrome.

PMID:29383837 SUPPORT Human Clinical

"we noted a high carrier frequency of an ancient startloss founder mutation"

The delineation study identifies a recurrent ancestral start-loss founder variant as a common cause of the syndrome.

PMID:24798461 SUPPORT Human Clinical

"two compound heterozygous loss-of-function mutations in C12orf57 identified by exome sequencing, including a novel nonsense mutation"

The report documents compound heterozygous loss-of-function variants, supporting a loss-of-function disease mechanism.

💊

Medical Actions

3

Antiseizure Medication

Action: pharmacotherapy MAXO:0000058

Agent: anticonvulsant agent NCIT:C264

Seizures in Temtamy syndrome are often intractable and managed with antiseizure (antiepileptic) drugs as supportive symptomatic therapy; no disease-modifying treatment exists.

Mechanism Target:

MODULATES Seizure — Antiseizure medication suppresses the seizures arising from increased excitatory drive, but does not address the underlying genetic defect.

Show evidence (1 reference)

PMID:24798461 SUPPORT Human Clinical

"including agenesis/hypoplasia of the corpus callosum, optic coloboma, and intractable seizures"

The intractable seizures of the syndrome are the target of symptomatic antiseizure therapy.

Show evidence (1 reference)

PMID:24798461 SUPPORT Human Clinical

"including agenesis/hypoplasia of the corpus callosum, optic coloboma, and intractable seizures"

The intractable seizures documented in patients are managed with antiseizure pharmacotherapy as supportive care.

Supportive and Multidisciplinary Care

Action: supportive care MAXO:0000950

Management is supportive and multidisciplinary, addressing developmental delay, intellectual disability, seizures, ophthalmologic involvement, and cardiac disease.

Show evidence (1 reference)

PMID:29383837 SUPPORT Human Clinical

"While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable"

The multisystem phenotype documented in the cohort requires multidisciplinary supportive management.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Given autosomal recessive inheritance and recurrent founder alleles in certain populations, genetic counseling and carrier testing are important for affected families.

Show evidence (1 reference)

PMID:29383837 SUPPORT Human Clinical

"especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability"

The high carrier frequency of a recessive founder mutation supports the value of genetic counseling and carrier testing.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Temtamy Syndrome:

Kabuki Syndrome MONDO:0016512

Overlapping Features Temtamy syndrome can present with overlapping features of Kabuki-like syndrome, including long palpebral fissures with eversion of the lateral lower eyelid and persistent fetal fingertip pads, making Kabuki syndrome an important clinical mimic.

Distinguishing Features

Biallelic C12orf57 variants confirm Temtamy syndrome.
Kabuki syndrome is caused by KMT2D or KDM6A variants.

Show evidence (1 reference)

PMID:37451886 SUPPORT Human Clinical

"The clinical features were in favor of Kabuki-like syndrome."

The case report documents phenotypic overlap with Kabuki-like syndrome, supporting it as a differential diagnosis.

{ }

Source YAML

click to show

name: Temtamy Syndrome
creation_date: "2026-06-04T00:00:00Z"
category: Mendelian
description: >-
  Temtamy syndrome is a rare autosomal recessive neurodevelopmental disorder
  caused by biallelic loss-of-function variants in C12orf57 (GRCC10). It is a
  syndromic form of intellectual disability characterized by dysgenesis,
  hypoplasia, or agenesis of the corpus callosum, ocular coloboma and
  microphthalmia, intractable seizures, craniofacial dysmorphism, and, in a
  substantial fraction of patients, congenital heart disease. A recurrent
  start-loss founder mutation (c.1A>G; p.M1?) is among the most common
  recessive causes of intellectual disability in the Saudi population. C12orf57
  encodes a small, evolutionarily conserved protein implicated in corpus
  callosum development and, more recently, in synaptic AMPA-receptor
  homeostatic downscaling in excitatory neurons.
disease_term:
  preferred_term: Temtamy syndrome
  term:
    id: MONDO:0009033
    label: temtamy syndrome
parents:
- Neurodevelopmental disorder
- Syndromic intellectual disability
synonyms:
- C12orf57-related disorder
- corpus callosum, agenesis of, with intellectual disability, ocular coloboma, and micrognathia
- Temtamy syndrome of corpus callosum and ocular abnormalities
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24798461
    reference_title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous and compound heterozygous mutations in C12orf57 have recently
      been described to cause an autosomal recessive syndromic form of
      intellectual disability
    explanation: >-
      The report explicitly classifies C12orf57-related disease as autosomal
      recessive.
pathophysiology:
- name: C12orf57 Loss of Function
  description: >-
    Biallelic loss-of-function variants in C12orf57 (GRCC10) — most commonly an
    ancestral start-loss founder mutation (c.1A>G; p.M1?) and other truncating
    or missense changes — abolish or severely reduce function of a small,
    poorly annotated 126-amino-acid protein that is ubiquitously expressed and
    tightly conserved across evolution. The protein is required for normal
    development of the human corpus callosum and is expressed in tissues
    including the eye and brain, linking its loss to the combined forebrain
    commissural and ocular developmental phenotype.
  genes:
  - preferred_term: C12orf57
    term:
      id: hgnc:29521
      label: C12orf57
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: corpus callosum development
    term:
      id: GO:0022038
      label: corpus callosum development
    modifier: ABNORMAL
  - preferred_term: eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: ABNORMAL
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23453666
    reference_title: "Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C12orf57 is ubiquitously expressed and encodes a poorly annotated 126
      amino acid protein of unknown function. This protein is without
      significant paralogs but has been tightly conserved across evolution. Our
      data suggest that this conserved gene is required for development of the
      human corpus callosum.
    explanation: >-
      The whole-exome study identifies C12orf57 as a conserved gene required for
      corpus callosum development, establishing the primary developmental defect.
  - reference: PMID:23453665
    reference_title: "Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Little is known about C12orf57 but we show that it is expressed in several
      mouse tissues, including the eye and brain.
    explanation: >-
      Expression in eye and brain links loss of C12orf57 to the combined ocular
      and CNS developmental phenotype.
  downstream:
  - target: Impaired Corpus Callosum and Forebrain Commissural Development
    description: >-
      Loss of the conserved C12orf57 protein impairs midline forebrain
      commissural development, producing agenesis, hypoplasia, or dysgenesis of
      the corpus callosum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23453666
      reference_title: "Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our data suggest that this conserved gene is required for development of
        the human corpus callosum.
      explanation: >-
        The founding cohort directly links C12orf57 loss to defective corpus
        callosum development, although the molecular intermediates remain
        unresolved.
  - target: Impaired Ocular Development
    description: >-
      C12orf57 expression in the developing eye and its association with
      colobomatous microphthalmia implicate its loss in defective ocular
      morphogenesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23453665
      reference_title: "Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our data strongly implicate mutations in C12orf57 in the pathogenesis of
        a clinically distinct autosomal-recessive syndromic form of colobomatous
        microphthalmia.
      explanation: >-
        The founding paper links C12orf57 loss to colobomatous microphthalmia,
        an ocular developmental defect.
  - target: Disrupted Synaptic AMPA-Receptor Homeostasis
    description: >-
      Beyond its developmental role, loss of C12orf57/GRCC10 disrupts activity
      dependent synaptic homeostatic downscaling in excitatory neurons,
      providing a candidate mechanism for the epilepsy and intellectual
      disability of the syndrome.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - CAMK4 activity modulation
    - CREB and ARC expression regulation
    - AMPA receptor downscaling
    evidence:
    - reference: PMID:39974932
      reference_title: "C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We further found that GRCC10/C12ORF57 modulates the activity of
        calcium/calmodulin dependent kinase 4 (CAMK4) and thereby regulates the
        expression of CREB and ARC.
      explanation: >-
        The mouse-model and in vitro study defines a molecular pathway
        (CAMK4-CREB-ARC) connecting C12orf57 loss to disrupted synaptic AMPA
        receptor homeostasis.
- name: Impaired Corpus Callosum and Forebrain Commissural Development
  description: >-
    Defective midline commissural development produces a spectrum of corpus
    callosum abnormalities ranging from complete agenesis to hypoplasia or
    dysgenesis, often accompanied by cerebral white matter abnormalities.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: corpus callosum development
    term:
      id: GO:0022038
      label: corpus callosum development
    modifier: ABNORMAL
  - preferred_term: commissural neuron axon guidance
    term:
      id: GO:0071679
      label: commissural neuron axon guidance
    modifier: ABNORMAL
  locations:
  - preferred_term: corpus callosum
    term:
      id: UBERON:0002336
      label: corpus callosum
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      63% (34/54) had corpus callosal abnormalities
    explanation: >-
      The combined cohort quantifies corpus callosal abnormalities as a frequent
      feature of the syndrome.
  downstream:
  - target: Corpus callosum abnormality
    description: >-
      Defective commissural development manifests as agenesis, hypoplasia, or
      dysgenesis of the corpus callosum on neuroimaging.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24798461
      reference_title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        an autosomal recessive syndromic form of intellectual disability,
        including agenesis/hypoplasia of the corpus callosum, optic coloboma, and
        intractable seizures
      explanation: >-
        The clinical description directly links the syndrome to
        agenesis/hypoplasia of the corpus callosum.
  - target: Cerebral white matter abnormality
    description: >-
      Brain white matter abnormalities accompany the commissural defect in a
      substantial fraction of patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29383837
      reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a high frequency of less recognized features such as congenital heart
        disease (51.4%), and brain white matter abnormalities (38%, 19/50)
      explanation: >-
        The delineation cohort documents brain white matter abnormalities as a
        recurrent imaging feature.
- name: Impaired Ocular Development
  description: >-
    Disrupted ocular morphogenesis produces a spectrum of eye malformations,
    including coloboma (iris, chorioretinal, optic disc) and microphthalmia,
    that defined the original colobomatous-microphthalmia presentation.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: ABNORMAL
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  evidence:
  - reference: PMID:23453665
    reference_title: "Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      colobomatous microphthalmia is associated with profound global
      developmental delay, intractable seizures, and corpus callosum
      abnormalities
    explanation: >-
      The founding paper documents colobomatous microphthalmia as the defining
      ocular phenotype.
  downstream:
  - target: Coloboma
    description: >-
      Ocular maldevelopment manifests as coloboma affecting the iris, retina, or
      optic disc.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29383837
      reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        14.5% (8/55) had coloboma
      explanation: >-
        The delineation cohort quantifies coloboma as a recurring ocular feature.
  - target: Microphthalmia
    description: >-
      Ocular maldevelopment can produce microphthalmia, the original defining
      ocular feature of the syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29383837
      reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        16.4% (9/55) had microphthalmia
      explanation: >-
        The delineation cohort quantifies microphthalmia among affected patients.
- name: Disrupted Synaptic AMPA-Receptor Homeostasis
  description: >-
    Loss of C12orf57/GRCC10 disrupts the homeostatic downscaling of synaptic
    AMPA receptors that normally accompanies elevated neuronal activity. In a
    Grcc10 knockout mouse, hippocampal neurons show increased AMPA receptor
    expression and larger miniature excitatory postsynaptic currents, with
    increased epileptiform activity, via modulation of CAMK4 and downstream CREB
    and ARC expression.
  cell_types:
  - preferred_term: glutamatergic neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  - preferred_term: hippocampal neuron
    term:
      id: CL:0002608
      label: hippocampal neuron
  genes:
  - preferred_term: CAMK4
    term:
      id: hgnc:1464
      label: CAMK4
  biological_processes:
  - preferred_term: regulation of AMPA receptor activity
    term:
      id: GO:2000311
      label: regulation of AMPA receptor activity
    modifier: ABNORMAL
  - preferred_term: regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39974932
    reference_title: "C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      hippocampal neurons in these mice exhibited significantly increased AMPA
      receptor expression levels and higher amplitude of miniature excitatory
      postsynaptic currents (mEPSCs)
    explanation: >-
      The knockout mouse model demonstrates the AMPA-receptor and synaptic
      current abnormalities downstream of Grcc10/C12orf57 loss.
  - reference: PMID:39974932
    reference_title: "C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      deletion of Grcc10 disrupts the characteristic synaptic AMPA receptor
      downscaling that accompanies increased activity in glutamatergic neurons
    explanation: >-
      The study identifies disrupted AMPA-receptor homeostatic downscaling as the
      core synaptic mechanism.
  downstream:
  - target: Seizure
    description: >-
      Disrupted AMPA-receptor downscaling increases excitatory drive and seizure
      susceptibility, recapitulated as increased epileptiform activity in the
      knockout model.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased AMPA receptor expression
    - increased excitatory postsynaptic currents
    evidence:
    - reference: PMID:39974932
      reference_title: "C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Grcc10 KO mice exhibit the characteristic phenotypic features seen in
        human TS patients, including increased epileptiform activity.
      explanation: >-
        The knockout model links disrupted synaptic homeostasis to increased
        epileptiform activity, paralleling the seizures seen in patients.
phenotypes:
- category: Clinical
  name: Intellectual disability
  description: >-
    Intellectual disability / developmental delay is a constant feature, present
    in all reported patients, and can be severe.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: OBLIGATE
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While all patients presented with intellectual disability/developmental
      delay, the frequency of other phenotypic features was variable
    explanation: >-
      The combined cohort of 56 patients reports intellectual disability in all
      affected individuals.
- category: Clinical
  name: Global developmental delay
  description: >-
    Affected children show profound global developmental delay.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23453665
    reference_title: "Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      colobomatous microphthalmia is associated with profound global
      developmental delay, intractable seizures, and corpus callosum
      abnormalities
    explanation: >-
      The founding report documents profound global developmental delay in
      affected patients.
- category: Clinical
  name: Seizure
  description: >-
    Seizures are frequent and often intractable, occurring in roughly
    three-quarters of patients.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: FREQUENT
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      73.2% (41/56) had epilepsy
    explanation: >-
      The delineation cohort quantifies epilepsy/seizures in 73.2% of patients,
      supporting a FREQUENT frequency band.
  - reference: PMID:24798461
    reference_title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including agenesis/hypoplasia of the corpus callosum, optic coloboma, and
      intractable seizures
    explanation: >-
      The report documents intractable seizures as part of the syndrome.
- category: Clinical
  name: Corpus callosum abnormality
  description: >-
    Agenesis, hypoplasia, or dysgenesis of the corpus callosum is a defining
    neuroanatomic feature, present in roughly two-thirds of patients.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  frequency: FREQUENT
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      63% (34/54) had corpus callosal abnormalities
    explanation: >-
      The delineation cohort quantifies corpus callosal abnormalities in 63% of
      patients, supporting a FREQUENT frequency band.
  - reference: PMID:24798461
    reference_title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including agenesis/hypoplasia of the corpus callosum, optic coloboma, and
      intractable seizures
    explanation: >-
      The report documents agenesis/hypoplasia of the corpus callosum as part of
      the syndrome.
- category: Clinical
  name: Agenesis of corpus callosum
  description: >-
    Complete agenesis of the corpus callosum occurs at the severe end of the
    commissural-defect spectrum.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:35791610
    reference_title: "C12orf57 pathogenic variants: a unique cause of developmental encephalopathy in a south Indian child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Temtamy syndrome, an extremely rare disorder characterized by intellectual
      disability, seizures, facial dysmorphism and agenesis of corpus callosum
    explanation: >-
      This case report lists agenesis of the corpus callosum among the defining
      features of the syndrome.
- category: Clinical
  name: Coloboma
  description: >-
    Ocular coloboma (iris, chorioretinal, or optic disc) is a characteristic eye
    malformation, present in roughly 15% of patients.
  phenotype_term:
    preferred_term: Coloboma
    term:
      id: HP:0000589
      label: Coloboma
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      14.5% (8/55) had coloboma
    explanation: >-
      The delineation cohort quantifies coloboma in 14.5% of patients, supporting
      an OCCASIONAL frequency band.
- category: Clinical
  name: Chorioretinal coloboma
  description: >-
    Chorioretinal coloboma is among the specific ocular coloboma subtypes
    reported in the syndrome.
  phenotype_term:
    preferred_term: Chorioretinal coloboma
    term:
      id: HP:0000567
      label: Chorioretinal coloboma
  evidence:
  - reference: PMID:24798461
    reference_title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two siblings with severe intellectual disability, hypoplasia of the corpus
      callosum, chorioretinal coloboma, and intractable seizures
    explanation: >-
      The report documents chorioretinal coloboma in two affected siblings.
- category: Clinical
  name: Microphthalmia
  description: >-
    Microphthalmia (small eye) was the original defining ocular feature and
    occurs in roughly 16% of patients.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      16.4% (9/55) had microphthalmia
    explanation: >-
      The delineation cohort quantifies microphthalmia in 16.4% of patients,
      supporting an OCCASIONAL frequency band.
- category: Clinical
  name: Facial dysmorphism
  description: >-
    Craniofacial dysmorphism is a recurrent feature of the syndrome.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:31853307
    reference_title: "Temtamy syndrome caused by a new C12orf57 variant in a Chinese boy, including pedigree analysis and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C12orf57 pathogenic variants are mainly associated with global
      developmental delay, epilepsy and dysmorphic facial appearances
    explanation: >-
      The literature-review case report identifies dysmorphic facial appearance
      as a main associated feature.
- category: Clinical
  name: Congenital heart disease
  description: >-
    Congenital heart disease is a less recognized but frequent feature,
    documented in roughly half of patients in the largest delineation cohort.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a high frequency of less recognized features such as congenital heart
      disease (51.4%), and brain white matter abnormalities (38%, 19/50)
    explanation: >-
      The combined cohort reports congenital heart disease in 51.4% of patients,
      supporting a FREQUENT frequency band.
- category: Clinical
  name: Cerebral white matter abnormality
  description: >-
    Brain white matter abnormalities accompany the commissural defect in a
    substantial fraction of patients.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brain white matter abnormalities (38%, 19/50)
    explanation: >-
      The delineation cohort documents brain white matter abnormalities in 38% of
      patients, supporting a FREQUENT frequency band.
- category: Clinical
  name: Autistic behavior
  description: >-
    Autism / autistic behavior has been reported as part of the
    neurodevelopmental phenotype.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:37451886
    reference_title: "A novel pathogenic compound heterozygous variant in C12orf57 gene in a child with Temtamy syndrome presenting with overlapping phenotypic features of Kabuki-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Temtamy syndrome is a rare syndromic intellectual developmental disorder
      that presents with global developmental delay, autism, seizures, and
      agenesis/dysgenesis of the corpus callosum
    explanation: >-
      The case report describes autism as part of the Temtamy syndrome
      phenotype.
genetic:
- name: C12orf57
  gene_term:
    preferred_term: C12orf57
    term:
      id: hgnc:29521
      label: C12orf57
  association: Pathogenic Variants
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:23453666
      reference_title: "Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        members affected with corpus callosum hypoplasia (CCH) lacked syndromic
        features and had consanguineous parents, suggesting recessive causes
      explanation: >-
        Affected individuals with consanguineous parents establish autosomal
        recessive inheritance of the C12orf57-related syndrome.
  evidence:
  - reference: PMID:23453666
    reference_title: "Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequence analysis identified C12orf57 mutations at the initiator
      methionine codon in four different families.
    explanation: >-
      The founding study identifies recurrent C12orf57 start-loss mutations in
      multiple families with the syndrome.
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we noted a high carrier frequency of an ancient startloss founder mutation
    explanation: >-
      The delineation study identifies a recurrent ancestral start-loss founder
      variant as a common cause of the syndrome.
  - reference: PMID:24798461
    reference_title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two compound heterozygous loss-of-function mutations in C12orf57
      identified by exome sequencing, including a novel nonsense mutation
    explanation: >-
      The report documents compound heterozygous loss-of-function variants,
      supporting a loss-of-function disease mechanism.
diagnosis:
- name: Molecular Genetic Testing
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  description: >-
    Exome or targeted sequencing of C12orf57 confirms the diagnosis by
    identifying biallelic pathogenic variants, frequently the recurrent
    start-loss founder allele.
  evidence:
  - reference: PMID:24798461
    reference_title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with genetically heterogeneous disorders such as intellectual
      disability or epilepsy, exome sequencing is a powerful tool to elucidate
      the underlying genetic cause.
    explanation: >-
      Exome sequencing is the diagnostic modality used to identify C12orf57
      variants in these patients.
differential_diagnoses:
- name: Kabuki Syndrome
  disease_term:
    preferred_term: Kabuki syndrome
    term:
      id: MONDO:0016512
      label: Kabuki syndrome
  description: >-
    Temtamy syndrome can present with overlapping features of Kabuki-like
    syndrome, including long palpebral fissures with eversion of the lateral
    lower eyelid and persistent fetal fingertip pads, making Kabuki syndrome an
    important clinical mimic.
  distinguishing_features:
  - Biallelic C12orf57 variants confirm Temtamy syndrome.
  - Kabuki syndrome is caused by KMT2D or KDM6A variants.
  evidence:
  - reference: PMID:37451886
    reference_title: "A novel pathogenic compound heterozygous variant in C12orf57 gene in a child with Temtamy syndrome presenting with overlapping phenotypic features of Kabuki-like syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical features were in favor of Kabuki-like syndrome.
    explanation: >-
      The case report documents phenotypic overlap with Kabuki-like syndrome,
      supporting it as a differential diagnosis.
clinical_trials: []
datasets: []
treatments:
- name: Antiseizure Medication
  description: >-
    Seizures in Temtamy syndrome are often intractable and managed with
    antiseizure (antiepileptic) drugs as supportive symptomatic therapy; no
    disease-modifying treatment exists.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_mechanisms:
  - target: Seizure
    treatment_effect: MODULATES
    description: >-
      Antiseizure medication suppresses the seizures arising from increased
      excitatory drive, but does not address the underlying genetic defect.
    evidence:
    - reference: PMID:24798461
      reference_title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        including agenesis/hypoplasia of the corpus callosum, optic coloboma, and
        intractable seizures
      explanation: >-
        The intractable seizures of the syndrome are the target of
        symptomatic antiseizure therapy.
  evidence:
  - reference: PMID:24798461
    reference_title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including agenesis/hypoplasia of the corpus callosum, optic coloboma, and
      intractable seizures
    explanation: >-
      The intractable seizures documented in patients are managed with
      antiseizure pharmacotherapy as supportive care.
- name: Supportive and Multidisciplinary Care
  description: >-
    Management is supportive and multidisciplinary, addressing developmental
    delay, intellectual disability, seizures, ophthalmologic involvement, and
    cardiac disease.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While all patients presented with intellectual disability/developmental
      delay, the frequency of other phenotypic features was variable
    explanation: >-
      The multisystem phenotype documented in the cohort requires
      multidisciplinary supportive management.
- name: Genetic Counseling
  description: >-
    Given autosomal recessive inheritance and recurrent founder alleles in
    certain populations, genetic counseling and carrier testing are important
    for affected families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29383837
    reference_title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      especially in those who trace their ancestry to Saudi Arabia where a
      founder C12orf57 mutation is among the most common recessive causes of
      intellectual disability
    explanation: >-
      The high carrier frequency of a recessive founder mutation supports the
      value of genetic counseling and carrier testing.
# NOTE: No GeneReviews chapter exists for Temtamy syndrome (C12orf57); the
# founding clinical/molecular descriptions (Zahrani 2013, Akizu 2013) and the
# combined delineation cohort (Alrakaf 2018) serve as the baseline references.
references:
- reference: PMID:23453665
  title: "Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia."
- reference: PMID:23453666
  title: "Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia."
- reference: PMID:24798461
  title: "Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures."
- reference: PMID:29383837
  title: "Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities."
- reference: PMID:31853307
  title: "Temtamy syndrome caused by a new C12orf57 variant in a Chinese boy, including pedigree analysis and literature review."
- reference: PMID:35791610
  title: "C12orf57 pathogenic variants: a unique cause of developmental encephalopathy in a south Indian child."
- reference: PMID:37451886
  title: "A novel pathogenic compound heterozygous variant in C12orf57 gene in a child with Temtamy syndrome presenting with overlapping phenotypic features of Kabuki-like syndrome."
- reference: PMID:39974932
  title: "C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis."

📚

References & Deep Research

References

8

PMID:23453665

Mutations in c12orf57 cause a syndromic form of colobomatous microphthalmia.

No top-level findings curated for this source.

PMID:23453666

Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia.

No top-level findings curated for this source.

PMID:24798461

Exome sequencing identifies compound heterozygous mutations in C12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures.

No top-level findings curated for this source.

PMID:29383837

Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities.

No top-level findings curated for this source.

PMID:31853307

Temtamy syndrome caused by a new C12orf57 variant in a Chinese boy, including pedigree analysis and literature review.

No top-level findings curated for this source.

PMID:35791610

C12orf57 pathogenic variants: a unique cause of developmental encephalopathy in a south Indian child.

No top-level findings curated for this source.

PMID:37451886

A novel pathogenic compound heterozygous variant in C12orf57 gene in a child with Temtamy syndrome presenting with overlapping phenotypic features of Kabuki-like syndrome.

No top-level findings curated for this source.

PMID:39974932

C12ORF57: a novel principal regulator of synaptic AMPA currents and excitatory neuronal homeostasis.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

1. Disease Information

Edison Scientific Literature 42 citations 2026-06-04T11:04:39.557651

1. Disease Information

1.1 Concise overview

C12orf57-related Temtamy syndrome (MIM 218340) is an extremely rare autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay / intellectual disability, epilepsy, frequent corpus callosum hypoplasia/agenesis, and variable ocular anomalies including coloboma, often with autistic features, hypotonia, and dysmorphic facial features. (wang2020temtamysyndromecaused pages 1-2, akizu2013wholeexomesequencingidentifies pages 2-4, platzer2014exomesequencingidentifies pages 3-5)

Temtamy preaxial brachydactyly syndrome (TPBS; MIM 605282) is an autosomal recessive multiple-congenital-anomaly syndrome with hallmark bilateral symmetric preaxial brachydactyly and hyperphalangism, frequently accompanied by hearing loss, dental anomalies, craniofacial dysmorphism, and growth retardation; it is caused by loss-of-function mutations in CHSY1. (li2010temtamypreaxialbrachydactyly pages 1-2, li2010temtamypreaxialbrachydactyly pages 5-7, li2010temtamypreaxialbrachydactyly pages 4-5)

1.2 Key identifiers and synonyms (from retrieved sources)

C12orf57-related Temtamy syndrome: reported as “Temtamy syndrome (MIM 218340)” in case-series literature. (wang2020temtamysyndromecaused pages 1-2, alfiya2022c12orf57pathogenicvariants pages 1-3)
TPBS: “Temtamy preaxial brachydactyly syndrome (MIM 605282)”. (li2010temtamypreaxialbrachydactyly pages 1-2)

Common alternative names used in retrieved sources (non-exhaustive; varies by author): - “Temtamy syndrome of corpus callosum and ocular abnormalities” (as cited in a 2024 founder-mutation perspective). (marafi2024foundermutationsand pages 6-7) - “Syndromic form of intellectual disability characterized by agenesis/hypoplasia of the corpus callosum, optic/chorioretinal coloboma, and intractable seizures” (used to describe C12orf57-related disease). (platzer2014exomesequencingidentifies pages 1-2)

1.3 Evidence types

Most available disease characterization in retrieved sources is derived from: - Aggregated case series / literature reviews (e.g., compiled cohorts of 17–56+ patients) (wang2020temtamysyndromecaused pages 2-4, platzer2014exomesequencingidentifies pages 3-5) - Individual case reports (e.g., a Chinese patient with a novel C12orf57 start-codon variant) (wang2020temtamysyndromecaused pages 1-2) - Genetic-discovery family studies (consanguineous multiplex families) including functional assays for one recurrent allele (akizu2013wholeexomesequencingidentifies pages 2-4, akizu2013wholeexomesequencingidentifies pages 5-7)

2. Etiology

2.1 Disease causal factors

A) C12orf57-related Temtamy syndrome (MIM 218340)

Cause: biallelic pathogenic variants in C12orf57, frequently affecting the translation initiation codon (start-loss). (wang2020temtamysyndromecaused pages 1-2, akizu2013wholeexomesequencingidentifies pages 2-4)
Inheritance: autosomal recessive with segregation consistent with full penetrance within reported pedigrees. (wang2020temtamysyndromecaused pages 2-4, akizu2013wholeexomesequencingidentifies pages 2-4)

B) TPBS (MIM 605282)

Cause: biallelic loss-of-function variants in CHSY1, encoding chondroitin synthase 1. (li2010temtamypreaxialbrachydactyly pages 1-2, li2010temtamypreaxialbrachydactyly pages 5-7)
Inheritance: autosomal recessive, commonly reported in consanguineous families. (li2010temtamypreaxialbrachydactyly pages 1-2, sher2014anovelchsy1 pages 2-4)

2.2 Risk factors

Consanguinity / endogamy is repeatedly observed in reported C12orf57 cases; in a compiled review of 56 patients, 49/56 (87.7%) were from consanguineous families. (wang2020temtamysyndromecaused pages 2-4)
Geographic clustering suggests population-specific recurrence (Middle East enrichment): in Wang’s 2020 review, 54/56 (96.4%) of reported patients were from Middle Eastern countries, consistent with founder effects and ascertainment patterns. (wang2020temtamysyndromecaused pages 1-2)

2.3 Protective factors / gene–environment interactions

No protective alleles or gene–environment interactions were identified in the retrieved sources.

3. Phenotypes

3.1 C12orf57-related Temtamy syndrome: phenotype spectrum (with frequencies)

The most quantitative phenotype synthesis in retrieved sources comes from Wang 2020 (n=56 literature review) and Platzer 2014 (n=17 aggregated from 7 families). (wang2020temtamysyndromecaused pages 2-4, platzer2014exomesequencingidentifies pages 3-5)

Clinical feature	Frequency/notes (with source and n/N)	Suggested HPO term(s)
Global developmental delay / developmental delay	56/56 (100%) in literature review summarized by Wang 2020; all 17/17 had developmental delay in Platzer 2014 cohort summary (wang2020temtamysyndromecaused pages 2-4, platzer2014exomesequencingidentifies pages 3-5)	HP:0001263 Global developmental delay; HP:0001268 Mental deterioration / developmental regression not established
Intellectual disability, severe	Moderate-to-severe intellectual disability reported in Akizu families; severe ID in 11/11 cases with specified cognitive testing in Platzer 2014 (akizu2013wholeexomesequencingidentifies pages 2-4, platzer2014exomesequencingidentifies pages 3-5)	HP:0010864 Intellectual disability, severe
Epilepsy / seizures	41/56 (73.7%) in Wang 2020 review; 41/56 (~73.2%) in Wang 2020 text; 15/17 (88%) in Platzer 2014 summary; onset by age ≤3 years in 9/9 specified cases in Platzer 2014 (wang2020temtamysyndromecaused pages 2-4, wang2020temtamysyndromecaused pages 4-6, platzer2014exomesequencingidentifies pages 3-5)	HP:0001250 Seizure; HP:0002373 EEG abnormality
Refractory / difficult-to-control seizures	Historically 37.5% relatively refractory and only 15.6% seizure-free in Wang 2020 review; difficult to control in 7/9 (78%) in Platzer 2014 despite multiple AED trials (wang2020temtamysyndromecaused pages 4-6, platzer2014exomesequencingidentifies pages 3-5)	HP:0001272 Cerebral seizure resistant to treatment
Absent or very limited speech	41/55 (74.5%) absent speech in Wang 2020 review; 15/17 had no active speech in Platzer 2014 summary (wang2020temtamysyndromecaused pages 2-4, platzer2014exomesequencingidentifies pages 3-5)	HP:0001344 Absent speech; HP:0000750 Delayed speech and language development
Generalized hypotonia	40/56 (71.9%) in Wang 2020 review; hypotonia present in Akizu families (wang2020temtamysyndromecaused pages 2-4, akizu2013wholeexomesequencingidentifies pages 2-4)	HP:0001290 Generalized hypotonia
Autistic behavior / autistic features	40/55 (72.7%) in Wang 2020 review; all 10/10 affected had autistic features in Akizu families; ASD reported in 6/17 (35%) in Platzer 2014 summary (wang2020temtamysyndromecaused pages 2-4, akizu2013wholeexomesequencingidentifies pages 2-4, platzer2014exomesequencingidentifies pages 3-5)	HP:0000729 Autistic behavior
Corpus callosum abnormality (hypoplasia/agenesis)	~34/54 (61.8%) in Wang 2020 review; corpus callosum absent in 3 and hypoplastic in 5 of 8 imaged in Akizu; 12/15 (80%) in Platzer 2014 summary (wang2020temtamysyndromecaused pages 4-6, akizu2013wholeexomesequencingidentifies pages 2-4, platzer2014exomesequencingidentifies pages 3-5)	HP:0001274 Agenesis of corpus callosum; HP:0002079 Hypoplasia of the corpus callosum
Ventriculomegaly / enlarged ventricles	17/50 (35.3%) in Wang 2020 review; thalamic hypoplasia with enlarged V-shaped third ventricle described in Akizu families (wang2020temtamysyndromecaused pages 4-6, akizu2013wholeexomesequencingidentifies pages 2-4)	HP:0002119 Ventriculomegaly; HP:0006842 Abnormality of the third ventricle
Ocular anomalies, overall	26/56 (46.4%) in Wang 2020 review (as summarized in Wang text); visual abnormalities in 4/10 in Akizu; visual impairment in 9/17 (53%) in Platzer 2014 summary (wang2020temtamysyndromecaused pages 2-4, akizu2013wholeexomesequencingidentifies pages 2-4, platzer2014exomesequencingidentifies pages 3-5)	HP:0000478 Abnormality of the eye
Coloboma / chorioretinal coloboma	8/55 (14.5%) coloboma in Wang 2020 review; optic/chorioretinal coloboma in 5/17 (29%) in Platzer 2014 summary (wang2020temtamysyndromecaused pages 4-6, platzer2014exomesequencingidentifies pages 3-5)	HP:0000589 Coloboma of optic disc; HP:0000490 Chorioretinal coloboma; HP:0000486 Strabismus not specifically established
Dysmorphic facial features	36/55 (66.1%) in Wang 2020 review; Wang abstract/text also notes dysmorphic craniofacial appearance as common (wang2020temtamysyndromecaused pages 4-6, wang2020temtamysyndromecaused pages 1-2)	HP:0001999 Facial dysmorphism
Atrial septal defect / cardiac defect	16/55 (30.4%) atrial septal defect in Wang 2020 review; cardiac defects variably reported in case literature (wang2020temtamysyndromecaused pages 4-6)	HP:0001631 Atrial septal defect
Spasticity	10/17 (59%) in Platzer 2014 summary (platzer2014exomesequencingidentifies pages 3-5)	HP:0001257 Spasticity
Visual impairment	9/17 (53%) in Platzer 2014 summary; abnormal visual function in 4/10 in Akizu families (akizu2013wholeexomesequencingidentifies pages 2-4, platzer2014exomesequencingidentifies pages 3-5)	HP:0000505 Visual impairment

Table: This table summarizes the main reported phenotypes of C12orf57-related Temtamy syndrome using frequencies from Wang 2020 and Platzer 2014, with related HPO suggestions. It is useful for structured phenotype annotation and for comparing feature prevalence across published case series.

Key clinical concepts (current understanding): - Neurodevelopmental impairment is universal (developmental delay 100% in Wang review). (wang2020temtamysyndromecaused pages 2-4) - Epilepsy is common (73.7% in Wang review; 88% in Platzer summary) and may be treatment-resistant in a substantial subset. (wang2020temtamysyndromecaused pages 4-6, platzer2014exomesequencingidentifies pages 3-5) - Brain imaging abnormalities frequently involve the corpus callosum; Akizu described variable severity from hypoplasia to agenesis within and across families. (akizu2013wholeexomesequencingidentifies pages 2-4) - Ocular involvement may include coloboma (14.5% in Wang review; 29% in Platzer summary). (wang2020temtamysyndromecaused pages 4-6, platzer2014exomesequencingidentifies pages 3-5)

3.2 Age of onset, progression, severity

C12orf57-related disease is typically early onset. In the Platzer aggregated series, where specified, seizure onset occurred by ≤3 years (9/9). (platzer2014exomesequencingidentifies pages 3-5)
Severity is variable, including within families, which has been proposed to relate to hypomorphic effects of start-codon variants that reduce (rather than abolish) protein production. (akizu2013wholeexomesequencingidentifies pages 5-7)

3.3 TPBS: phenotype spectrum (qualitative)

TPBS has a distinct phenotype dominated by limb development anomalies: - “Typical preaxial brachydactyly of digits 1–3” with hyper- and symphalangism, duplicated phalanges/metatarsals, and additional skeletal anomalies (radio-ulnar synostosis, carpal/tarsal fusions). (li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 4-5) - Syndromic features include facial dysmorphism, dental anomalies, growth retardation/short stature, and frequent sensorineural hearing loss. (li2010temtamypreaxialbrachydactyly pages 1-2, sher2014anovelchsy1 pages 2-4)

3.4 Quality-of-life impact

No standardized QoL instruments (e.g., EQ-5D, PROMIS) were identified in retrieved sources. However, the high rates of absent speech, severe ID, and refractory seizures indicate substantial functional impact in C12orf57-related disease. (wang2020temtamysyndromecaused pages 2-4, platzer2014exomesequencingidentifies pages 3-5)

4. Genetic / Molecular Information

4.1 Causal genes

C12orf57 (Temtamy syndrome; MIM 218340). (wang2020temtamysyndromecaused pages 1-2, akizu2013wholeexomesequencingidentifies pages 2-4)
CHSY1 (TPBS; MIM 605282). (li2010temtamypreaxialbrachydactyly pages 1-2)

4.2 Pathogenic variants (examples with evidence)

Disease entity	Gene	Variant (c.; p.)	Variant type	Evidence/notes (founder, segregation, functional)	Reported in (paper, year)	URL
Temtamy syndrome (C12orf57-related)	C12orf57	c.1A>G; p.Met1? / p.M1V	Start-loss / initiator codon variant	Homozygous in multiple consanguineous Arab families; segregated with disease under AR inheritance; absent from >1,400 exomes and ethnically matched controls in Akizu; recurrent in Arab patients and suggested founder effect; functional data show AUG→GUG can still initiate translation but with markedly reduced protein levels; 2024 ASD study again found the homozygous variant in affected brothers (akizu2013wholeexomesequencingidentifies pages 2-4, akizu2013wholeexomesequencingidentifies pages 5-7, alsarraj2024thegeneticlandscape pages 10-11, platzer2014exomesequencingidentifies pages 3-5, alfiya2022c12orf57pathogenicvariants pages 3-4)	Akizu et al., 2013; Platzer et al., 2014; Al-Sarraj et al., 2024; Alfiya et al., 2022	https://doi.org/10.1016/j.ajhg.2013.02.004; https://doi.org/10.1002/ajmg.a.36592; https://doi.org/10.3389/fgene.2024.1363849; https://doi.org/10.1007/s12041-022-01371-0
Temtamy syndrome (C12orf57-related)	C12orf57	c.3G>C; p.Met1Ile	Start-loss / start-codon variant	Novel homozygous variant in a Chinese boy; segregated with AR inheritance and full penetrance in pedigree; predicted to abolish translation / cause loss of function; expanded ethnic spectrum beyond predominantly Middle Eastern cases (wang2020temtamysyndromecaused pages 1-2, wang2020temtamysyndromecaused pages 4-6, wang2020temtamysyndromecaused pages 2-4)	Wang et al., 2020	https://doi.org/10.3892/etm.2019.8183
Temtamy syndrome (C12orf57-related)	C12orf57	c.184C>T; p.Gln62*	Nonsense / stop-gain	Novel nonsense allele reported in trans with c.1A>G in two siblings from nonconsanguineous German parents; compound heterozygous loss-of-function genotype confirmed by parental studies; associated with severe ID, callosal hypoplasia, chorioretinal coloboma, and intractable seizures (platzer2014exomesequencingidentifies pages 3-5, platzer2014exomesequencingidentifies pages 1-2, platzer2014exomesequencingidentifies pages 2-3)	Platzer et al., 2014	https://doi.org/10.1002/ajmg.a.36592
Temtamy syndrome (C12orf57-related)	C12orf57	c.C43T; p.Q15X	Nonsense / stop-gain	Premature stop codon; reported as compound heterozygous with c.1A>G in a South Indian child; Sanger-confirmed in proband and parents; interpreted as truncating loss-of-function under ACMG framework (alfiya2022c12orf57pathogenicvariants pages 3-4, alfiya2022c12orf57pathogenicvariants pages 4-5)	Alfiya et al., 2022	https://doi.org/10.1007/s12041-022-01371-0
Temtamy preaxial brachydactyly syndrome (TPBS)	CHSY1	c.14delG; p.G5AfsX30	Frameshift	Homozygous LOF allele in TPBS families; cosegregated with autosomal recessive disease; predicted truncation / nonfunctional protein (li2010temtamypreaxialbrachydactyly pages 5-7, li2010temtamypreaxialbrachydactyly pages 4-5)	Li et al., 2010	https://doi.org/10.1016/j.ajhg.2010.10.003
Temtamy preaxial brachydactyly syndrome (TPBS)	CHSY1	c.55-84del30; p.G19_L28del	In-frame deletion	Reported exon 1 pathogenic deletion in TPBS; part of recurrent CHSY1 loss-of-function spectrum in consanguineous families; absent from controls in original study (li2010temtamypreaxialbrachydactyly pages 1-2, li2010temtamypreaxialbrachydactyly pages 2-4, li2010temtamypreaxialbrachydactyly pages 4-5)	Li et al., 2010	https://doi.org/10.1016/j.ajhg.2010.10.003
Temtamy preaxial brachydactyly syndrome (TPBS)	CHSY1	c.205C>T; p.Q69X	Nonsense	Protein-truncating LOF allele identified in TPBS families with AR segregation; supports CHSY1 haploinsufficiency is not mechanism, but biallelic loss is pathogenic (li2010temtamypreaxialbrachydactyly pages 1-2, li2010temtamypreaxialbrachydactyly pages 5-7, li2010temtamypreaxialbrachydactyly pages 4-5)	Li et al., 2010	https://doi.org/10.1016/j.ajhg.2010.10.003
Temtamy preaxial brachydactyly syndrome (TPBS)	CHSY1	c.321-3C>G	Splice-site	Acceptor splice variant causing exon 2 skipping, frameshift and premature truncation; strong functional evidence for loss of function (li2010temtamypreaxialbrachydactyly pages 5-7)	Li et al., 2010	https://doi.org/10.1016/j.ajhg.2010.10.003
Temtamy preaxial brachydactyly syndrome (TPBS)	CHSY1	c.1616C>G; p.P539R	Missense	Affects highly conserved residue in CHSY1; interpreted as deleterious and disruptive of protein function; part of pathogenic CHSY1 spectrum in TPBS (li2010temtamypreaxialbrachydactyly pages 5-7, sher2014anovelchsy1 pages 2-4)	Li et al., 2010	https://doi.org/10.1016/j.ajhg.2010.10.003
Temtamy preaxial brachydactyly syndrome (TPBS)	CHSY1	c.1897G>A; p.D633N	Missense	Homozygous in Pakistani family; parents heterozygous carriers; absent in 100 matched controls; alters conserved Asp633 within DXD motif required for glycosyltransferase activity, supporting enzymatic loss of function (sher2014anovelchsy1 pages 4-4, sher2014anovelchsy1 pages 2-4)	Sher & Naeem, 2014	https://doi.org/10.1016/j.ejmg.2013.11.001

Table: This table summarizes key pathogenic variants reported for the two distinct entities often called Temtamy syndrome: C12orf57-related Temtamy syndrome and CHSY1-related Temtamy preaxial brachydactyly syndrome. It highlights variant class, segregation, founder evidence, and functional support using only the gathered evidence snippets.

Notable quantitative variant statistics (C12orf57-related): - In Wang’s 2020 review of 56 patients, c.1A>G was the most frequent reported variant (45/56; 80.3%). (wang2020temtamysyndromecaused pages 4-6)

Evidence supporting loss-of-function: - For C12orf57 start-codon variant c.1A>G, Akizu showed the mutant AUG→GUG start can still initiate translation but produces markedly reduced protein levels, consistent with a loss-of-function/hypomorphic mechanism. (akizu2013wholeexomesequencingidentifies pages 5-7)

4.3 Modifier genes / epigenetic information

No modifier genes or epigenetic mechanisms specific to Temtamy syndrome were identified in retrieved sources.

4.4 Chromosomal abnormalities (Temtamy-like)

A 2003 report described a Temtamy-like phenotype (callosal agenesis, colobomas, profound ID, hearing loss) with a de novo balanced translocation t(2;9)(p24;q32), highlighting historical locus-mapping approaches and the possibility of chromosomal disruption in Temtamy-like presentations. (talisetti2003temtamy‐likesyndromeassociated pages 1-3)

5. Environmental Information

No environmental, lifestyle, toxicant, or infectious causal factors were identified in the retrieved sources. These syndromes are primarily genetic. (wang2020temtamysyndromecaused pages 1-2, li2010temtamypreaxialbrachydactyly pages 1-2)

6. Mechanism / Pathophysiology

6.1 C12orf57-related Temtamy syndrome (proposed mechanism; limited mechanistic detail available)

Causal chain (supported components): 1. Biallelic C12orf57 variants (often start-loss) → 2. Reduced C12orf57 protein levels (experimental evidence for c.1A>G) and cytoplasmic localization of the protein → 3. Disrupted neurodevelopmental processes required for corpus callosum development and broader brain development → 4. Clinical manifestations: callosal hypoplasia/agenesis, seizures/epilepsy, developmental delay/ID, autistic features, and ocular anomalies. (akizu2013wholeexomesequencingidentifies pages 5-7, akizu2013wholeexomesequencingidentifies pages 2-4)

Functional notes: - Akizu found the major neural transcript to be highly enriched in fetal brain and concluded the gene is “required for development of the human corpus callosum,” but molecular pathways remain poorly defined. (akizu2013wholeexomesequencingidentifies pages 5-7, akizu2013wholeexomesequencingidentifies pages 1-2) - A 2024 cerebral organoid/ribosome study (preprint) described C12orf57 as “an important factor for early brain development” and noted that its mRNA contains a TOP-like element, making its translation sensitive to ribosome availability and global translation state; this is a mechanistic clue at the level of translational regulation rather than disease-specific causation. (ni2024aninappropriatedecline pages 13-17)

Suggested GO / CL terms (hypothesis-generating; not explicitly asserted in sources): - GO (process): corpus callosum development; regulation of translation; neurogenesis. - CL (cell types, based on organoid discussion): radial glia / neural progenitor cells (mentioned as impacted in organoid study). (ni2024aninappropriatedecline pages 13-17)

6.2 TPBS (CHSY1) mechanism: chondroitin sulfate biosynthesis with BMP/NOTCH crosstalk

Causal chain (supported components): 1. Biallelic CHSY1 loss-of-function → 2. Impaired chondroitin sulfate biosynthesis (CHSY1 provides enzymatic activities needed to build CS repeating disaccharides) → 3. Perturbed extracellular matrix/proteoglycan-mediated developmental signaling and morphogenesis → 4. Limb/digit, craniofacial, and inner-ear developmental anomalies consistent with TPBS. (li2010temtamypreaxialbrachydactyly pages 5-7)

Pathways and processes: - BMP signaling: CHSY1/chsy1 is described as a “potential target of BMP signaling,” with zebrafish data indicating BMP signaling negatively regulates chsy1 expression and BMP pathway perturbations phenocopy chsy1 knockdown. (li2010temtamypreaxialbrachydactyly pages 5-7, li2010temtamypreaxialbrachydactyly pages 1-2) - NOTCH signaling: A separate 2010 study proposed that CHSY1 inhibits NOTCH extracellularly via a Fringe domain and that loss leads to increased Notch signaling (e.g., jag2 upregulation; lim1 silencing) contributing to abnormal ossification/patterning. (tian2010lossofchsy1 pages 9-10, tian2010lossofchsy1 pages 8-9)

Suggested GO / CL / pathway terms (supported directionally by the above): - GO (process): glycosaminoglycan biosynthetic process; cartilage development; limb development; Notch signaling pathway; BMP signaling pathway. - CL (cell types): chondrocytes; inner-ear sensory epithelium/hair-cell–adjacent epithelium (zebrafish expression in chondrocytes and inner ear). (li2010temtamypreaxialbrachydactyly pages 5-7)

7. Anatomical Structures Affected

C12orf57-related Temtamy syndrome

CNS: corpus callosum (hypoplasia/agenesis), thalamic/ventricular abnormalities described in family studies. (akizu2013wholeexomesequencingidentifies pages 2-4)
Suggested UBERON: corpus callosum; thalamus; lateral ventricle; third ventricle.
Eye: optic/chorioretinal coloboma and other ocular anomalies. (platzer2014exomesequencingidentifies pages 3-5, wang2020temtamysyndromecaused pages 4-6)
Suggested UBERON: retina; choroid; optic nerve.
Heart: atrial septal defects reported in an aggregated case review. (wang2020temtamysyndromecaused pages 4-6)

TPBS (CHSY1)

Limbs/digits: preaxial digits 1–3 (hands/feet), metacarpals/metatarsals, carpal/tarsal bones. (li2010temtamypreaxialbrachydactyly pages 4-5)
Auditory system: sensorineural hearing impairment is frequent. (li2010temtamypreaxialbrachydactyly pages 4-5)

8. Temporal Development

C12orf57-related Temtamy syndrome

Onset: congenital/infancy presentation with developmental delay; seizures typically begin in early childhood and may start in infancy. (wang2020temtamysyndromecaused pages 1-2, platzer2014exomesequencingidentifies pages 3-5)
Course: chronic lifelong neurodevelopmental disability; seizure control is variable, with a substantial refractory subset. (wang2020temtamysyndromecaused pages 4-6, platzer2014exomesequencingidentifies pages 3-5)

TPBS

Onset: congenital limb malformations are present at birth (by definition of brachydactyly/hyperphalangism syndrome). (li2010temtamypreaxialbrachydactyly pages 1-2)

9. Inheritance and Population

C12orf57-related Temtamy syndrome

Inheritance: autosomal recessive with frequent consanguinity. (akizu2013wholeexomesequencingidentifies pages 2-4, wang2020temtamysyndromecaused pages 2-4)
Founder effect: Platzer explicitly states that the recurrent c.1A>G (p.Met1?) observed in Arab-descent patients “strongly suggests a founder effect within the Arab population.” (platzer2014exomesequencingidentifies pages 3-5)
Epidemiology: prevalence/incidence not available in retrieved sources. However, case aggregation provides a minimal evidence base:
Wang 2020 summarized 56 reported patients with C12orf57 pathogenic variants at that time. (wang2020temtamysyndromecaused pages 2-4)
Platzer 2014 summarized 17 patients from 7 families (as-of their publication). (platzer2014exomesequencingidentifies pages 3-5)

TPBS

Inheritance: autosomal recessive. (li2010temtamypreaxialbrachydactyly pages 1-2)
Epidemiology: not available in retrieved sources.

10. Diagnostics

10.1 Clinical evaluation (C12orf57-related)

Common diagnostic components described across reports include: - Neurologic assessment and EEG for seizures. (wang2020temtamysyndromecaused pages 1-2, talisetti2003temtamy‐likesyndromeassociated pages 1-3) - Brain MRI to assess corpus callosum and ventricles. (wang2020temtamysyndromecaused pages 1-2, akizu2013wholeexomesequencingidentifies pages 2-4) - Ophthalmologic evaluation for coloboma/microphthalmia. (wang2020temtamysyndromecaused pages 4-6, talisetti2003temtamy‐likesyndromeassociated pages 1-3) - Cardiac evaluation (e.g., ASD/VSD) when indicated. (wang2020temtamysyndromecaused pages 4-6)

10.2 Genetic testing

Whole-exome sequencing (WES) is repeatedly used to identify causal C12orf57 variants in affected children and families, with segregation analysis by Sanger sequencing. (wang2020temtamysyndromecaused pages 2-4, akizu2013wholeexomesequencingidentifies pages 2-4)
A representative filtering/interpretation pipeline (depth thresholds, population frequency filters, in silico predictors, Sanger confirmation) is described in Wang 2020. (wang2020temtamysyndromecaused pages 2-4)

10.3 Differential diagnosis

Not comprehensively addressed in retrieved sources; however, historical “Temtamy-like” reports stress that overlapping syndromes with corpus callosum agenesis and ocular colobomas exist, and chromosomal abnormalities can produce similar phenotypes. (talisetti2003temtamy‐likesyndromeassociated pages 1-3)

11. Outcome / Prognosis

C12orf57-related Temtamy syndrome

Quantitative outcome data are limited, but severe neurodevelopmental impairment is common: severe ID in 11/11 where specified in Platzer’s cohort summary and absent speech in a majority. (platzer2014exomesequencingidentifies pages 3-5)
Seizure prognosis is variable: Wang 2020 cites a substantial refractory proportion and a relatively small seizure-free fraction in historical cases. (wang2020temtamysyndromecaused pages 4-6)

No survival curves or life expectancy estimates were identified in retrieved sources.

12. Treatment

12.1 Pharmacotherapy

Antiseizure medications are the primary disease-directed therapy described. In a single C12orf57-related case report, oxcarbazepine dosing was escalated and the child was reported “seizure-free for 1 month” during follow-up; this illustrates symptomatic management rather than disease modification. (wang2020temtamysyndromecaused pages 1-2)

MAXO suggestions (general, not explicitly in sources): anticonvulsant therapy; developmental therapy; supportive care.

12.2 Supportive/rehabilitative care

Given the high rates of developmental delay, hypotonia, and absent speech, supportive therapies (PT/OT/speech therapy) are implied but not described quantitatively in retrieved sources.

12.3 Clinical trials / advanced therapeutics

No disease-specific interventional clinical trials were identified in this run. (clinical-trials search returned none relevant)

13. Prevention

Primary prevention is not applicable for a monogenic disorder in the usual sense, but genetic counseling and carrier testing are directly relevant due to autosomal recessive inheritance, particularly in consanguineous families. (wang2020temtamysyndromecaused pages 2-4)
Secondary prevention: early identification of seizures and developmental issues to initiate symptomatic therapies.
Reproductive options: prenatal/preimplantation genetic testing is not explicitly discussed in retrieved sources, but the literature emphasizes segregation testing and recurrence risk awareness. (wang2020temtamysyndromecaused pages 2-4)

14. Other Species / Natural Disease

No naturally occurring non-human disease analogs were identified in retrieved sources.

15. Model Organisms

C12orf57-related Temtamy syndrome

Akizu reports conservation and notes a fly RNAi screen where knockdown of the fly ortholog produced a nonspecific “malformation death” phenotype in ~50% of treated flies, but without a detailed phenotypic match to human disease. (akizu2013wholeexomesequencingidentifies pages 7-8)
A 2024 human cerebral organoid study (preprint) provides mechanistic context regarding translation sensitivity of TOP-like transcripts including C12orf57, but is not a Temtamy syndrome disease model per se. (ni2024aninappropriatedecline pages 13-17)

TPBS (CHSY1)

Zebrafish morphants: multiple studies show chsy1 knockdown produces developmental defects, including skeletal/jaw defects, pectoral fin defects (~65%), and ocular anomalies (>50%), partially phenocopying human TPBS and supporting conserved developmental roles. (li2010temtamypreaxialbrachydactyly pages 1-2, tian2010lossofchsy1 pages 8-9)

Recent developments (prioritized 2023–2024)

Founder mutation framing (2024): A Disease Models & Mechanisms Perspective highlights that some rare diseases in Arab populations may be largely driven by founder variants and lists C12ORF57 among such examples; it also cites “Temtamy syndrome of corpus callosum and ocular abnormalities” in its reference list. This is interpretive/public-health context rather than new mechanistic or variant discovery. (marafi2024foundermutationsand pages 4-5, marafi2024foundermutationsand pages 6-7)
Variant recurrence in modern cohorts (2024): A Frontiers in Genetics ASD cohort reports segregation of a homozygous C12orf57 start-codon variant (c.A1G/p.M1V; CADD 21.9) in affected siblings and notes prior reporting in consanguineous Saudi/Kuwaiti patients with global developmental delay, autism, and epilepsy—demonstrating continuing clinical relevance of this recurrent allele in Middle Eastern populations. (alsarraj2024thegeneticlandscape pages 10-11)
Systems-level translational regulation (2024 preprint): A bioRxiv study suggests C12orf57 is among transcripts with TOP-like motifs whose translation is sensitive to ribosome availability during early neurodevelopment in cerebral organoids. This provides a plausible mechanistic clue for why reduced C12orf57 dosage might be impactful in neurodevelopment, but it does not establish a Temtamy-specific pathway. (ni2024aninappropriatedecline pages 13-17)
High-throughput 5′UTR functional screening (2023 preprint): A medRxiv study included C12orf57 among genes screened for 5′UTR variant effects on translation, but the authors report they could not validate endogenous protein changes for C12orf57 due to antibody limitations (no correct-sized band), so it does not provide definitive new functional findings for C12orf57. (plassmeyer2023amassivelyparallel pages 21-23, plassmeyer2023amassivelyparallel pages 32-35)

Real-world applications / implementations

Clinical genomics (WES) as standard-of-care for heterogeneous syndromic neurodevelopmental disorders: Multiple Temtamy syndrome diagnoses in the retrieved literature were enabled by WES with segregation testing, illustrating real-world deployment of genomic diagnostics in rare disease. (wang2020temtamysyndromecaused pages 2-4, akizu2013wholeexomesequencingidentifies pages 2-4)
Population genetics / founder mutation programs: The 2024 founder-mutation perspective and the continued observation of recurrent C12orf57 start-codon variants in Middle Eastern pedigrees support the utility of region-specific carrier screening and counseling strategies (conceptual; implementation details not provided in retrieved sources). (marafi2024foundermutationsand pages 4-5, platzer2014exomesequencingidentifies pages 3-5)

Data gaps / limitations of this report

MONDO/Orphanet/ICD/MeSH identifiers and prevalence/incidence were not available from the retrieved texts in this run.
No disease-specific guidelines, standardized clinical criteria, or interventional trials were identified in the retrieved sources.
Mechanistic understanding of C12orf57 remains limited; available evidence primarily supports loss-of-function via reduced protein dosage, with emerging hints about translation regulation sensitivity. (akizu2013wholeexomesequencingidentifies pages 5-7, ni2024aninappropriatedecline pages 13-17)

Appendix: Key quoted statements from abstracts / key excerpts (as requested)

C12orf57 start-codon functional effect: the mutant allele “was able to produce some protein, although less efficiently than the wild-type” and “Cells transduced with the mutant construct show notably reduced protein levels.” (akizu2013wholeexomesequencingidentifies pages 5-7)
Founder effect statement (C12orf57 c.1A>G): recurrent observation “strongly suggests a founder effect within the Arab population.” (platzer2014exomesequencingidentifies pages 3-5)
Diagnostic yield and phenotype frequencies (Wang 2020 review): developmental delay 56/56 (100%), seizures 41/56 (73.7%), hypotonia 40/56 (71.9%), autistic behavior 40/55 (72.7%). (wang2020temtamysyndromecaused pages 2-4)

Retrieved figure/table evidence

Wang 2020 includes a table summarizing clinical-feature frequencies and variants across 56 reported cases, and a pedigree/variant figure; these were retrieved as images in this run. (wang2020temtamysyndromecaused media b3d8bfd5, wang2020temtamysyndromecaused media 805b1c71, wang2020temtamysyndromecaused media 21e24220)

References

(wang2020temtamysyndromecaused pages 1-2): Yanqin Wang, Ming Li, Yuanyuan Luo, Xin Zhao, Shuang Liao, Li Jiang, Xiujuan Li, and Min Zhong. Temtamy syndrome caused by a new c12orf57 variant in a chinese boy, including pedigree analysis and literature review. Experimental and therapeutic medicine, 19 1:327-332, Nov 2020. URL: https://doi.org/10.3892/etm.2019.8183, doi:10.3892/etm.2019.8183. This article has 8 citations and is from a peer-reviewed journal.
(li2010temtamypreaxialbrachydactyly pages 1-2): Yun Li, Kathrin Laue, Samia Temtamy, Mona Aglan, L. Damla Kotan, Gökhan Yigit, Husniye Canan, Barbara Pawlik, Gudrun Nürnberg, Emma L. Wakeling, Oliver W. Quarrell, Ingelore Baessmann, Matthew B. Lanktree, Mustafa Yilmaz, Robert A. Hegele, Khalda Amr, Klaus W. May, Peter Nürnberg, A. Kemal Topaloglu, Matthias Hammerschmidt, and Bernd Wollnik. Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of bmp signaling. The American Journal of Human Genetics, 87:757-767, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.10.003, doi:10.1016/j.ajhg.2010.10.003. This article has 89 citations.
(akizu2013wholeexomesequencingidentifies pages 2-4): Naiara Akizu, Nuri M. Shembesh, Tawfeg Ben-Omran, Laila Bastaki, Asma Al-Tawari, Maha S. Zaki, Roshan Koul, Emily Spencer, Rasim Ozgur Rosti, Eric Scott, Elizabeth Nickerson, Stacey Gabriel, Gilberto da Gente, Jiang Li, Matthew A. Deardorff, Laura K. Conlin, Margaret A. Horton, Elaine H. Zackai, Elliott H. Sherr, and Joseph G. Gleeson. Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia. American journal of human genetics, 92 3:392-400, Mar 2013. URL: https://doi.org/10.1016/j.ajhg.2013.02.004, doi:10.1016/j.ajhg.2013.02.004. This article has 43 citations and is from a highest quality peer-reviewed journal.
(platzer2014exomesequencingidentifies pages 3-5): Konrad Platzer, Irina Hüning, Carolin Obieglo, Thomas Schwarzmayr, Rainer Gabriel, Tim M. Strom, Gabriele Gillessen‐Kaesbach, and Frank J. Kaiser. Exome sequencing identifies compound heterozygous mutations in c12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures. American Journal of Medical Genetics Part A, 164:1976-1980, Aug 2014. URL: https://doi.org/10.1002/ajmg.a.36592, doi:10.1002/ajmg.a.36592. This article has 14 citations.
(akizu2013wholeexomesequencingidentifies pages 5-7): Naiara Akizu, Nuri M. Shembesh, Tawfeg Ben-Omran, Laila Bastaki, Asma Al-Tawari, Maha S. Zaki, Roshan Koul, Emily Spencer, Rasim Ozgur Rosti, Eric Scott, Elizabeth Nickerson, Stacey Gabriel, Gilberto da Gente, Jiang Li, Matthew A. Deardorff, Laura K. Conlin, Margaret A. Horton, Elaine H. Zackai, Elliott H. Sherr, and Joseph G. Gleeson. Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia. American journal of human genetics, 92 3:392-400, Mar 2013. URL: https://doi.org/10.1016/j.ajhg.2013.02.004, doi:10.1016/j.ajhg.2013.02.004. This article has 43 citations and is from a highest quality peer-reviewed journal.
(wang2020temtamysyndromecaused pages 4-6): Yanqin Wang, Ming Li, Yuanyuan Luo, Xin Zhao, Shuang Liao, Li Jiang, Xiujuan Li, and Min Zhong. Temtamy syndrome caused by a new c12orf57 variant in a chinese boy, including pedigree analysis and literature review. Experimental and therapeutic medicine, 19 1:327-332, Nov 2020. URL: https://doi.org/10.3892/etm.2019.8183, doi:10.3892/etm.2019.8183. This article has 8 citations and is from a peer-reviewed journal.
(platzer2014exomesequencingidentifies pages 2-3): Konrad Platzer, Irina Hüning, Carolin Obieglo, Thomas Schwarzmayr, Rainer Gabriel, Tim M. Strom, Gabriele Gillessen‐Kaesbach, and Frank J. Kaiser. Exome sequencing identifies compound heterozygous mutations in c12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures. American Journal of Medical Genetics Part A, 164:1976-1980, Aug 2014. URL: https://doi.org/10.1002/ajmg.a.36592, doi:10.1002/ajmg.a.36592. This article has 14 citations.
(wang2020temtamysyndromecaused pages 2-4): Yanqin Wang, Ming Li, Yuanyuan Luo, Xin Zhao, Shuang Liao, Li Jiang, Xiujuan Li, and Min Zhong. Temtamy syndrome caused by a new c12orf57 variant in a chinese boy, including pedigree analysis and literature review. Experimental and therapeutic medicine, 19 1:327-332, Nov 2020. URL: https://doi.org/10.3892/etm.2019.8183, doi:10.3892/etm.2019.8183. This article has 8 citations and is from a peer-reviewed journal.
(li2010temtamypreaxialbrachydactyly pages 2-4): Yun Li, Kathrin Laue, Samia Temtamy, Mona Aglan, L. Damla Kotan, Gökhan Yigit, Husniye Canan, Barbara Pawlik, Gudrun Nürnberg, Emma L. Wakeling, Oliver W. Quarrell, Ingelore Baessmann, Matthew B. Lanktree, Mustafa Yilmaz, Robert A. Hegele, Khalda Amr, Klaus W. May, Peter Nürnberg, A. Kemal Topaloglu, Matthias Hammerschmidt, and Bernd Wollnik. Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of bmp signaling. The American Journal of Human Genetics, 87:757-767, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.10.003, doi:10.1016/j.ajhg.2010.10.003. This article has 89 citations.
(li2010temtamypreaxialbrachydactyly pages 4-5): Yun Li, Kathrin Laue, Samia Temtamy, Mona Aglan, L. Damla Kotan, Gökhan Yigit, Husniye Canan, Barbara Pawlik, Gudrun Nürnberg, Emma L. Wakeling, Oliver W. Quarrell, Ingelore Baessmann, Matthew B. Lanktree, Mustafa Yilmaz, Robert A. Hegele, Khalda Amr, Klaus W. May, Peter Nürnberg, A. Kemal Topaloglu, Matthias Hammerschmidt, and Bernd Wollnik. Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of bmp signaling. The American Journal of Human Genetics, 87:757-767, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.10.003, doi:10.1016/j.ajhg.2010.10.003. This article has 89 citations.
(li2010temtamypreaxialbrachydactyly pages 5-7): Yun Li, Kathrin Laue, Samia Temtamy, Mona Aglan, L. Damla Kotan, Gökhan Yigit, Husniye Canan, Barbara Pawlik, Gudrun Nürnberg, Emma L. Wakeling, Oliver W. Quarrell, Ingelore Baessmann, Matthew B. Lanktree, Mustafa Yilmaz, Robert A. Hegele, Khalda Amr, Klaus W. May, Peter Nürnberg, A. Kemal Topaloglu, Matthias Hammerschmidt, and Bernd Wollnik. Temtamy preaxial brachydactyly syndrome is caused by loss-of-function mutations in chondroitin synthase 1, a potential target of bmp signaling. The American Journal of Human Genetics, 87:757-767, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.10.003, doi:10.1016/j.ajhg.2010.10.003. This article has 89 citations.
(sher2014anovelchsy1 pages 2-4): Gulab Sher and Muhammad Naeem. A novel chsy1 gene mutation underlies temtamy preaxial brachydactyly syndrome in a pakistani family. European journal of medical genetics, 57 1:21-4, Jan 2014. URL: https://doi.org/10.1016/j.ejmg.2013.11.001, doi:10.1016/j.ejmg.2013.11.001. This article has 28 citations and is from a peer-reviewed journal.
(tian2010lossofchsy1 pages 9-10): Jing Tian, Ling Ling, Mohammad Shboul, Hane Lee, Brian O'Connor, Barry Merriman, Stanley F. Nelson, Simon Cool, Osama H. Ababneh, Azmy Al-Hadidy, Amira Masri, Hanan Hamamy, and Bruno Reversade. Loss of chsy1, a secreted fringe enzyme, causes syndromic brachydactyly in humans via increased notch signaling. American journal of human genetics, 87 6:768-78, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.11.005, doi:10.1016/j.ajhg.2010.11.005. This article has 121 citations and is from a highest quality peer-reviewed journal.
(sher2014anovelchsy1 pages 4-4): Gulab Sher and Muhammad Naeem. A novel chsy1 gene mutation underlies temtamy preaxial brachydactyly syndrome in a pakistani family. European journal of medical genetics, 57 1:21-4, Jan 2014. URL: https://doi.org/10.1016/j.ejmg.2013.11.001, doi:10.1016/j.ejmg.2013.11.001. This article has 28 citations and is from a peer-reviewed journal.
(alfiya2022c12orf57pathogenicvariants pages 1-3): F. Alfiya, Manna Jose, Soumya V. Chandrasekharan, Soumya Sundaram, Madhusoodanan Urulangodi, Bejoy Thomas, Ashalatha Radhakrishnan, Moinak Banerjee, and Ramshekhar N. Menon. C12orf57 pathogenic variants: a unique cause of developmental encephalopathy in a south indian child. Journal of Genetics, Jun 2022. URL: https://doi.org/10.1007/s12041-022-01371-0, doi:10.1007/s12041-022-01371-0. This article has 5 citations and is from a peer-reviewed journal.
(marafi2024foundermutationsand pages 6-7): Dana Marafi. Founder mutations and rare disease in the arab world. Disease Models & Mechanisms, Jun 2024. URL: https://doi.org/10.1242/dmm.050715, doi:10.1242/dmm.050715. This article has 18 citations and is from a domain leading peer-reviewed journal.
(platzer2014exomesequencingidentifies pages 1-2): Konrad Platzer, Irina Hüning, Carolin Obieglo, Thomas Schwarzmayr, Rainer Gabriel, Tim M. Strom, Gabriele Gillessen‐Kaesbach, and Frank J. Kaiser. Exome sequencing identifies compound heterozygous mutations in c12orf57 in two siblings with severe intellectual disability, hypoplasia of the corpus callosum, chorioretinal coloboma, and intractable seizures. American Journal of Medical Genetics Part A, 164:1976-1980, Aug 2014. URL: https://doi.org/10.1002/ajmg.a.36592, doi:10.1002/ajmg.a.36592. This article has 14 citations.
(alsarraj2024thegeneticlandscape pages 10-11): Yasser Al-Sarraj, Rowaida Z. Taha, Eman Al-Dous, Dina Ahram, Somayyeh Abbasi, Eman Abuazab, Hibah Shaath, Wesal Habbab, Khaoula Errafii‬, Yosra Bejaoui, Maryam AlMotawa, Namat Khattab, Yasmin Abu Aqel, Karim E. Shalaby, Amina Al-Ansari, Marios Kambouris, Adel Abouzohri, Iman Ghazal, Mohammed Tolfat, Fouad Alshaban, Hatem El-Shanti, and Omar M. E. Albagha. The genetic landscape of autism spectrum disorder in the middle eastern population. Frontiers in Genetics, Mar 2024. URL: https://doi.org/10.3389/fgene.2024.1363849, doi:10.3389/fgene.2024.1363849. This article has 11 citations and is from a peer-reviewed journal.
(alfiya2022c12orf57pathogenicvariants pages 3-4): F. Alfiya, Manna Jose, Soumya V. Chandrasekharan, Soumya Sundaram, Madhusoodanan Urulangodi, Bejoy Thomas, Ashalatha Radhakrishnan, Moinak Banerjee, and Ramshekhar N. Menon. C12orf57 pathogenic variants: a unique cause of developmental encephalopathy in a south indian child. Journal of Genetics, Jun 2022. URL: https://doi.org/10.1007/s12041-022-01371-0, doi:10.1007/s12041-022-01371-0. This article has 5 citations and is from a peer-reviewed journal.
(alfiya2022c12orf57pathogenicvariants pages 4-5): F. Alfiya, Manna Jose, Soumya V. Chandrasekharan, Soumya Sundaram, Madhusoodanan Urulangodi, Bejoy Thomas, Ashalatha Radhakrishnan, Moinak Banerjee, and Ramshekhar N. Menon. C12orf57 pathogenic variants: a unique cause of developmental encephalopathy in a south indian child. Journal of Genetics, Jun 2022. URL: https://doi.org/10.1007/s12041-022-01371-0, doi:10.1007/s12041-022-01371-0. This article has 5 citations and is from a peer-reviewed journal.
(talisetti2003temtamy‐likesyndromeassociated pages 1-3): Anita Talisetti, Shawnia R. Forrester, David Gregory, Lisa Johnson, Michael C. Schneider, and Virginia E. Kimonis. Temtamy‐like syndrome associated with translocation of 2p24 and 9q32. Clinical Dysmorphology, 12:175–177, Jul 2003. URL: https://doi.org/10.1097/01.mcd.0000072161.33788.56, doi:10.1097/01.mcd.0000072161.33788.56. This article has 20 citations and is from a peer-reviewed journal.
(akizu2013wholeexomesequencingidentifies pages 1-2): Naiara Akizu, Nuri M. Shembesh, Tawfeg Ben-Omran, Laila Bastaki, Asma Al-Tawari, Maha S. Zaki, Roshan Koul, Emily Spencer, Rasim Ozgur Rosti, Eric Scott, Elizabeth Nickerson, Stacey Gabriel, Gilberto da Gente, Jiang Li, Matthew A. Deardorff, Laura K. Conlin, Margaret A. Horton, Elaine H. Zackai, Elliott H. Sherr, and Joseph G. Gleeson. Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia. American journal of human genetics, 92 3:392-400, Mar 2013. URL: https://doi.org/10.1016/j.ajhg.2013.02.004, doi:10.1016/j.ajhg.2013.02.004. This article has 43 citations and is from a highest quality peer-reviewed journal.
(ni2024aninappropriatedecline pages 13-17): Chunyang Ni, Leqian Yu, Barbara Vona, Dayea Park, Yulei Wei, Daniel A Schmitz, Yudong Wei, Yi Ding, Masahiro Sakurai, Emily Ballard, Yan Liu, Ashwani Kumar, Chao Xing, Hyung-Goo Kim, Cumhur Ekmekci, Ehsan Ghayoor Karimiani, Shima Imannezhad, Fatemeh Eghbal, Reza Shervin Badv, Eva Maria Christina Schwaibold, Mohammadreza Dehghani, Mohammad Yahya Vahidi Mehrjardi, Zahra Metanat, Hosein Eslamiyeh, Ebtissal Khouj, Saleh Mohammed Nasser Alhajj, Aziza Chedrawi, César Augusto Pinheiro Ferreira Alves, Henry Houlden, Michael Kruer, Fowzan S. Alkuraya, Can Cenik, Reza Maroofian, Jun Wu, and Michael Buszczak. An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders. BioRxiv, Jan 2024. URL: https://doi.org/10.1101/2024.01.09.574708, doi:10.1101/2024.01.09.574708. This article has 4 citations.
(tian2010lossofchsy1 pages 8-9): Jing Tian, Ling Ling, Mohammad Shboul, Hane Lee, Brian O'Connor, Barry Merriman, Stanley F. Nelson, Simon Cool, Osama H. Ababneh, Azmy Al-Hadidy, Amira Masri, Hanan Hamamy, and Bruno Reversade. Loss of chsy1, a secreted fringe enzyme, causes syndromic brachydactyly in humans via increased notch signaling. American journal of human genetics, 87 6:768-78, Dec 2010. URL: https://doi.org/10.1016/j.ajhg.2010.11.005, doi:10.1016/j.ajhg.2010.11.005. This article has 121 citations and is from a highest quality peer-reviewed journal.
(akizu2013wholeexomesequencingidentifies pages 7-8): Naiara Akizu, Nuri M. Shembesh, Tawfeg Ben-Omran, Laila Bastaki, Asma Al-Tawari, Maha S. Zaki, Roshan Koul, Emily Spencer, Rasim Ozgur Rosti, Eric Scott, Elizabeth Nickerson, Stacey Gabriel, Gilberto da Gente, Jiang Li, Matthew A. Deardorff, Laura K. Conlin, Margaret A. Horton, Elaine H. Zackai, Elliott H. Sherr, and Joseph G. Gleeson. Whole-exome sequencing identifies mutated c12orf57 in recessive corpus callosum hypoplasia. American journal of human genetics, 92 3:392-400, Mar 2013. URL: https://doi.org/10.1016/j.ajhg.2013.02.004, doi:10.1016/j.ajhg.2013.02.004. This article has 43 citations and is from a highest quality peer-reviewed journal.
(marafi2024foundermutationsand pages 4-5): Dana Marafi. Founder mutations and rare disease in the arab world. Disease Models & Mechanisms, Jun 2024. URL: https://doi.org/10.1242/dmm.050715, doi:10.1242/dmm.050715. This article has 18 citations and is from a domain leading peer-reviewed journal.
(plassmeyer2023amassivelyparallel pages 21-23): Stephen P. Plassmeyer, Colin P. Florian, Michael J. Kasper, Rebecca Chase, Shayna Mueller, Yating Liu, Kelli McFarland White, Courtney F. Jungers, Slavica Pavlovic Djuranovic, Sergej Djuranovic, and Joseph D. Dougherty. A massively parallel screen of 5′utr mutations identifies variants impacting translation and protein production in neurodevelopmental disorder genes. MedRxiv, Nov 2023. URL: https://doi.org/10.1101/2023.11.02.23297961, doi:10.1101/2023.11.02.23297961. This article has 15 citations.
(plassmeyer2023amassivelyparallel pages 32-35): Stephen P. Plassmeyer, Colin P. Florian, Michael J. Kasper, Rebecca Chase, Shayna Mueller, Yating Liu, Kelli McFarland White, Courtney F. Jungers, Slavica Pavlovic Djuranovic, Sergej Djuranovic, and Joseph D. Dougherty. A massively parallel screen of 5′utr mutations identifies variants impacting translation and protein production in neurodevelopmental disorder genes. MedRxiv, Nov 2023. URL: https://doi.org/10.1101/2023.11.02.23297961, doi:10.1101/2023.11.02.23297961. This article has 15 citations.
(wang2020temtamysyndromecaused media b3d8bfd5): Yanqin Wang, Ming Li, Yuanyuan Luo, Xin Zhao, Shuang Liao, Li Jiang, Xiujuan Li, and Min Zhong. Temtamy syndrome caused by a new c12orf57 variant in a chinese boy, including pedigree analysis and literature review. Experimental and therapeutic medicine, 19 1:327-332, Nov 2020. URL: https://doi.org/10.3892/etm.2019.8183, doi:10.3892/etm.2019.8183. This article has 8 citations and is from a peer-reviewed journal.
(wang2020temtamysyndromecaused media 805b1c71): Yanqin Wang, Ming Li, Yuanyuan Luo, Xin Zhao, Shuang Liao, Li Jiang, Xiujuan Li, and Min Zhong. Temtamy syndrome caused by a new c12orf57 variant in a chinese boy, including pedigree analysis and literature review. Experimental and therapeutic medicine, 19 1:327-332, Nov 2020. URL: https://doi.org/10.3892/etm.2019.8183, doi:10.3892/etm.2019.8183. This article has 8 citations and is from a peer-reviewed journal.
(wang2020temtamysyndromecaused media 21e24220): Yanqin Wang, Ming Li, Yuanyuan Luo, Xin Zhao, Shuang Liao, Li Jiang, Xiujuan Li, and Min Zhong. Temtamy syndrome caused by a new c12orf57 variant in a chinese boy, including pedigree analysis and literature review. Experimental and therapeutic medicine, 19 1:327-332, Nov 2020. URL: https://doi.org/10.3892/etm.2019.8183, doi:10.3892/etm.2019.8183. This article has 8 citations and is from a peer-reviewed journal.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Concise overview

1.2 Key identifiers and synonyms (from retrieved sources)

1.3 Evidence types

2. Etiology

2.1 Disease causal factors

A) C12orf57-related Temtamy syndrome (MIM 218340)

B) TPBS (MIM 605282)

2.2 Risk factors

2.3 Protective factors / gene–environment interactions

3. Phenotypes

3.1 C12orf57-related Temtamy syndrome: phenotype spectrum (with frequencies)

3.2 Age of onset, progression, severity

3.3 TPBS: phenotype spectrum (qualitative)

3.4 Quality-of-life impact

4. Genetic / Molecular Information

4.1 Causal genes

4.2 Pathogenic variants (examples with evidence)

4.3 Modifier genes / epigenetic information

4.4 Chromosomal abnormalities (Temtamy-like)

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 C12orf57-related Temtamy syndrome (proposed mechanism; limited mechanistic detail available)

6.2 TPBS (CHSY1) mechanism: chondroitin sulfate biosynthesis with BMP/NOTCH crosstalk

7. Anatomical Structures Affected

C12orf57-related Temtamy syndrome

TPBS (CHSY1)

8. Temporal Development

C12orf57-related Temtamy syndrome

TPBS

9. Inheritance and Population

C12orf57-related Temtamy syndrome

TPBS

10. Diagnostics

10.1 Clinical evaluation (C12orf57-related)

10.2 Genetic testing

10.3 Differential diagnosis

11. Outcome / Prognosis

C12orf57-related Temtamy syndrome

12. Treatment

12.1 Pharmacotherapy

12.2 Supportive/rehabilitative care

12.3 Clinical trials / advanced therapeutics

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

C12orf57-related Temtamy syndrome

TPBS (CHSY1)

Recent developments (prioritized 2023–2024)

Real-world applications / implementations

Data gaps / limitations of this report

Appendix: Key quoted statements from abstracts / key excerpts (as requested)

Retrieved figure/table evidence

Artifacts