Ferguson-Bonni neurodevelopmental syndrome

Mendelian MONDO:0859220 Pathograph 22 Show in embeddings browser Mendelian neurodevelopmental disorder hereditary disease

Ferguson-Bonni neurodevelopmental syndrome is a rare autosomal recessive ANAPC7-related Mendelian neurodevelopmental disorder characterized by developmental delay, intellectual disability, hypotonia with early motor delay, and variable craniofacial, skeletal, growth, and hearing findings. The defining mechanism is loss of APC7, a core anaphase-promoting complex subunit required for neuronal ubiquitin signaling and heterochromatin regulation.

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1
Inheritance
4
Pathophys.
15
Phenotypes
1
Gaps
22
Pathograph
1
Genes
8
Medical Actions
2
Differentials
1
Models
2
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Reported affected individuals are homozygous for a loss-of-function ANAPC7 founder deletion, while heterozygous relatives are clinically unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:34942119 SUPPORT Human Clinical
"Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC)."
The PubMed abstract supports loss of APC7 as the disease cause; the inheritance mode is curated from the full article and MedGen summary.
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Discussions and Knowledge Gaps

1
Is cleft palate an independently documented finding in this cohort, or does the curated claim reflect conflation with the separately evidenced Pierre Robin sequence in patient 2137?
KNOWLEDGE GAP OPEN gap_cleft_palate_pierre_robin_conflation
Attached to
phenotypes#Cleft palate phenotypes#Pierre Robin sequence
Cleft palate is absent from both the cached full-text of the defining paper and the HPO annotation set for OMIM:619699, unlike every other supplemental-table finding in this entry, which are independently corroborated by that same HPO annotation set. Pierre Robin sequence is a triad (micrognathia, glossoptosis, and airway obstruction) that often, but not always, includes cleft palate, and is independently and verbatim evidenced in patient 2137. Access to the paper's Table S2 is needed to determine whether cleft palate was scored as a distinct finding in one or more patients or whether the claim originated from the Pierre Robin sequence observation alone.
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Pathophysiology

4
ANAPC7 loss of function
Biallelic ANAPC7 loss reduces APC7 protein, removing a core subunit of the anaphase-promoting complex/cyclosome E3 ubiquitin ligase.
ANAPC7 hgnc:17380 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ANAPC7 (hgnc:17380). hgnc:17380 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired APC substrate recruitment and ubiquitination APC7 loss compromises recruitment and ubiquitination of APC substrates.
Show evidence (1 reference)
PMID:34942119 SUPPORT Human Clinical
"Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC)."
This identifies APC7 loss as the initiating disease mechanism.
Impaired APC substrate recruitment and ubiquitination
APC7 loss impairs anaphase-promoting complex substrate recruitment and ubiquitination, reducing APC/C-dependent protein turnover in the developing nervous system.
APC-dependent protein catabolism GO:0031145 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased APC-dependent protein catabolism, annotated with anaphase-promoting complex-dependent catabolic process (GO:0031145). GO:0031145 is a biological process from the Gene Ontology. ↓ DECREASED ubiquitin-dependent protein catabolic process GO:0006511 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ubiquitin-dependent protein catabolic process (GO:0006511). GO:0006511 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neuronal Ki-67 substrate accumulation Reduced APC7-dependent ubiquitination allows APC substrates such as Ki-67 to accumulate.
Show evidence (1 reference)
PMID:34942119 SUPPORT In Vitro
"In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates."
This directly supports impaired APC substrate recruitment and ubiquitination after APC7 loss.
Neuronal Ki-67 substrate accumulation
In patient-mutation mouse brain and patient-derived cells, APC7 loss causes accumulation of the chromatin-associated APC substrate Ki-67 in neurons.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. cerebellar granule cell CL:0001031 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar granule cell (CL:0001031). CL:0001031 is a cell type from the Cell Ontology.
Downstream
Neuronal heterochromatin dysregulation Accumulated Ki-67 localizes to constitutive heterochromatin in neurons.
Show evidence (2 references)
PMID:34942119 SUPPORT Model Organism
"In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons."
This supports Ki-67 as a neuron-relevant APC7-dependent substrate in the disease model.
PMID:34942119 SUPPORT Model Organism
"Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain."
This links APC7/Cdh1-APC function to neuronal Ki-67 protein accumulation in vivo.
Neuronal heterochromatin dysregulation
Deregulated Ki-67 localizes to constitutive heterochromatin, implicating APC7-dependent ubiquitin signaling in neuronal chromatin architecture during brain development.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
heterochromatin organization GO:0070828 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal heterochromatin organization (GO:0070828). GO:0070828 is a biological process from the Gene Ontology. ⚠ ABNORMAL neuron development GO:0048666 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neuron development (GO:0048666). GO:0048666 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Global developmental delay Disrupted neuronal chromatin regulation impairs early neurodevelopmental milestones.
Intellectual disability Impaired APC7-dependent neuronal chromatin regulation contributes to cognitive impairment.
Motor delay Neurodevelopmental disruption contributes to delayed motor milestone acquisition.
Show evidence (2 references)
PMID:34942119 SUPPORT Model Organism
"Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin."
This directly supports heterochromatin localization of deregulated Ki-67 after APC7 loss.
PMID:34942119 SUPPORT Model Organism
"Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease."
This supports neuronal heterochromatin regulation as a central disease mechanism.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Ferguson-Bonni neurodevelopmental syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Ear 1
Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Sourced from the paper's supplemental clinical-characteristics table (Table S2), which is not present in the cached full text, so no verbatim snippet is available. Independently corroborated by the HPO annotation set for OMIM:619699 (hearing impairment in 5/11 patients in the same cohort).
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
The paper's supplemental clinical-characteristics table (Table S2, not captured in the cached full text) lists hearing loss among the clinical findings in multiple affected patients; no verbatim quote is available.
Eye 2
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
The main text supports craniofacial deformities generally; the hypertelorism-specific finding is listed in the paper's supplemental clinical-characteristics table (Table S2), which is not captured in the cached full text. Independently corroborated by the HPO annotation set for OMIM:619699 (hypertelorism in 6/11 patients in the same cohort).
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Skeletal and/or craniofacial deformities were seen in a subset of patients"
The main text supports craniofacial deformities in a subset of patients; the hypertelorism-specific detail is in the paper's supplemental clinical-characteristics table (Table S2), which is not captured in the cached full text.
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Sourced from the paper's supplemental clinical-characteristics table (Table S2), which is not present in the cached full text, so no verbatim snippet is available. Independently corroborated by the HPO annotation set for OMIM:619699 (strabismus in 5/11 patients in the same cohort).
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
The paper's supplemental clinical-characteristics table (Table S2, not captured in the cached full text) lists strabismus in affected patients; no verbatim quote is available.
Head and Neck 5
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Skeletal and/or craniofacial deformities were seen in a subset of patients"
The paper reports craniofacial deformities in a subset of affected individuals and illustrates Pierre Robin sequence in one patient.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
The main text supports craniofacial deformities generally; the micrognathia-specific finding is listed in the paper's supplemental clinical-characteristics table (Table S2), which is not captured in the cached full text. Independently corroborated by the HPO annotation set for OMIM:619699 (micrognathia in 6/11 patients in the same cohort).
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Skeletal and/or craniofacial deformities were seen in a subset of patients"
The main text supports craniofacial deformities in a subset of patients; the micrognathia-specific detail is in the paper's supplemental clinical-characteristics table (Table S2), which is not captured in the cached full text.
High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High-arched palate, annotated with High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
The main text supports craniofacial deformities generally; the high-arched-palate-specific finding is listed in the paper's supplemental clinical-characteristics table (Table S2), which is not captured in the cached full text. Independently corroborated by the HPO annotation set for OMIM:619699 (high palate in 3/11 patients in the same cohort).
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Skeletal and/or craniofacial deformities were seen in a subset of patients"
The main text supports craniofacial deformities in a subset of patients; the high-arched-palate-specific detail is in the paper's supplemental clinical-characteristics table (Table S2), which is not captured in the cached full text.
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Unlike the other supplemental-table findings in this entry, cleft palate is absent from both the cached full text and the HPO annotation set for OMIM:619699, and may reflect conflation with the separately evidenced Pierre-Robin sequence in patient 2137 (a triad that often, but not always, includes cleft palate) rather than an independently documented finding. No verbatim quote is available to support this claim as an independent phenotype; the evidence block is intentionally left empty pending access to the paper's Table S2 rather than citing an unverifiable snippet. See the `gap_cleft_palate_pierre_robin_conflation` discussion for the open question this raises.
Microcephaly OCCASIONAL HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"body and head size were low, though microcephaly was found in only one patient"
The primary paper reports low head size with microcephaly in one patient.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Sourced from the paper's supplemental clinical-characteristics table (Table S2), which is not present in the cached full text, so no verbatim snippet is available. Independently corroborated by the HPO annotation set for OMIM:619699 (hypotonia in 8/11 patients in the same cohort).
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
The paper's supplemental clinical-characteristics table (Table S2, not captured in the cached full text) lists hypotonia among the neurologic findings in affected patients; no verbatim quote is available.
Pectus excavatum HP:0000767 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pectus excavatum (HP:0000767). HP:0000767 is a phenotype from the Human Phenotype Ontology.
The main text supports skeletal/craniofacial deformities generally; the pectus-excavatum-specific finding is listed in the paper's supplemental clinical-characteristics table (Table S2), which is not captured in the cached full text. Independently corroborated by the HPO annotation set for OMIM:619699 (pectus excavatum in 7/11 patients in the same cohort).
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Skeletal and/or craniofacial deformities were seen in a subset of patients"
The main text supports skeletal/craniofacial deformities in a subset of patients; the pectus-excavatum-specific detail is in the paper's supplemental clinical-characteristics table (Table S2), which is not captured in the cached full text.
Nervous System 3
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Chromosomal microarray analysis of 11 young people of Old Order Amish heritage who displayed developmental delay and intellectual disability revealed a deletion within the ANAPC7 locus."
The affected cohort was ascertained with developmental delay and intellectual disability caused by ANAPC7 deletion.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34942119 SUPPORT Human Clinical
"Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC)."
This directly supports intellectual disability as the defining syndrome feature.
Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Together with intellectual disability, acquisition of early motor milestones was also delayed"
The paper directly reports delayed early motor milestone acquisition in affected individuals.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"body and head size were low, though microcephaly was found in only one patient"
The source supports reduced body size in affected individuals; this is mapped conservatively to short stature pending more granular anthropometry.
Other 1
Pierre Robin sequence HP:0000201 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pierre Robin sequence, annotated with Pierre-Robin sequence (HP:0000201). HP:0000201 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Patient 2137 with the ANAPC7 intellectual disability syndrome exhibits Pierre-Robin sequence."
The Figure 3 legend documents Pierre Robin sequence in patient 2137.
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Genetic Associations

1
ANAPC7 (Causal biallelic loss-of-function ANAPC7 variant)
Gene: ANAPC7 hgnc:17380 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ANAPC7 (hgnc:17380). hgnc:17380 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:34942119 SUPPORT Human Clinical
"Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC)."
This directly supports loss of APC7 as the causal genetic mechanism.
💊

Medical Actions

8
Supportive developmental care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management is supportive and tailored to developmental, cognitive, communication, hearing, and musculoskeletal needs.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Chromosomal microarray analysis of 11 young people of Old Order Amish heritage who displayed developmental delay and intellectual disability revealed a deletion within the ANAPC7 locus."
The patient cohort supports developmental delay and intellectual disability as management targets; supportive care is symptom-directed rather than disease-modifying.
Physical therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physical therapy may be used to address hypotonia and delayed motor milestone acquisition.
Target Phenotypes: Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology. Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Together with intellectual disability, acquisition of early motor milestones was also delayed"
The cohort supports delayed motor milestones as a therapy target, although no Ferguson-Bonni-specific physical-therapy trial exists.
Speech and language therapy
Action: speech therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Speech-language evaluation and therapy should be offered when communication delay is present, particularly because global developmental delay, intellectual disability, and hearing impairment can affect language acquisition.
Target Phenotypes: Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology. Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
The supplemental table (Table S2, not captured in the cached full text) supports hearing impairment as a communication risk; speech-language therapy is modeled as phenotype-directed supportive care, not as disease-specific treatment evidence. No verbatim quote is available.
Hearing management
Audiology-guided hearing management, including hearing aids or other amplification and communication supports when indicated, is appropriate for affected individuals with documented hearing impairment.
Target Phenotypes: Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
The supplemental table (Table S2, not captured in the cached full text) supports hearing loss as a management target; specific device choice should follow audiologic findings. No verbatim quote is available.
Educational and behavioral supports
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Individualized educational planning, cognitive supports, occupational therapy, and behavioral intervention should be guided by developmental, adaptive-function, and school-based assessments. Human behavioral features were not separately documented in the defining cohort, so behavioral support is included only as needs-based developmental management.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Chromosomal microarray analysis of 11 young people of Old Order Amish heritage who displayed developmental delay and intellectual disability revealed a deletion within the ANAPC7 locus."
Developmental delay and intellectual disability support individualized educational and cognitive/behavioral planning.
Feeding, nutrition, and growth support
Action: feeding therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is feeding therapy, annotated with Swallowing Therapy (NCIT:C156237). NCIT:C156237 is a clinical intervention from the NCI Thesaurus. Ontology label: Swallowing Therapy NCIT:C156237
Feeding evaluation, nutrition assessment, and growth monitoring should be used when low growth parameters, cleft palate, high-arched palate, or Pierre Robin sequence create feeding, airway, or nutrition concerns.
Target Phenotypes: Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology. Pierre Robin sequence HP:0000201 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pierre Robin sequence, annotated with Pierre-Robin sequence (HP:0000201). HP:0000201 is a phenotype from the Human Phenotype Ontology. Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Patient 2137 with the ANAPC7 intellectual disability syndrome exhibits Pierre-Robin sequence."
Pierre Robin sequence can drive feeding and airway management needs in affected individuals.
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"body and head size were low, though microcephaly was found in only one patient"
Low body size supports growth and nutrition monitoring as part of supportive care.
Phenotype-directed specialty surveillance
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Surveillance should be individualized to reported findings, with ophthalmology for strabismus or retinal findings, audiology for hearing impairment, and cardiology, surgery, orthopedics, endocrinology, or craniofacial referral when congenital organ anomalies are present.
Target Phenotypes: Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology. Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology. Pectus excavatum HP:0000767 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pectus excavatum (HP:0000767). HP:0000767 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
Strabismus in the supplemental table (Table S2, not captured in the cached full text) supports phenotype-directed ophthalmologic follow-up; no verbatim quote is available.
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
Rare congenital findings in the supplemental table (Table S2, not captured in the cached full text) support specialty follow-up when those findings are present, without implying universal multisystem surveillance. No verbatim quote is available.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling is appropriate for families because the syndrome is inherited in an autosomal recessive pattern.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"All affected patients were homozygous for the mutant ANAPC7 allele, whereas heterozygous siblings and parents were unaffected clinically."
Homozygous disease with unaffected heterozygotes supports autosomal-recessive counseling.
🔬

Diagnosis

6
ANAPC7 deletion and sequence testing
Chromosomal microarray or copy-number analysis can detect the recurrent ANAPC7 exons 4-6 deletion; gene panel or exome/genome sequencing should include ANAPC7 when evaluating syndromic developmental delay with recessive inheritance, hearing loss, and craniofacial or skeletal findings.
chromosomal microarray testing NCIT:C18477 NCI Thesaurus (NCIT)
Results: Homozygous pathogenic ANAPC7 loss-of-function variants establish the molecular diagnosis.
Show evidence (2 references)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Chromosomal microarray analysis of 11 young people of Old Order Amish heritage who displayed developmental delay and intellectual disability revealed a deletion within the ANAPC7 locus."
The defining patient cohort was diagnosed by chromosomal microarray identifying an ANAPC7 deletion.
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"All affected patients were homozygous for the mutant ANAPC7 allele, whereas heterozygous siblings and parents were unaffected clinically."
Homozygous ANAPC7 loss with unaffected heterozygotes supports recessive molecular diagnosis.
Developmental and cognitive assessment
Developmental pediatrics, neuropsychology, and therapy assessments should document global developmental delay, intellectual disability, motor milestones, adaptive needs, communication needs, educational supports, and functional trajectory.
neurodevelopmental assessment NCIT:C95403 NCI Thesaurus (NCIT)
Results: Developmental delay, intellectual disability, and delayed independent sitting or walking support the syndrome phenotype.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Together with intellectual disability, acquisition of early motor milestones was also delayed"
The primary paper supports focused developmental and motor assessment.
Audiology evaluation
Baseline and follow-up audiologic evaluation should be considered because hearing loss was reported in several affected individuals and may affect speech and language development.
diagnostic procedure of auditory system NCIT:C38036 NCI Thesaurus (NCIT)
Results: Hearing loss prompts hearing-management and communication-support planning.
Hearing loss is sourced from the paper's supplemental clinical-characteristics table (Table S2), which is not present in the cached full text, so no verbatim snippet is available.
Show evidence (1 reference)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
The supplemental table (Table S2, not captured in the cached full text) supports hearing evaluation in affected individuals; no verbatim quote is available.
Growth and craniofacial assessment
Growth monitoring should include weight, length/height, and head circumference. Craniofacial evaluation should assess micrognathia, high-arched palate, cleft palate, Pierre Robin sequence, feeding or airway concerns, and need for specialty referral.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Results: Low body/head size or craniofacial anomalies guide feeding, airway, nutrition, and surgical referrals.
Per-patient body weight, length, and head circumference measurements are from Figure S3D's legend, which is not present in the cached full text, so no verbatim per-patient snippet is available beyond the main-text summary sentence cited below. Do not source a snippet from the cache's "body weight" hits — those describe mouse growth-delay measurements, not the human cohort.
Show evidence (2 references)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"body and head size were low, though microcephaly was found in only one patient"
The main text confirms low body and head size in affected patients (with microcephaly in only one); the per-patient breakdown is in Figure S3D, not captured in the cached full text.
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
"Patient 2137 with the ANAPC7 intellectual disability syndrome exhibits Pierre-Robin sequence."
Pierre Robin sequence supports targeted craniofacial and feeding/airway assessment.
Ophthalmology and phenotype-directed organ screening
Ophthalmologic assessment and phenotype-directed evaluation of cardiac, diaphragm, chest wall, auditory canal, and endocrine findings should be considered when clinical examination suggests organ involvement, because Table S2 reports strabismus and rare additional congenital anomalies.
eye examination NCIT:C38060 NCI Thesaurus (NCIT)
Results: Strabismus, retinal findings, cardiac defects, diaphragmatic hernia, or chest-wall anomalies guide specialty surveillance.
Strabismus and the rare congenital findings (diaphragmatic hernia, unilateral ptosis, microcephaly, patent foramen ovale) are sourced from the paper's supplemental clinical-characteristics table (Table S2), which is not present in the cached full text, so no verbatim snippet is available for either.
Show evidence (2 references)
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
Strabismus in the supplemental table (Table S2, not captured in the cached full text) supports ophthalmologic evaluation; no verbatim quote is available.
DOI:10.1016/j.molcel.2021.11.031 SUPPORT Human Clinical
The supplemental table (Table S2, not captured in the cached full text) lists rare congenital findings that support phenotype-directed specialty screening rather than universal organ surveillance.
Ubiquitin-proteasome neurodevelopmental differential diagnosis
Diagnosis should distinguish ANAPC7-related recessive disease from other ubiquitin-proteasome or chromatin-associated neurodevelopmental syndromes, including PSMD12-related Stankiewicz-Isidor syndrome and USP7-related Hao-Fountain syndrome, using inheritance, gene testing, and phenotype pattern.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Results: Biallelic ANAPC7 loss supports Ferguson-Bonni syndrome over dominant PSMD12 or USP7 disorders.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Ferguson-Bonni neurodevelopmental syndrome:

Stankiewicz-Isidor syndrome MONDO:0054591
Overlapping Features PSMD12-related neurodevelopmental disorder overlaps through developmental delay, intellectual disability, craniofacial dysmorphism, and ubiquitin- proteasome biology.
Distinguishing Features
  • PSMD12 haploinsufficiency and typically autosomal dominant inheritance, rather than biallelic ANAPC7 loss.
Hao-Fountain syndrome MONDO:0014805
Overlapping Features USP7-related neurodevelopmental disorder overlaps through global developmental delay, intellectual disability, severe speech delay, hypotonia, dysmorphic features, and altered ubiquitin-system regulation.
Distinguishing Features
  • USP7 mutation or 16p13.2 microdeletion, rather than ANAPC7 loss.
🐁

Animal Models

1
Anapc7 patient-specific exon 4-6 deletion knock-in Mouse knock-in
Mice carrying the patient-specific Anapc7 deletion model loss of APC7 in brain, altered neuronal APC/C substrate handling, and nervous-system functional phenotypes.
Neuronal Ki-67 substrate accumulation Neuronal heterochromatin dysregulation
Species
Mouse
Genotype
Anapc7 patient-specific exon 4-6 deletion knock-in
Genes
ANAPC7 hgnc:17380 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns ANAPC7 (hgnc:17380). hgnc:17380 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:34942119 SUPPORT Model Organism
"In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons."
This supports the patient-mutation mouse as a mechanistic model of APC7-dependent neuronal substrate regulation.
{ }

Source YAML

click to show 
name: Ferguson-Bonni neurodevelopmental syndrome
creation_date: "2026-04-29T23:27:33Z"
description: >-
  Ferguson-Bonni neurodevelopmental syndrome is a rare autosomal recessive
  ANAPC7-related Mendelian neurodevelopmental disorder characterized by
  developmental delay, intellectual disability, hypotonia with early motor
  delay, and variable craniofacial, skeletal, growth, and hearing findings.
  The defining mechanism is loss of APC7, a core anaphase-promoting complex
  subunit required for neuronal ubiquitin signaling and heterochromatin
  regulation.
category: Mendelian
parents:
- Mendelian neurodevelopmental disorder
- hereditary disease
synonyms:
- FERBON
- ANAPC7-related neurodevelopmental syndrome
disease_term:
  preferred_term: Ferguson-Bonni neurodevelopmental syndrome
  term:
    id: MONDO:0859220
    label: Ferguson-Bonni neurodevelopmental syndrome
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Reported affected individuals are homozygous for a loss-of-function ANAPC7
    founder deletion, while heterozygous relatives are clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report an intellectual disability syndrome caused by the loss of
      APC7, a core component of the E3 ubiquitin ligase anaphase promoting
      complex (APC).
    explanation: >-
      The PubMed abstract supports loss of APC7 as the disease cause; the
      inheritance mode is curated from the full article and MedGen summary.
genetic:
- name: ANAPC7
  association: Causal biallelic loss-of-function ANAPC7 variant
  gene_term:
    preferred_term: ANAPC7
    term:
      id: hgnc:17380
      label: ANAPC7
  notes: >-
    The defining allele is a founder deletion spanning ANAPC7 exons 4-6 that
    causes a frameshift and loss of APC7 protein.
  evidence:
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report an intellectual disability syndrome caused by the loss of
      APC7, a core component of the E3 ubiquitin ligase anaphase promoting
      complex (APC).
    explanation: This directly supports loss of APC7 as the causal genetic mechanism.
pathophysiology:
- name: ANAPC7 loss of function
  description: >-
    Biallelic ANAPC7 loss reduces APC7 protein, removing a core subunit of the
    anaphase-promoting complex/cyclosome E3 ubiquitin ligase.
  genes:
  - preferred_term: ANAPC7
    term:
      id: hgnc:17380
      label: ANAPC7
  evidence:
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report an intellectual disability syndrome caused by the loss of
      APC7, a core component of the E3 ubiquitin ligase anaphase promoting
      complex (APC).
    explanation: This identifies APC7 loss as the initiating disease mechanism.
  downstream:
  - target: Impaired APC substrate recruitment and ubiquitination
    description: APC7 loss compromises recruitment and ubiquitination of APC substrates.
- name: Impaired APC substrate recruitment and ubiquitination
  description: >-
    APC7 loss impairs anaphase-promoting complex substrate recruitment and
    ubiquitination, reducing APC/C-dependent protein turnover in the developing
    nervous system.
  biological_processes:
  - preferred_term: APC-dependent protein catabolism
    modifier: DECREASED
    term:
      id: GO:0031145
      label: anaphase-promoting complex-dependent catabolic process
  - preferred_term: ubiquitin-dependent protein catabolic process
    modifier: DECREASED
    term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
  evidence:
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In mechanistic studies, we uncover a critical role for APC7 during the
      recruitment and ubiquitination of APC substrates.
    explanation: This directly supports impaired APC substrate recruitment and ubiquitination after APC7 loss.
  downstream:
  - target: Neuronal Ki-67 substrate accumulation
    description: Reduced APC7-dependent ubiquitination allows APC substrates such as Ki-67 to accumulate.
- name: Neuronal Ki-67 substrate accumulation
  description: >-
    In patient-mutation mouse brain and patient-derived cells, APC7 loss causes
    accumulation of the chromatin-associated APC substrate Ki-67 in neurons.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  evidence:
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In proteomics analyses of the brain from mice harboring the
      patient-specific APC7 mutation, we identify the chromatin-associated
      protein Ki-67 as an APC7-dependent substrate of the APC in neurons.
    explanation: This supports Ki-67 as a neuron-relevant APC7-dependent substrate in the disease model.
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20,
      leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting
      that APC7 is required for the function of Cdh1-APC in the brain.
    explanation: This links APC7/Cdh1-APC function to neuronal Ki-67 protein accumulation in vivo.
  downstream:
  - target: Neuronal heterochromatin dysregulation
    description: Accumulated Ki-67 localizes to constitutive heterochromatin in neurons.
- name: Neuronal heterochromatin dysregulation
  description: >-
    Deregulated Ki-67 localizes to constitutive heterochromatin, implicating
    APC7-dependent ubiquitin signaling in neuronal chromatin architecture during
    brain development.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: heterochromatin organization
    modifier: ABNORMAL
    term:
      id: GO:0070828
      label: heterochromatin organization
  - preferred_term: neuron development
    modifier: ABNORMAL
    term:
      id: GO:0048666
      label: neuron development
  evidence:
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to
      constitutive heterochromatin.
    explanation: This directly supports heterochromatin localization of deregulated Ki-67 after APC7 loss.
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings define an essential function for APC7 and Cdh1-APC in
      neuronal heterochromatin regulation, with implications for understanding
      human brain development and disease.
    explanation: This supports neuronal heterochromatin regulation as a central disease mechanism.
  downstream:
  - target: Global developmental delay
    description: Disrupted neuronal chromatin regulation impairs early neurodevelopmental milestones.
  - target: Intellectual disability
    description: Impaired APC7-dependent neuronal chromatin regulation contributes to cognitive impairment.
  - target: Motor delay
    description: Neurodevelopmental disruption contributes to delayed motor milestone acquisition.
phenotypes:
- name: Global developmental delay
  category: Neurodevelopmental
  diagnostic: true
  description: Global developmental delay is a core pediatric manifestation of the syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal microarray analysis of 11 young people of Old Order Amish
      heritage who displayed developmental delay and intellectual disability
      revealed a deletion within the ANAPC7 locus.
    explanation: >-
      The affected cohort was ascertained with developmental delay and
      intellectual disability caused by ANAPC7 deletion.
- name: Intellectual disability
  category: Neurodevelopmental
  diagnostic: true
  description: Intellectual disability is the defining cognitive phenotype.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report an intellectual disability syndrome caused by the loss of
      APC7, a core component of the E3 ubiquitin ligase anaphase promoting
      complex (APC).
    explanation: This directly supports intellectual disability as the defining syndrome feature.
- name: Motor delay
  category: Neurodevelopmental
  description: Early motor milestone acquisition is delayed in affected individuals.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Together with intellectual disability, acquisition of early motor
      milestones was also delayed
    explanation: >-
      The paper directly reports delayed early motor milestone acquisition in
      affected individuals.
- name: Hypotonia
  category: Neuromuscular
  description: Hypotonia is reported with early motor delay.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  notes: >-
    Sourced from the paper's supplemental clinical-characteristics table
    (Table S2), which is not present in the cached full text, so no verbatim
    snippet is available. Independently corroborated by the HPO annotation
    set for OMIM:619699 (hypotonia in 8/11 patients in the same cohort).
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      The paper's supplemental clinical-characteristics table (Table S2, not
      captured in the cached full text) lists hypotonia among the neurologic
      findings in affected patients; no verbatim quote is available.
- name: Abnormal facial shape
  category: Craniofacial
  description: Dysmorphic facial features are variably reported in affected individuals.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal and/or craniofacial deformities were seen in a subset of patients
    explanation: >-
      The paper reports craniofacial deformities in a subset of affected
      individuals and illustrates Pierre Robin sequence in one patient.
- name: Short stature
  category: Growth
  description: Low body size and short stature are reported in the clinical spectrum.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      body and head size were low, though microcephaly was found in only one
      patient
    explanation: >-
      The source supports reduced body size in affected individuals; this is
      mapped conservatively to short stature pending more granular anthropometry.
- name: Hearing impairment
  category: Auditory
  description: Hearing loss may occur as an additional feature.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  notes: >-
    Sourced from the paper's supplemental clinical-characteristics table
    (Table S2), which is not present in the cached full text, so no verbatim
    snippet is available. Independently corroborated by the HPO annotation
    set for OMIM:619699 (hearing impairment in 5/11 patients in the same
    cohort).
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      The paper's supplemental clinical-characteristics table (Table S2, not
      captured in the cached full text) lists hearing loss among the clinical
      findings in multiple affected patients; no verbatim quote is available.
- name: Micrognathia
  category: Craniofacial
  description: Micrognathia is reported in multiple affected individuals.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  notes: >-
    The main text supports craniofacial deformities generally; the
    micrognathia-specific finding is listed in the paper's supplemental
    clinical-characteristics table (Table S2), which is not captured in the
    cached full text. Independently corroborated by the HPO annotation set
    for OMIM:619699 (micrognathia in 6/11 patients in the same cohort).
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal and/or craniofacial deformities were seen in a subset of patients
    explanation: >-
      The main text supports craniofacial deformities in a subset of patients;
      the micrognathia-specific detail is in the paper's supplemental
      clinical-characteristics table (Table S2), which is not captured in the
      cached full text.
- name: High palate
  category: Craniofacial
  description: High-arched palate is part of the variable craniofacial spectrum.
  phenotype_term:
    preferred_term: High-arched palate
    term:
      id: HP:0000218
      label: High palate
  notes: >-
    The main text supports craniofacial deformities generally; the
    high-arched-palate-specific finding is listed in the paper's supplemental
    clinical-characteristics table (Table S2), which is not captured in the
    cached full text. Independently corroborated by the HPO annotation set
    for OMIM:619699 (high palate in 3/11 patients in the same cohort).
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal and/or craniofacial deformities were seen in a subset of patients
    explanation: >-
      The main text supports craniofacial deformities in a subset of patients;
      the high-arched-palate-specific detail is in the paper's supplemental
      clinical-characteristics table (Table S2), which is not captured in the
      cached full text.
- name: Cleft palate
  category: Craniofacial
  description: Cleft palate is reported in a subset of affected individuals.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  notes: >-
    Unlike the other supplemental-table findings in this entry, cleft palate
    is absent from both the cached full text and the HPO annotation set for
    OMIM:619699, and may reflect conflation with the separately evidenced
    Pierre-Robin sequence in patient 2137 (a triad that often, but not always,
    includes cleft palate) rather than an independently documented finding.
    No verbatim quote is available to support this claim as an independent
    phenotype; the evidence block is intentionally left empty pending access
    to the paper's Table S2 rather than citing an unverifiable snippet. See
    the `gap_cleft_palate_pierre_robin_conflation` discussion for the open
    question this raises.
- name: Pierre Robin sequence
  category: Craniofacial
  description: One illustrated affected patient had Pierre Robin sequence.
  phenotype_term:
    preferred_term: Pierre Robin sequence
    term:
      id: HP:0000201
      label: Pierre-Robin sequence
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 2137 with the ANAPC7 intellectual disability syndrome exhibits Pierre-Robin sequence."
    explanation: The Figure 3 legend documents Pierre Robin sequence in patient 2137.
- name: Hypertelorism
  category: Craniofacial
  description: Hypertelorism is reported among variable craniofacial findings.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  notes: >-
    The main text supports craniofacial deformities generally; the
    hypertelorism-specific finding is listed in the paper's supplemental
    clinical-characteristics table (Table S2), which is not captured in the
    cached full text. Independently corroborated by the HPO annotation set
    for OMIM:619699 (hypertelorism in 6/11 patients in the same cohort).
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal and/or craniofacial deformities were seen in a subset of patients
    explanation: >-
      The main text supports craniofacial deformities in a subset of patients;
      the hypertelorism-specific detail is in the paper's supplemental
      clinical-characteristics table (Table S2), which is not captured in the
      cached full text.
- name: Strabismus
  category: Ophthalmologic
  description: Strabismus is reported in multiple affected individuals.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  notes: >-
    Sourced from the paper's supplemental clinical-characteristics table
    (Table S2), which is not present in the cached full text, so no verbatim
    snippet is available. Independently corroborated by the HPO annotation
    set for OMIM:619699 (strabismus in 5/11 patients in the same cohort).
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      The paper's supplemental clinical-characteristics table (Table S2, not
      captured in the cached full text) lists strabismus in affected patients;
      no verbatim quote is available.
- name: Microcephaly
  category: Growth
  description: Microcephaly was uncommon, reported in one affected individual.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "body and head size were low, though microcephaly was found in only one patient"
    explanation: The primary paper reports low head size with microcephaly in one patient.
- name: Pectus excavatum
  category: Skeletal
  description: Pectus excavatum is reported among skeletal findings.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  notes: >-
    The main text supports skeletal/craniofacial deformities generally; the
    pectus-excavatum-specific finding is listed in the paper's supplemental
    clinical-characteristics table (Table S2), which is not captured in the
    cached full text. Independently corroborated by the HPO annotation set
    for OMIM:619699 (pectus excavatum in 7/11 patients in the same cohort).
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal and/or craniofacial deformities were seen in a subset of patients
    explanation: >-
      The main text supports skeletal/craniofacial deformities in a subset of
      patients; the pectus-excavatum-specific detail is in the paper's
      supplemental clinical-characteristics table (Table S2), which is not
      captured in the cached full text.
animal_models:
- species: Mouse
  genotype: Anapc7 patient-specific exon 4-6 deletion knock-in
  category: knock-in
  description: >-
    Mice carrying the patient-specific Anapc7 deletion model loss of APC7 in
    brain, altered neuronal APC/C substrate handling, and nervous-system
    functional phenotypes.
  genes:
  - preferred_term: ANAPC7
    term:
      id: hgnc:17380
      label: ANAPC7
  associated_phenotypes:
  - Neuronal Ki-67 substrate accumulation
  - Neuronal heterochromatin dysregulation
  evidence:
  - reference: PMID:34942119
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In proteomics analyses of the brain from mice harboring the
      patient-specific APC7 mutation, we identify the chromatin-associated
      protein Ki-67 as an APC7-dependent substrate of the APC in neurons.
    explanation: This supports the patient-mutation mouse as a mechanistic model of APC7-dependent neuronal substrate regulation.
diagnosis:
- name: ANAPC7 deletion and sequence testing
  description: >-
    Chromosomal microarray or copy-number analysis can detect the recurrent
    ANAPC7 exons 4-6 deletion; gene panel or exome/genome sequencing should
    include ANAPC7 when evaluating syndromic developmental delay with recessive
    inheritance, hearing loss, and craniofacial or skeletal findings.
  diagnosis_term:
    preferred_term: chromosomal microarray testing
    term:
      id: NCIT:C18477
      label: Microarray Analysis
  results: Homozygous pathogenic ANAPC7 loss-of-function variants establish the molecular diagnosis.
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal microarray analysis of 11 young people of Old Order Amish
      heritage who displayed developmental delay and intellectual disability
      revealed a deletion within the ANAPC7 locus.
    explanation: >-
      The defining patient cohort was diagnosed by chromosomal microarray
      identifying an ANAPC7 deletion.
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected patients were homozygous for the mutant ANAPC7 allele, whereas
      heterozygous siblings and parents were unaffected clinically.
    explanation: Homozygous ANAPC7 loss with unaffected heterozygotes supports recessive molecular diagnosis.
- name: Developmental and cognitive assessment
  description: >-
    Developmental pediatrics, neuropsychology, and therapy assessments should
    document global developmental delay, intellectual disability, motor
    milestones, adaptive needs, communication needs, educational supports, and
    functional trajectory.
  diagnosis_term:
    preferred_term: neurodevelopmental assessment
    term:
      id: NCIT:C95403
      label: Developmental Neuropsychological Assessment
  results: Developmental delay, intellectual disability, and delayed independent sitting or walking support the syndrome phenotype.
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Together with intellectual disability, acquisition of early motor
      milestones was also delayed
    explanation: The primary paper supports focused developmental and motor assessment.
- name: Audiology evaluation
  description: >-
    Baseline and follow-up audiologic evaluation should be considered because
    hearing loss was reported in several affected individuals and may affect
    speech and language development.
  diagnosis_term:
    preferred_term: diagnostic procedure of auditory system
    term:
      id: NCIT:C38036
      label: Audiometric Test
  results: Hearing loss prompts hearing-management and communication-support planning.
  notes: >-
    Hearing loss is sourced from the paper's supplemental clinical-characteristics
    table (Table S2), which is not present in the cached full text, so no
    verbatim snippet is available.
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      The supplemental table (Table S2, not captured in the cached full text)
      supports hearing evaluation in affected individuals; no verbatim quote
      is available.
- name: Growth and craniofacial assessment
  description: >-
    Growth monitoring should include weight, length/height, and head
    circumference. Craniofacial evaluation should assess micrognathia,
    high-arched palate, cleft palate, Pierre Robin sequence, feeding or airway
    concerns, and need for specialty referral.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Low body/head size or craniofacial anomalies guide feeding, airway, nutrition, and surgical referrals.
  notes: >-
    Per-patient body weight, length, and head circumference measurements are
    from Figure S3D's legend, which is not present in the cached full text,
    so no verbatim per-patient snippet is available beyond the main-text
    summary sentence cited below. Do not source a snippet from the cache's
    "body weight" hits — those describe mouse growth-delay measurements, not
    the human cohort.
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "body and head size were low, though microcephaly was found in only one patient"
    explanation: >-
      The main text confirms low body and head size in affected patients
      (with microcephaly in only one); the per-patient breakdown is in
      Figure S3D, not captured in the cached full text.
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 2137 with the ANAPC7 intellectual disability syndrome exhibits Pierre-Robin sequence."
    explanation: Pierre Robin sequence supports targeted craniofacial and feeding/airway assessment.
- name: Ophthalmology and phenotype-directed organ screening
  description: >-
    Ophthalmologic assessment and phenotype-directed evaluation of cardiac,
    diaphragm, chest wall, auditory canal, and endocrine findings should be
    considered when clinical examination suggests organ involvement, because
    Table S2 reports strabismus and rare additional congenital anomalies.
  diagnosis_term:
    preferred_term: eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  results: Strabismus, retinal findings, cardiac defects, diaphragmatic hernia, or chest-wall anomalies guide specialty surveillance.
  notes: >-
    Strabismus and the rare congenital findings (diaphragmatic hernia,
    unilateral ptosis, microcephaly, patent foramen ovale) are sourced from
    the paper's supplemental clinical-characteristics table (Table S2), which
    is not present in the cached full text, so no verbatim snippet is
    available for either.
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      Strabismus in the supplemental table (Table S2, not captured in the
      cached full text) supports ophthalmologic evaluation; no verbatim quote
      is available.
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      The supplemental table (Table S2, not captured in the cached full text)
      lists rare congenital findings that support
      phenotype-directed specialty screening rather than universal organ
      surveillance.
- name: Ubiquitin-proteasome neurodevelopmental differential diagnosis
  description: >-
    Diagnosis should distinguish ANAPC7-related recessive disease from other
    ubiquitin-proteasome or chromatin-associated neurodevelopmental syndromes,
    including PSMD12-related Stankiewicz-Isidor syndrome and USP7-related
    Hao-Fountain syndrome, using inheritance, gene testing, and phenotype
    pattern.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Biallelic ANAPC7 loss supports Ferguson-Bonni syndrome over dominant PSMD12 or USP7 disorders.
treatments:
- name: Supportive developmental care
  description: >-
    Management is supportive and tailored to developmental, cognitive,
    communication, hearing, and musculoskeletal needs.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal microarray analysis of 11 young people of Old Order Amish
      heritage who displayed developmental delay and intellectual disability
      revealed a deletion within the ANAPC7 locus.
    explanation: >-
      The patient cohort supports developmental delay and intellectual
      disability as management targets; supportive care is symptom-directed
      rather than disease-modifying.
- name: Physical therapy
  description: >-
    Physical therapy may be used to address hypotonia and delayed motor
    milestone acquisition.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Together with intellectual disability, acquisition of early motor
      milestones was also delayed
    explanation: >-
      The cohort supports delayed motor milestones as a therapy target, although
      no Ferguson-Bonni-specific physical-therapy trial exists.
- name: Speech and language therapy
  description: >-
    Speech-language evaluation and therapy should be offered when communication
    delay is present, particularly because global developmental delay,
    intellectual disability, and hearing impairment can affect language
    acquisition.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  notes: >-
    Hearing loss is sourced from the paper's supplemental clinical-characteristics
    table (Table S2), which is not present in the cached full text, so no
    verbatim snippet is available.
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      The supplemental table (Table S2, not captured in the cached full text)
      supports hearing impairment as a communication risk; speech-language
      therapy is modeled as phenotype-directed supportive care, not as
      disease-specific treatment evidence. No verbatim quote is available.
- name: Hearing management
  description: >-
    Audiology-guided hearing management, including hearing aids or other
    amplification and communication supports when indicated, is appropriate for
    affected individuals with documented hearing impairment.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid usage
  target_phenotypes:
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  notes: >-
    Hearing loss is sourced from the paper's supplemental clinical-characteristics
    table (Table S2), which is not present in the cached full text, so no
    verbatim snippet is available.
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      The supplemental table (Table S2, not captured in the cached full text)
      supports hearing loss as a management target; specific device choice
      should follow audiologic findings. No verbatim quote is available.
- name: Educational and behavioral supports
  description: >-
    Individualized educational planning, cognitive supports, occupational
    therapy, and behavioral intervention should be guided by developmental,
    adaptive-function, and school-based assessments. Human behavioral features
    were not separately documented in the defining cohort, so behavioral support
    is included only as needs-based developmental management.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal microarray analysis of 11 young people of Old Order Amish
      heritage who displayed developmental delay and intellectual disability
      revealed a deletion within the ANAPC7 locus.
    explanation: >-
      Developmental delay and intellectual disability support individualized
      educational and cognitive/behavioral planning.
- name: Feeding, nutrition, and growth support
  description: >-
    Feeding evaluation, nutrition assessment, and growth monitoring should be
    used when low growth parameters, cleft palate, high-arched palate, or Pierre
    Robin sequence create feeding, airway, or nutrition concerns.
  treatment_term:
    preferred_term: feeding therapy
    term:
      id: NCIT:C156237
      label: Swallowing Therapy
  target_phenotypes:
  - preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  - preferred_term: Pierre Robin sequence
    term:
      id: HP:0000201
      label: Pierre-Robin sequence
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 2137 with the ANAPC7 intellectual disability syndrome exhibits Pierre-Robin sequence."
    explanation: >-
      Pierre Robin sequence can drive feeding and airway management needs in
      affected individuals.
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      body and head size were low, though microcephaly was found in only one
      patient
    explanation: >-
      Low body size supports growth and nutrition monitoring as part of
      supportive care.
- name: Phenotype-directed specialty surveillance
  description: >-
    Surveillance should be individualized to reported findings, with
    ophthalmology for strabismus or retinal findings, audiology for hearing
    impairment, and cardiology, surgery, orthopedics, endocrinology, or
    craniofacial referral when congenital organ anomalies are present.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  - preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  notes: >-
    Strabismus and the rare congenital findings (diaphragmatic hernia,
    unilateral ptosis, microcephaly, patent foramen ovale) are sourced from
    the paper's supplemental clinical-characteristics table (Table S2), which
    is not present in the cached full text, so no verbatim snippet is
    available for either.
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      Strabismus in the supplemental table (Table S2, not captured in the
      cached full text) supports phenotype-directed ophthalmologic follow-up;
      no verbatim quote is available.
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    explanation: >-
      Rare congenital findings in the supplemental table (Table S2, not
      captured in the cached full text) support specialty follow-up when
      those findings are present, without implying universal multisystem
      surveillance. No verbatim quote is available.
- name: Genetic counseling
  description: >-
    Genetic counseling is appropriate for families because the syndrome is
    inherited in an autosomal recessive pattern.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: DOI:10.1016/j.molcel.2021.11.031
    reference_title: >-
      APC7 mediates ubiquitin signaling in constitutive heterochromatin in the
      developing mammalian brain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected patients were homozygous for the mutant ANAPC7 allele, whereas
      heterozygous siblings and parents were unaffected clinically.
    explanation: Homozygous disease with unaffected heterozygotes supports autosomal-recessive counseling.
differential_diagnoses:
- name: Stankiewicz-Isidor syndrome
  description: >-
    PSMD12-related neurodevelopmental disorder overlaps through developmental
    delay, intellectual disability, craniofacial dysmorphism, and ubiquitin-
    proteasome biology.
  distinguishing_features:
  - >-
    PSMD12 haploinsufficiency and typically autosomal dominant inheritance,
    rather than biallelic ANAPC7 loss.
  disease_term:
    preferred_term: Stankiewicz-Isidor syndrome
    term:
      id: MONDO:0054591
      label: Stankiewicz-Isidor syndrome
- name: Hao-Fountain syndrome
  description: >-
    USP7-related neurodevelopmental disorder overlaps through global
    developmental delay, intellectual disability, severe speech delay,
    hypotonia, dysmorphic features, and altered ubiquitin-system regulation.
  distinguishing_features:
  - USP7 mutation or 16p13.2 microdeletion, rather than ANAPC7 loss.
  disease_term:
    preferred_term: Hao-Fountain syndrome
    term:
      id: MONDO:0014805
      label: Hao-Fountain syndrome
references:
- reference: PMID:34942119
  title: APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain.
  findings: []
- reference: DOI:10.1016/j.molcel.2021.11.031
  title: APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain.
  findings: []
discussions:
- discussion_id: gap_cleft_palate_pierre_robin_conflation
  prompt: >-
    Is cleft palate an independently documented finding in this cohort, or
    does the curated claim reflect conflation with the separately evidenced
    Pierre Robin sequence in patient 2137?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Cleft palate
  - phenotypes#Pierre Robin sequence
  rationale: >-
    Cleft palate is absent from both the cached full-text of the defining
    paper and the HPO annotation set for OMIM:619699, unlike every other
    supplemental-table finding in this entry, which are independently
    corroborated by that same HPO annotation set. Pierre Robin sequence is a
    triad (micrognathia, glossoptosis, and airway obstruction) that often,
    but not always, includes cleft palate, and is independently and verbatim
    evidenced in patient 2137. Access to the paper's Table S2 is needed to
    determine whether cleft palate was scored as a distinct finding in one or
    more patients or whether the claim originated from the Pierre Robin
    sequence observation alone.
notes: >-
  Asta retrieval was run for this entry. Because the Asta result set was mostly
  broad neurodevelopmental-disorder literature, the curation relies on the
  defining ANAPC7 paper and focused PubMed/MedGen/PMC checks. The current human
  phenotype evidence is a single 11-person Old Order Amish cohort, so frequency
  claims should remain provisional and case/cohort-level. The downstream
  mechanism is kept distinct from the human genetic association: APC7 loss in
  affected individuals is human clinical evidence, while APC substrate handling,
  neuronal Ki-67 accumulation, and heterochromatin dysregulation come from
  in-vitro or mouse-model experiments. Seizures, brain MRI/neuroimaging
  findings, and human behavioral features were checked in the primary paper and
  supplement but were not modeled because they were not documented as human
  cohort findings.
📚

References & Deep Research

References

2
PMID:34942119
APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain.
No top-level findings curated for this source.
DOI:10.1016/j.molcel.2021.11.031
APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain.
No top-level findings curated for this source.

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Ferguson-Bonni neurodevelopmental syndrome. Core disease mechanisms, molec...
Asta Scientific Corpus Retrieval 20 citations 2026-04-29T19:27:55.749131

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Ferguson-Bonni neurodevelopmental syndrome. Core disease mechanisms, molec...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] The Role of Alpha-Synuclein and Other Parkinson’s Genes in Neurodevelopmental and Neurodegenerative Disorders

  • Authors: C. Torres, Z. Wassouf, Z. Wassouf, Faria Zafar, D. Sastre et al.
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/aedea7861a666c1aa7570fc071cccc377ad33d96
  • DOI: 10.3390/ijms21165724
  • PMID: 32785033
  • PMCID: 7460874
  • Citations: 56
  • Influential citations: 1
  • Summary: Clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD are focused on to re-conceptualize how these disorders are understood and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
  • Evidence snippets:
  • Snippet 1 (score: 0.430) > Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.

[2] Chromatin modifiers in neurodevelopment

  • Authors: Sarallah Rezazadeh, H. Ji, Cecilia Giulivi
  • Year: 2025
  • Venue: Frontiers in Molecular Neuroscience
  • URL: https://www.semanticscholar.org/paper/7a4d8c063c2b3a908a65bcb637cd818edad8db92
  • DOI: 10.3389/fnmol.2025.1551107
  • PMID: 40469903
  • PMCID: 12133960
  • Citations: 2
  • Summary: This mini review delves into key chromatin modifiers, including the histone methyl transferases NSD1 and ASH1L, the methyl-CpG-binding repressor MeCP2, and the enzymatic repressor EZH2, and spotlight their pivotal roles in early brain development and neurological disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.412) > Therefore, while epigenetic changes are essential for understanding specific aspects of neurodevelopmental disorders, it is crucial to view these mechanisms as part of a larger, more complex system that encompasses genetic, proteomic, and metabolic factors. Few examples underscore that while epigenetic mechanisms-such as DNA methylation and histone modificationsare essential in regulating gene expression and contribute to neurodevelopmental disorders, they do not fully explain the complex pathophysiology of these diseases. In many cases, the genetic mutations, absence of or dysfunction of protein, or toxic protein aggregation (e.g., Fragile X syndrome, HD) that occur in these disorders play a central role in the clinical phenotypes. Therefore, a comprehensive understanding of neurodevelopmental disorders must integrate epigenetic mechanisms and the broader genetic, proteomic, and cellular pathways that contribute to disease. An integrative approach that considers not only the regulation of gene expression but also the functional consequences of these changes at the protein, metabolic and cellular pathway levels will be essential for advancing our understanding of these intricate disorders and developing effective interventions and treatments. . B., Villate, O., Llano, I., Ocio, I., Martí, I., et al. (2020). Targeted next-generation sequencing in patients with suggestive X-linked intellectual disability. Genes 11:51. doi: 10.3390/genes11010051

[3] Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes.

  • Authors: Ana I. Silva, F. Ehrhart, M. Ulfarsson, H. Stefánsson, K. Stefánsson et al.
  • Year: 2022
  • Venue: Biological psychiatry
  • URL: https://www.semanticscholar.org/paper/c856263af3dabb593698bdd11a313648b05a16c5
  • DOI: 10.1016/j.biopsych.2022.03.018
  • PMID: 35659384
  • Citations: 14
  • Influential citations: 1
  • Summary: New approaches that integrate human molecular data with neuroimaging, cognitive, and animal model data, while taking into account critical developmental time points are needed to better understand the link between key molecular mechanisms and convergent psychiatric phenotypes.
  • Evidence snippets:
  • Snippet 1 (score: 0.411) > ISSN: 0006-3223 Biological Psychiatry September 1, 2022; 92:341-361 www.sobp.org/journal molecular pathways have been identified across genetic risk variants and across neurodevelopmental disorders. In recent years, magnetic resonance imaging (MRI) studies on CNV cohorts have led to important discoveries on genetic drivers of altered brain structure and function. However, identifying convergent brain effects and linking cellular mechanisms to these changes has proved more challenging. With growing initiatives of data-sharing and large-scale collaborations across research groups, exciting opportunities are emerging to combine multidimensional data from neuroimaging, cognitive, and bioinformatics studies to identify key pathogenic mechanisms in the path from genome to clinical phenotypes. > In this narrative review, we provide an overview of biological findings on CNVs and neurodevelopmental disorders, placing a special focus on both convergent and locus-specific brain abnormalities across CNVs from human and animal studies. We further discuss the need to develop integrated approaches combining multiomics databases (e.g., transcriptomics, proteomics, and metabolomics) with neuroimaging and clinical data to identify relevant disease mechanisms that can be targeted using novel therapies.

[4] Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders

  • Authors: James J. Fink, E. Levine
  • Year: 2018
  • Venue: Frontiers in Neurology
  • URL: https://www.semanticscholar.org/paper/25fb8e8d9f748ef2664990bbdf42e80cf103c000
  • DOI: 10.3389/fneur.2018.00237
  • PMID: 29713304
  • PMCID: 5911479
  • Citations: 23
  • Summary: Electrophysiological analysis at the earliest stages of neuronal development is critical for identifying changes in activity and excitability that can contribute to synaptic dysfunction and identify targets for disease-modifying therapies.
  • Evidence snippets:
  • Snippet 1 (score: 0.410) > Animal models of neurodevelopmental disorders have provided invaluable insights into the molecular-, cellular-, and circuit-level defects associated with a plethora of genetic disruptions. In many cases, these deficits have been linked to changes in disease-relevant behaviors, but very few of these findings have been translated to treatments for human disease. This may be due to significant species differences and the difficulty in modeling disorders that involve deletion or duplication of multiple genes. The identification of primary underlying pathophysiology in these models is confounded by the accumulation of secondary disease phenotypes in the mature nervous system, as well as potential compensatory mechanisms. The discovery of induced pluripotent stem cell technology now provides a tool to accurately model complex genetic neurogenetic disorders. Using this technique, patient-specific cell lines can be generated and differentiated into specific subtypes of neurons that can be used to identify primary cellular and molecular phenotypes. It is clear that impairments in synaptic structure and function are a common pathophysiology across neurodevelopmental disorders, and electrophysiological analysis at the earliest stages of neuronal development is critical for identifying changes in activity and excitability that can contribute to synaptic dysfunction and identify targets for disease-modifying therapies.

[5] Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

  • Authors: A. Morsy, Angelica V Carmona, P. Trippier
  • Year: 2021
  • Venue: Molecules
  • URL: https://www.semanticscholar.org/paper/d510bd31c2c0312641423e0a06892605943439bc
  • DOI: 10.3390/molecules26206235
  • PMID: 34684815
  • PMCID: 8538546
  • Citations: 10
  • Influential citations: 2
  • Summary: An overview of available iPSC models for a number of different NCLs is provided and findings in these models that may spur target identification and drug development are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > The NCLs encompasses a group of rare, fatal, pediatric neurodegenerative lysosomal storage disorders.Several gene mutations (CLN1-CLN8, CLN10-CLN14) can lead to NCL; however, a partial understanding of the function of the disease-associated proteins has hindered therapy development.Current treatment options are only symptomatic and focus on delaying progression.To date, there are only two clinically approved drugs, Brineuria, for the treatment of CLN2 disease, and Neurogene's recently approved gene therapy to treat CLN5 disease.Different organism models have become available for NCL disease research which have provided a myriad of important information about the protein function or dysfunction for each of the associated genes, possible disease mechanisms, and have enabled detailed preclinical studies and in a small number of cases, clinical trials. > Herein, we have highlighted the contributions of different disease models to NCL research, focusing on the established patient-derived iPSC phenotypic screening models.The ability of iPSCs to encompass the precise pattern of genetic variants, along with acquiring disease pathogenesis and phenotype makes them a more translational model compared to mice and eliminates the problem of species difference.However, compared to animal models, fewer iPSC models currently exist. > The brain is a complex network of many different cellular phenotypes and screening compounds in just one phenotype, i.e., neurons, is not a complete representation of the environment in the brain.While most studies in NCL patient-derived iPSCs employ either NPCs or neurons there are emerging studies looking at biochemical and pathophysiology effects of NCL on other cell phenotypes, one such example is the use of BMECs to model the blood-brain barrier that identified an impaired barrier phenotype in CLN3.Differentiation of iPSCs into other phenotypes including oligodendrocytes, astrocytes, microglia etc. is ongoing and results are expected in due course.These cell types will allow the construction of increasingly complex co-culture models that more readily represent the human brain and thus allow a greater understanding of the disease.

[6] Prominent and Regressive Brain Developmental Disorders Associated with Nance-Horan Syndrome

  • Authors: C. Casto, V. Dipasquale, I. Ceravolo, A. Gambadauro, Emanuela Aliberto et al.
  • Year: 2021
  • Venue: Brain Sciences
  • URL: https://www.semanticscholar.org/paper/d2d8619c882943bdd94ddc65f420190f03bf28b6
  • DOI: 10.3390/brainsci11091150
  • PMID: 34573171
  • PMCID: 8465299
  • Citations: 11
  • Summary: A Sicilian family affected with congenital cataracts and dental anomalies and diagnosed with NHS by whole-exome sequencing is described and the affected boy from this family presented a late regression of cognitive, motor, language, and adaptive skills, as well as broad behavioral anomalies.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > Genetic brain developmental disorders with associated psychomotor regression include a broad variety of monogenic conditions with expanding clinical differential diagnosis, genetic heterogeneity, and associated disease mechanisms [1][2][3].Despite being in the era of next-generation sequencing (NGS), the etiology and disease mechanisms underlying regressive neurodevelopmental impairment remain undetermined in a certain proportion of cases [4,5].Defining the full spectrum of disease-causing molecular pathways underlying neurodevelopmental disorders will help to diagnose and monitor developmental trajectories in children affected with these conditions [6][7][8][9][10][11] The neurodevelopmental condition known as 'Nance-Horan syndrome' (NHS) (OMIM 302350) is characterized by frequent intellectual disability and autistic features against a background of broad congenital anomalies, including congenital cataracts and dental abnormalities; distinctive facial features such as long and narrow face, anteverted pinnae, broad nose, and brachymetacarpia may also frequently occur in these patients [12][13][14][15][16][17][18].Heterozygous females may present mild and variable clinical signs [19].Various mutations in NHS and minor variations of the phenotypical features have been described [18][19][20].NHS is caused by mutations in the NHS gene located on Xp22.13 [21], which is expressed in the midbrain, retina, lens, and tooth [22,23].To date, the most frequently reported pathogenic mutations are either nonsense or frameshift mutations, which result in either nonsense mediated decay (NMD) of the respective mRNA or truncation of the respective protein [18,21].In addition, a few microdeletions at Xp22. 13, involving the NHS gene, have been also identified [17,22], some of which encompass also other genes, such as the CDKL5 gene [24,25].

[7] Developmental Neuropathology and Neurodegeneration of Down Syndrome: Current Knowledge in Humans

  • Authors: Zinnat Hasina, Nicole Wang, Chi-Chiu Wang
  • Year: 2022
  • Venue: Frontiers in Cell and Developmental Biology
  • URL: https://www.semanticscholar.org/paper/449cb787c6a9e6f60c35d84c11a78bd08c0a7c9f
  • DOI: 10.3389/fcell.2022.877711
  • PMID: 35676933
  • PMCID: 9168127
  • Citations: 17
  • Influential citations: 1
  • Summary: This work summarizes current information about the neuropathology and neurodegeneration of the brain from conception to adulthood of foetuses and individuals with DS at anatomical, cellular, and molecular levels in humans.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > Individuals with Down syndrome (DS) suffer from developmental delay, intellectual disability, and an early-onset of neurodegeneration, Alzheimer’s-like disease, or precocious dementia due to an extra chromosome 21. Studying the changes in anatomical, cellular, and molecular levels involved may help to understand the pathogenesis and develop target treatments, not just medical, but also surgical, cell and gene therapy, etc., for individuals with DS. Here we aim to identify key neurodevelopmental manifestations, locate knowledge gaps, and try to build molecular networks to better understand the mechanisms and clinical importance. We summarize current information about the neuropathology and neurodegeneration of the brain from conception to adulthood of foetuses and individuals with DS at anatomical, cellular, and molecular levels in humans. Understanding the alterations and characteristics of developing Down syndrome will help target treatment to improve the clinical outcomes. Early targeted intervention/therapy for the manifestations associated with DS in either the prenatal or postnatal period may be useful to rescue the neuropathology and neurodegeneration in DS.

[8] Treatment of Neurodevelopmental Disorders in Adulthood

  • Authors: E. Castrén, Y. Elgersma, L. Maffei, R. Hagerman
  • Year: 2012
  • Venue: The Journal of Neuroscience
  • URL: https://www.semanticscholar.org/paper/2c1e2c2eed4cb2efe39fe8658cbd629540207bba
  • DOI: 10.1523/JNEUROSCI.3287-12.2012
  • PMID: 23055475
  • Citations: 66
  • Influential citations: 2
  • Summary: Findings in mouse models of neurodevelopmental disorders suggest that it is possible to reverse certain molecular, electrophysiological, and behavioral deficits associated with these disorders in adults by genetic or pharmacological manipulations or by pharmacotherapy.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > Neurodevelopmental disorders first appear during the course of development and maturation, and they are caused by a variety of genetic and environmental conditions (Ehninger et al., 2008). Down syndrome, fragile X syndrome (FXS), Rett syndrome, neurofibromatosis, and tuberous sclerosis are major developmental syndromes leading to intellectual disability (Ehninger et al., 2008;Auerbach et al., 2011;Zoghbi and Bear, 2012), but in the majority of cases, the molecular and neuronal mechanisms underlying the clinical phenotype remain unknown. Neurodevelopmental disorders affect ϳ1-2% of the population, and because of their typically life-long course they are very costly. Therefore, even a minor improvement in the performance of these patients would be of great significance to the patients themselves, to families, and to society. > The molecular background of many genetic syndromes leading to neurodevelopmental disorders has been elucidated during the last few years (West and Greenberg, 2011). These findings have paved a way for the discovery of pathways affected in neurodevelopmental disorders and the development of mouse models of these disorders. It has turned out that many of the genes associated with neurodevelopmental disorders play a role in synaptic function (West and Greenberg, 2011;Zoghbi and Bear, 2012), in particular in the regulation of protein synthesis in synapses (Bhakar et al., 2012). These studies have also revealed that in several genes associated with neurodevelopmental disorders, both reduced and enhanced expression bring about phenotypes, often with strikingly similar clinical features (Ramocki and Zoghbi, 2008), emphasizing the need for precise maintenance of optimal levels of synaptic regulatory proteins. The elucidation of neuronal pathways that are dysfunctional in different neurodevelopmental disorders has inspired a search of drug treatments that may alleviate the cognitive problems (Ehninger et al., 2008;Wetmore and Garner, 2010). It has turned out that enhanced expression of the dysfunctional gene or increased/decreased signaling in the affected pathways at least in some cases partially reversed the symptoms even when the treatment was started

[9] Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

  • Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
  • Year: 2024
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
  • DOI: 10.3389/fmed.2024.1425038
  • PMID: 39135718
  • PMCID: 11317438
  • Citations: 1
  • Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > Rett syndrome (RTT, #312750) and Rett-like syndromes, e.g., CDKL5 deficiency disorder (CDD, #300672) and FOXG1-syndrome (or FOXG1-related encephalopathy, #613454) are rare monogenic neurodevelopmental disorders (NDDs). The relative recent recognition of their distinct clinical entities (1,2) has deepened our understanding of their underlying pathogenic mechanisms and clinical characteristics (Table 1). Although each disorder exhibits unique clinical features, they share common core symptoms and neurological traits (Table 1), suggesting that these disorders share critical molecular etiology. > Identifying shared pathways holds significant implications for targeted therapies development and drug repurposing (DR). DR, which involves using existing drugs for new therapeutic purposes, represents a promising approach in the treatment across multiple diseases especially for neurological disorders (3,4). The complex structure of the central nervous system (CNS), coupled with the challenge of penetrating the blood-brain barrier, poses significant hurdles in the development of new drugs for neuropathological conditions, making DR of particular interest for these disorders. Notable successes of DR in NDDs include e.g., repurposing of fenfluramine in Dravet syndrome (5) or bumetanide (6) and pregnenolone (7) for autism spectrum disorders. These studies validate DR as a valid treatment approach for multiple neuropathological conditions. > We here discuss the current state of art of DR efforts in RTT, CDD and FOXG1-syndrome, with particular emphasis on the shared molecular pathways and the identification of common drug targets across the three conditions. For a more detailed overview on the molecular and circuit mechanisms underlying each syndrome, please refer to (8)(9)(10) for RTT, (11,12) for CDD and (2, 13) for FOXG1-syndrome (2,13).

[10] Clinical features and genetic analysis of a family with t(5;9) (p15;p24) balanced translocation leading to Cri-du-chat syndrome in offspring

  • Authors: Jing Zhao, Ping Chen, Yijia Ren, Shurong Li, Weiyi Zhang et al.
  • Year: 2025
  • Venue: Frontiers in Genetics
  • URL: https://www.semanticscholar.org/paper/5caf88001c66b473b6565f9e75eb6a4f1a8c4a0a
  • DOI: 10.3389/fgene.2025.1550937
  • PMID: 40406061
  • PMCID: 12094932
  • Citations: 1
  • Summary: This study reports a rare familial balanced translocation pedigree, particularly noting that the offspring can suffer from Cri-du-chat syndrome, which suggests a potential new genetic model for this syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > Using the Metascape database for GO enrichment analysis of the region containing 60 OMIM genes from 5p15.33p14.1 revealed the potential molecular mechanisms of the disease. The results showed that OMIM genes in the 5p15.33p14.1 region are mainly enriched in Na+/Cl-dependent neurotransmitter transporters, cell-cell adhesion mediated by cadherin, nephron epithelium development, and other signaling pathways (Figure 5A). Disease enrichment analysis showed that genes in this region are mainly associated with Cri-du-chat syndrome (Figure 5B) . Cri-du-chat syndrome is closely related to developmental abnormalities, neurological defects, and craniofacial malformations. Enrichment analysis supports the involvement of molecular mechanisms related to Wnt signaling, neurotransmitter transport, ubiquitination pathways, particularly through diseasegene associations from DisGeNET and GO functional enrichment. These results provide clues for revealing the molecular network of the disease and guide future research. > Using the Metascape database, GO enrichment analysis of 45 OMIM genes located in the 9p24.3-p22.3 region was performed. The results showed that OMIM genes in the 9p24.3-p22.3 region are mainly enriched in signaling pathways such as positive regulation of leukocyte activation, response to amine, cell population proliferation, positive regulation of cell development, etc. (Figure 5C). Disease enrichment analysis revealed that genes in this region are mainly associated with Chromosome 9p deletion syndrome (Figure 5D). This study, through multidimensional bioinformatics analysis, not only clarified the core biological functions of genes in the 9p24.3-p22.3 region, but also revealed their potential association mechanisms with major diseases, providing important theoretical basis and directional guidance for subsequent gene function validation, molecular mechanism research, and clinical translation. Balanced translocation carriers have the opportunity to produce phenotypically normal offspring, but they are at a higher risk of recurrent miscarriages and offspring with chromosomal abnormalities.

[11] Further delineation of EBF3-related syndromic neurodevelopmental disorder in twelve Chinese patients

  • Authors: Jitao Zhu, Wenhui Li, Sha Yu, Wei Lu, Qiong Xu et al.
  • Year: 2023
  • Venue: Frontiers in Pediatrics
  • URL: https://www.semanticscholar.org/paper/a102a60d4a7104dbfc9de63bba735fb74a2594bd
  • DOI: 10.3389/fped.2023.1091532
  • PMID: 36937983
  • PMCID: 10020332
  • Citations: 4
  • Summary: This study further expanded the gene mutation spectrum of EBF3-related NDD by identifying five missense variants (four novel variants and one known variant) and seven copy number variations (CNVs) of E BF3 gene using next-generation sequencing.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > Neurodevelopmental disorders (NDDs) account for a significant proportion of congenital disorders, which impose an enormous financial burden on families and society. Researches have suggested that hundreds of genes are involved in the pathogenesis of NDDs, but the underlying mechanisms remain unclear (1). Affected individuals present with various neurological symptoms, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), epilepsy and other minor symptoms such as decreased pain sensitivity or hyperactivity (2,3). In addition, patients may also present with phenotypes in other systems, such as congenital heart defects, skeletal or muscular abnormalities, metabolic disorders, gastrointestinal problems, distinctive facial features or strabismus, etc. Despite the high heterogeneity of pathogenic genes and the diverse clinical features of NDDs, advances in next-generation sequencing technology have facilitated the diagnosis of such diseases (4,5). > EBF3 is one of the causative genes that lead to syndromic NDDs. The earliest reports of EBF3-related NDD dated back to 2017, in which a total of 21 cases were summarized and analyzed (6)(7)(8). In their description, multiple systems were involved, including central nervous system (CNS), genitourinary system, skeletal system, etc. Major phenotypes included DD/ID, ataxia, hypotonia, structural CNS malformations, genitourinary abnormalities, subtle facial features, and strabismus. Other less common phenotypes included dysarthria, constipation, decreased pain sensitivity during development, and behavioral deficits such as attention deficit and ASD or ASD-like symptoms. Since then, more than 30 additional cases of EBF3-related NDDs have been reported (9)(10)(11)(12)(13)(14)(15)(16). A recent meta-analysis integrated previously published 42 cases with detailed patient information and their 41 new cases, and quantified the risk and severity of patient phenotypes based on these 83 patients (17).

[12] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 38
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[13] Hao‐Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum

  • Authors: Moritz Claudius Wimmer, H. Brennenstuhl, Steffen Hirsch, Laura Dötsch, Samy Unser et al.
  • Year: 2023
  • Venue: Clinical Genetics
  • URL: https://www.semanticscholar.org/paper/b1ea56aec4ea458d4d273fc69b330c3dbe7f8750
  • DOI: 10.1111/cge.14480
  • PMID: 38221796
  • Citations: 14
  • Summary: A questionnaire‐based study was performed to characterize the phenotype of Hao‐Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.379) > Hao‐Fountain syndrome (HAFOUS, OMIM: #616863) is a neurodevelopmental disorder caused by pathogenic variants in the gene USP7 coding for USP7, a protein involved in several crucial cellular homeostatic mechanisms and the recently described MUST complex. The phenotype of HAFOUS is insufficiently understood, yet there is a great need to better understand the spectrum of disease, genotype–phenotype correlations, and disease trajectories. We now present a larger cohort of 32 additional individuals and provide further clinical information about six previously reported individuals. A questionnaire‐based study was performed to characterize the phenotype of Hao‐Fountain syndrome more clearly, to highlight new traits, and to better distinguish the disease from related neurodevelopmental disorders. In addition to confirming previously described features, we report hyperphagia and increased body weight in a subset of individuals. HAFOUS patients present an increased rate of birth complications, congenital anomalies, and abnormal pain thresholds. Speech impairment emerges as a potential hallmark of Hao‐Fountain syndrome. Cognitive testing reports reveal borderline intellectual functioning on average, although some individuals score in the range of intellectual disability. Finally, we created a syndrome‐specific severity score. This score neither indicates a sex‐ nor age‐specific difference of clinical severity, yet highlights a more severe outcome when amino acid changes colocalize to the catalytic domain of the USP7 protein.

[14] Identification of a novel NSD1 pathogenic variant in a Senegalese child with Sotos syndrome

  • Authors: J. Diop, Aminata Mbaye, Karamba Diallo, É. Pasmant, Seydi Abdoul Ba et al.
  • Year: 2025
  • Venue: Journal of Genetic Engineering & Biotechnology
  • URL: https://www.semanticscholar.org/paper/c368f6595e3c28511e3628c4a4f26439d29da666
  • DOI: 10.1016/j.jgeb.2025.100642
  • PMID: 41839667
  • PMCID: 12797062
  • Summary: The first case of Sotos syndrome from Senegal is reported, confirmed by genetic testing, and a novel heterozygous mutation in exon 5 of the NSD1 gene in the index case is detected, resulting in a frameshift and a premature stop codon.
  • Evidence snippets:
  • Snippet 1 (score: 0.379) > Sotos syndrome is a rare genetic disorder characterized by a broad spectrum of clinical features, primarily documented in adult population, with limited reports in pediatric cohorts 7 . We reported here the first genetically confirmed case of Sotos syndrome in Senegal. The patient exhibited the hallmark clinical features of Sotos syndrome, including the characteristic facial phenotype; overgrowth mainly involving height and /or head circumference; frontal bossing; temporal baldness and receding frontal hairline. 7,21 Furthermore, the patient exhibited markedly large hands and feet and excessive body growth (size > Z3DS) also in concordance with clinical features of Sotos syndrome. Sotos syndrome is often linked to developmental and neurological issues, as well as heart disease, and ophthalmological disorders 22 . Unfortunately, we were not able to investigate these organ systems in our patient, which limits our understanding of any related complications. > The mutation of the NSD1 gene NM_022455: c.2306dup, p. Gly771Trpfs*38) identified in the index case is a nucleotide duplication at position 2306, causing a shift in the reading frame. The consequence is the introduction of a premature termination codon 38 amino acids downstream, leading to truncated protein synthesis. The variant is expected to lead to a loss of function of NSD1, primarily via nonsensemediated mRNA decay (NMD), a cellular surveillance mechanism that targets transcripts harboring premature termination codons. > The major clinical features of Sotos syndrome were observed in our patient, supporting the pathogenic role of frameshift mutation in the NSD1 gene that led to a haploinsufficiency. However, in some cases, the 5q35 microduplication was confirmed and the patients manifest "reversed Sotos Syndrome as short stature and microcephaly without facial feature. > The de novo nature of the variant, confirmed by its absence in the non-affected parents, strongly suggests a pathogenic role in the index case. De novo variants in NSD1 are well-documented as the major molecular mechanism underlying Sotos syndrome. The identified variant has not been previously reported in major population databases such as gnomAD or ClinVar, but similar truncating mutations in NSD1 have been frequently associated with Sotos syndrome.

[15] Novel BRAT1 variant associated with neurodevelopmental disorder with cerebellar atrophy and seizure: Case report and a literature review

  • Authors: M. Ghasemi, Sahand Tehrani Fateh, Farzad Hashemi-Gorji, Morteza Sheikhi Nooshabadi, S. Alijanpour et al.
  • Year: 2024
  • Venue: Epilepsy & Behavior Reports
  • URL: https://www.semanticscholar.org/paper/4017120f59d4696de48a080ad50f80c8f1b23bbb
  • DOI: 10.1016/j.ebr.2024.100702
  • PMID: 39188779
  • PMCID: 11345683
  • Citations: 1
  • Summary: Highlights • Identification of a novel variant of the BRAT1 gene (c.398A>G;p.His133Arg).• WES is useful for identifying causative variant in rare neurodevelopmental disorders.• BRAT1-related disorders have variability in the clinical presentation.
  • Evidence snippets:
  • Snippet 1 (score: 0.379) > Neurodevelopmental disorders encompass a diverse range of conditions characterized by impaired cognitive, motor, and social functioning. Genetic factors play a significant role in the etiology of these disorders, and the identification of disease-causing genes is crucial for understanding their underlying mechanisms and improving diagnostic accuracy [1]. One such gene of interest is BRAT1, which has been implicated in various neurodevelopmental disorders [2]. > BRAT1 (BRCA1-associated protein required for ATM activation-1) is a critical gene involved in DNA repair and the maintenance of genomic stability. Mutations in BRAT1 have been associated with a spectrum of neurodevelopmental disorders, including intellectual disability, epilepsy, speech delay, and motor impairments. Biallelic mutations in this gene have been linked to two phenotypes including, neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS #MIM 618056) [20], as well as lethal neonatal rigidity and multifocal seizure syndrome (RMFSL#MIM 614498) [21,22]. The RMFSL phenotype is the severe form of disease, and the NEDCAS phenotype is the milder form of BRAT1-related disease. The RMFSL phenotype is presented with severe encephalopathy, drug-resistant epilepsy, cerebral atrophy, and early death. In contrast, the NEDCAS phenotype is presented with intellectual disability, cerebellar atrophy, ataxia, nystagmus, and a higher life expectancy. However, the full extent of BRAT1 genotype-phenotype correlations and the underlying disease mechanisms remain to be fully elucidated [2]. > The goal of this study is to identify a causative variant through whole exome sequencing (WES) in a patient with neurodevelopmental disorders. Furthermore, we conducted a literature review to compare the clinical features observed in individuals with BRAT1 mutations, which can help to improve our understanding of the relationship between genotype and phenotype in BRAT1-related disorders.

[16] GRIN2B-related neurodevelopmental disorder: current understanding of pathophysiological mechanisms

  • Authors: S. Sabo, Jessica M. Lahr, Madelyn Offer, Anika LA Weekes, M. Sceniak
  • Year: 2023
  • Venue: Frontiers in Synaptic Neuroscience
  • URL: https://www.semanticscholar.org/paper/261e9ad3a207becd3d96e20fa3139a66b5318a25
  • DOI: 10.3389/fnsyn.2022.1090865
  • PMID: 36704660
  • PMCID: 9873235
  • Citations: 51
  • Influential citations: 2
  • Summary: Together, the existing data provide insight into the pathophysiological mechanisms that underlie GRIN2B-related neurodevelopmental disorder and emphasize the importance of comparing the effects of individual, disease-associated variants.
  • Evidence snippets:
  • Snippet 1 (score: 0.378) > The GRIN2B-related neurodevelopmental disorder is a rare disease caused by mutations in the GRIN2B gene, which encodes the GluN2B subunit of NMDA receptors. Most individuals with GRIN2B-related neurodevelopmental disorder present with intellectual disability and developmental delay. Motor impairments, autism spectrum disorder, and epilepsy are also common. A large number of pathogenic de novo mutations have been identified in GRIN2B. However, it is not yet known how these variants lead to the clinical symptoms of the disease. Recent research has begun to address this issue. Here, we describe key experimental approaches that have been used to better understand the pathophysiology of this disease. We discuss the impact of several distinct pathogenic GRIN2B variants on NMDA receptor properties. We then critically review pivotal studies examining the synaptic and neurodevelopmental phenotypes observed when disease-associated GluN2B variants are expressed in neurons. These data provide compelling evidence that various GluN2B mutants interfere with neuronal differentiation, dendrite morphogenesis, synaptogenesis, and synaptic plasticity. Finally, we identify important open questions and considerations for future studies aimed at understanding this complex disease. Together, the existing data provide insight into the pathophysiological mechanisms that underlie GRIN2B-related neurodevelopmental disorder and emphasize the importance of comparing the effects of individual, disease-associated variants. Understanding the molecular, cellular and circuit phenotypes produced by a wide range of GRIN2B variants should lead to the identification of core neurodevelopmental phenotypes that characterize the disease and lead to its symptoms. This information could help guide the development and application of effective therapeutic strategies for treating individuals with GRIN2B-related neurodevelopmental disorder.

[17] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

  • Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
  • Year: 2023
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
  • DOI: 10.3390/genes14091734
  • PMID: 37761876
  • PMCID: 10531442
  • Citations: 11
  • Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.377) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[18] Spatiotemporal 7q11.23 Protein Network Implicates the GTF2I-PRKDC-DDR Pathway During Early-Fetal Brain Development in Psychiatric Diseases

  • Authors: G. Lin, Liang Chen, Weidi Wang, Wenxiang Cai, Weichen Song et al.
  • Year: 2020
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/6a2df6310ac4d8f7f3f76da6f21f8a221ebf1cce
  • DOI: 10.21203/rs.3.rs-93461/v1
  • Summary: Striatum, hippocampus, and amygdala are crucial regions for establishing connectivity between 7q11.23 proteins and their partners in early and late fetal periods, and the results suggested that GTF2I-PRKDC-DDR and GTF 2I-BRCA1-dDR pathway is crucial for the 7q 11.23 CNV genes to contribute to the pathogenesis of psychiatric diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.376) > A different approach of addressing this issue is based on creating animal or cell models to help identify the related molecular and cellular mechanisms. For instance, mice with a heterozygous deletion of GTF2I or GTF2IRD1 show defects in skeletal and craniofacial. [14]. In addition, the embryos of these mice present with a small head; this is consistent with the clinical phenotype of patients carrying a 7q11. 23 deletion. Nevertheless, the signaling pathways affected by this CNV remain unknown. > Replication factor C subunit 2 (RFC2), another 7q11.23 gene, encodes a subunit of the replication factor C (RFC) complex [15] and is known to play a role in ATR signaling [16,17]. Haploinsufficiency for RFC2 leaded to G2/M checkpoint arrest after DNA damage [18]. However, little is known about how genes with the 7q11.23 deletion/duplication may affect the occurrence of neurodevelopmental disorders because these genes are involved not only in multiple developmental stages but also within different tissues. Hence, genes exhibiting 7q11.23 deletion/duplication play different roles in different developmental stages and different anatomic structures. > CNVs have been reported to modulate gene expression, which, ultimately, might affect disease predisposition or clinical phenotypes [19,20]. Several researches have investigated CNV pathogenesis in psychiatric disorders by constructing a static topological network based on a single developmental stage [21]. Within different developmental periods, protein expression can change, as can protein-protein interactions (PPIs) [22]. Nevertheless, protein expression is a dynamic process that can occur in a different manner across different anatomical areas [23,24]. Analyses of molecular networks can reveal biological modularity and complex signaling pathways [25,26]. Previous studies discovered the pathogenesis of CNVs by constructing dynamic protein-protein interaction (PPI) networks according to alterations of protein expression in different anatomical areas and during different developmental periods [27,28]. > In addition, multiple studies mentioned above focused only on one or two genes and were unable to demonstrate how the 7q11.23 CNV is involved in brain development.

[19] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

  • Authors: Kyung-Yil Lee
  • Year: 2022
  • Venue: Cell & Bioscience
  • URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
  • DOI: 10.1186/s13578-022-00920-5
  • PMID: 36384812
  • PMCID: 9668226
  • Citations: 9
  • Influential citations: 1
  • Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
  • Evidence snippets:
  • Snippet 1 (score: 0.374) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[20] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

  • Authors: W. Tulalamba, T. Janvilisri
  • Year: 2012
  • Venue: International Journal of Cell Biology
  • URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
  • DOI: 10.1155/2012/594681
  • PMID: 22500174
  • PMCID: 3303613
  • Citations: 93
  • Influential citations: 5
  • Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.374) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

Notes

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