cerebellar ataxia, brain abnormalities, and cardiac conduction defects

Mendelian MONDO:0859200 Pathograph 29 Show in embeddings browser Mendelian neurodevelopmental disorder autosomal recessive cerebellar ataxia RNA exosomopathy

Cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC syndrome) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. Reported patients present in infancy with hypotonia, global developmental delay affecting motor skills, failure to thrive, short stature, feeding difficulties and esotropia, and brain MRI shows cerebellar hypoplasia or atrophy, pontocerebellar hypoplasia, ventriculomegaly and hypomyelination. A distinctive feature in a subset of patients is progressive cardiac conduction and rhythm disease (complete heart block, sinus node dysfunction, atrioventricular block and ventricular tachycardia) with a recognized risk of sudden cardiac death; cardiac involvement is variable and has been absent in some patients. Renal thrombotic microangiopathy after a viral trigger has been reported in one patient and is now recognized across RNA-exosome disorders. EXOSC5 is one of several RNA-exosome subunit genes (EXOSC2, EXOSC3, EXOSC8, EXOSC9) linked to Mendelian neurodegenerative disease, and the literature on CABAC remains small (about ten reported patients). Disease mechanism appears to vary with the specific pathogenic variant.

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1
Inheritance
6
Pathophys.
22
Phenotypes
29
Pathograph
1
Genes
4
Variants
3
Medical Actions
2
Differentials
1
Models
3
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
CABAC syndrome is inherited in an autosomal recessive manner. Affected individuals carry biallelic EXOSC5 variants (homozygous in consanguineous families, or compound heterozygous), and unaffected parents are heterozygous carriers.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34089229 SUPPORT Human Clinical
"More recently, EXOSC5 (MIM *606492) was found to underlie an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies."
States that EXOSC5-related disease is an autosomal recessive neurodevelopmental disorder.
PMID:39062862 SUPPORT Human Clinical
"the parents were consanguineous (of Syrian descent) and both heterozygous carriers of this EXOSC5 variant."
Documents recessive transmission with heterozygous carrier parents in a consanguineous family.
⚙

Pathophysiology

6
EXOSC5 Subunit Dysfunction
Biallelic EXOSC5 variants (recurrent hypomorphic missense such as p.Thr114Ile plus null alleles including intragenic deletions and frameshifts) alter EXOSC5, a structural subunit of the RNA exosome. Some variants reduce RNA exosome function and alter interactions with other exosome subunits; the Slavotinek study concludes that disease mechanism varies with the specific variant. The nine-subunit exosome core (EXOSC1-9) is catalytically inactive and the 3' to 5' exoribonuclease activity is supplied by the associated DIS3 and EXOSC10 nucleases, so the GO:0000175 binding here represents the activity of the whole complex that EXOSC5 scaffolds rather than a catalytic function lost from EXOSC5 itself.
EXOSC5 hgnc:24662 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EXOSC5 (hgnc:24662). hgnc:24662 is a gene from the HUGO Gene Nomenclature Committee.
RNA exosome 3' to 5' exoribonuclease activity GO:0000175 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased RNA exosome 3' to 5' exoribonuclease activity, annotated with 3'-5'-RNA exonuclease activity (GO:0000175). GO:0000175 is a molecular function from the Gene Ontology.
Downstream
Impaired RNA Exosome-Mediated RNA Processing and Degradation Loss or reduction of the EXOSC5 structural subunit impairs the RNA exosome's 3' to 5' processing and degradation of coding and non-coding RNA.
Show evidence (2 references)
PMID:32504085 SUPPORT Human Clinical
"We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome."
Establishes EXOSC5 as a structural RNA-exosome subunit altered by biallelic disease variants.
PMID:32504085 SUPPORT In Vitro
"Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits."
Yeast and mammalian-cell modeling shows pathogenic variants impair exosome function and subunit interactions.
Impaired RNA Exosome-Mediated RNA Processing and Degradation
The RNA exosome is an essential ribonuclease complex required for processing and degradation of coding and non-coding RNA; reduced EXOSC5 function impairs this activity. The specific RNA targets and the basis for selective tissue vulnerability are not established.
RNA processing and degradation GO:0006401 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased RNA processing and degradation, annotated with RNA catabolic process (GO:0006401). GO:0006401 is a biological process from the Gene Ontology.
RNA exosome complex GO:0000178 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves RNA exosome complex, annotated with exosome (RNase complex) (GO:0000178). GO:0000178 is a cellular component from the Gene Ontology.
Downstream
Cerebellar and Pontine Hypoplasia Impaired RNA exosome function disrupts brain development, producing cerebellar and pontine hypoplasia; the mechanism of selective neural vulnerability is not established.
Ventriculomegaly Ventriculomegaly is part of the brain abnormality that follows impaired RNA exosome function.
CNS hypomyelination Hypomyelination is part of the brain abnormality that follows impaired RNA exosome function.
Microcephaly Reduced brain growth manifests as microcephaly.
Cardiac Conduction System Vulnerability Cardiac conduction tissue is vulnerable in a subset of patients; the mechanism linking RNA exosome dysfunction to conduction disease is not established and is inferred from the phenotype.
Impaired Ribosome Assembly An intact RNA exosome is required for ribosome assembly, so exosome dysfunction is proposed to impair ribosome production.
Show evidence (1 reference)
PMID:32504085 SUPPORT BACKGROUND Other
"The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs."
States the molecular function of the RNA exosome that EXOSC5 loss impairs.
Cerebellar and Pontine Hypoplasia
Hypoplasia and progressive atrophy of the cerebellum and pons, with ventriculomegaly and hypomyelination, are the core brain abnormalities and drive the neurological phenotype.
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology. pons UBERON:0000988 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pons (UBERON:0000988). UBERON:0000988 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
exosc5 loss-of-function zebrafish zebrafish partially recapitulates Loss of exosc5 reduces head and eye size, modeling impaired brain growth; it does not reproduce the specific human cerebellar/pontine hypoplasia or the cardiac phenotype.
Downstream
Ataxia Cerebellar hypoplasia and atrophy underlie the cerebellar ataxia that names the syndrome.
Hypotonia
Global developmental delay
Motor delay
Cerebellar hypoplasia Cerebellar hypoplasia is the imaging manifestation of this structural node.
Cerebellar atrophy Progressive cerebellar volume loss is the atrophic manifestation of this structural node.
Hypoplasia of the pons Pontine hypoplasia is the brainstem manifestation of this structural node.
Seizure The brain malformation underlies seizures in a severely affected patient.
Feeding difficulties Feeding difficulty arises from neurological coordinative problems and axial hypotonia.
Show evidence (2 references)
PMID:34089229 SUPPORT Human Clinical
"two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination"
Documents cerebellar volume loss and hypomyelination in affected siblings.
PMID:39062862 SUPPORT Human Clinical
"The cerebral MRI showed pontocerebellar hypoplasia, an immature gyral pattern, and a small aspect of the neurocranium with a small biparietal diameter."
Documents pontocerebellar hypoplasia on brain MRI.
Cardiac Conduction System Vulnerability
Progressive disease of the cardiac conduction system occurs in a subset of patients and can include complete heart block, sinus node dysfunction, atrioventricular block and ventricular tachycardia, with a risk of sudden cardiac death. Cardiac involvement is variable and has been absent on repeated evaluation in some patients.
cardiac conduction system UBERON:0002350 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cardiac conduction system, annotated with conducting system of heart (UBERON:0002350). UBERON:0002350 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Atrioventricular block
Sinus node dysfunction
Ventricular tachycardia
Intraventricular conduction delay
Show evidence (2 references)
PMID:34089229 SUPPORT Human Clinical
"cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT)"
Enumerates the conduction and rhythm abnormalities arising in the conduction system.
PMID:39062862 SUPPORT Human Clinical
"Repeated cardiac evaluations were performed because of previously described severe cardiac conduction problems, but showed no significant abnormalities"
Documents that cardiac conduction involvement is variable and may be absent.
Impaired Ribosome Assembly
Because the RNA exosome is required for ribosome assembly, exosome dysfunction is proposed to impair ribosome production; altered ribosome production could lead to cell cycle arrest and apoptosis. This step is hypothesized rather than demonstrated in affected tissue.
ribosome biogenesis GO:0042254 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ribosome biogenesis (GO:0042254). GO:0042254 is a biological process from the Gene Ontology.
Downstream
Endothelial Cell Apoptosis It is hypothesized that defective processing of RNA induces ribosomal dysfunction in endothelial cells, leading to apoptosis.
Show evidence (1 reference)
PMID:39062862 SUPPORT BACKGROUND Other
"Alterations in ribosome production could ultimately lead to cell cycle arrest and apoptosis"
States the proposed link from impaired ribosome production to apoptosis.
Endothelial Cell Apoptosis
Proposed endothelial injury: ribosomal dysfunction in endothelial cells leads to apoptosis, the cellular event upstream of the thrombotic microangiopathy cascade. Observed consequence in one EXOSC5 patient who developed renal thrombotic microangiopathy after a rotavirus infection; the mechanism is hypothesized and complement-independent.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Downstream
Renal thrombotic microangiopathy
Show evidence (1 reference)
PMID:39062862 SUPPORT BACKGROUND Other
"It is hypothesized that infection causes an accumulation of viral RNA or defective processing of (viral) RNA in the cell, inducing ribosomal dysfunction in the endothelial cells resulting in apoptosis, and consequently leading to the cascade resulting in TMA"
States the hypothesized endothelial-cell apoptosis mechanism that this node represents.
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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 cerebellar ataxia, brain abnormalities, and cardiac conduction defects 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

22
Cardiovascular 4
Atrioventricular block Third degree atrioventricular block HP:0001709 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Complete heart block, annotated with Third degree atrioventricular block (HP:0001709). HP:0001709 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"An unusual feature of EXOSC5-related disease is the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals."
Complete heart block (third-degree atrioventricular block) occurs in a subset of patients.
Sinus node dysfunction Sick sinus syndrome HP:0011704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sinus node dysfunction, annotated with Sick sinus syndrome (HP:0011704). HP:0011704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"cardiac conduction and rhythm abnormalities including sinus node dysfunction"
Sinus node dysfunction is reported among the conduction abnormalities.
Ventricular tachycardia HP:0004756 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular tachycardia (HP:0004756). HP:0004756 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"atrioventricular block, and ventricular tachycardia (VT)"
Ventricular tachycardia is reported among the rhythm abnormalities.
Intraventricular conduction delay Prolonged QRS complex HP:0006677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intraventricular conduction delay, annotated with Prolonged QRS complex (HP:0006677). HP:0006677 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT)"
Intraventricular conduction delay is listed among the reported conduction abnormalities.
Digestive 1
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"The clinical features of these patients include failure to thrive, short stature, feeding difficulties"
Feeding difficulty is a core clinical feature.
Ear 1
Mixed hearing impairment HP:0000410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mixed conductive and sensorineural hearing loss, annotated with Mixed hearing impairment (HP:0000410). HP:0000410 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39062862 SUPPORT Human Clinical
"An audiological examination at five weeks revealed mixed (conductive and sensorineural) hearing loss in both ears."
Mixed hearing loss was found in one patient.
Eye 1
Esotropia HP:0000565 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Esotropia (HP:0000565). HP:0000565 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"developmental delays that affect motor skills, hypotonia and esotropia"
Esotropia is reported among the clinical features.
Head and Neck 2
Microcephaly 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)
PMID:34089229 SUPPORT Human Clinical
"two siblings with microcephaly, developmental delay, cerebellar volume loss"
Microcephaly is reported in affected siblings.
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysmorphic facies, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies."
Dysmorphic facies is part of the clinical description.
Musculoskeletal 1
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.
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"developmental delays that affect motor skills, hypotonia and esotropia"
Hypotonia is a core clinical feature.
Nervous System 9
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar ataxia, annotated with Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39062862 SUPPORT Human Clinical
"the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia"
Cerebellar ataxia is the cardinal neurological feature naming the syndrome.
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)
PMID:34089229 SUPPORT Human Clinical
"an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies."
Developmental delay is a defining feature of EXOSC5-related disease.
Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor developmental delay, annotated with Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"developmental delays that affect motor skills"
Developmental delay affecting motor skills is reported in the patients.
Cerebellar hypoplasia HP:0001321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hypoplasia (HP:0001321). HP:0001321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"Brain MRI revealed cerebellar hypoplasia and ventriculomegaly."
Brain MRI shows cerebellar hypoplasia.
Cerebellar atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar volume loss, annotated with Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination"
Progressive cerebellar volume loss is documented in affected siblings.
Hypoplasia of the pons HP:0012110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pontocerebellar hypoplasia, annotated with Hypoplasia of the pons (HP:0012110). HP:0012110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39062862 SUPPORT Human Clinical
"The cerebral MRI showed pontocerebellar hypoplasia, an immature gyral pattern, and a small aspect of the neurocranium with a small biparietal diameter."
MRI shows pontocerebellar hypoplasia, i.e. hypoplasia of the pons and cerebellum.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"Brain MRI revealed cerebellar hypoplasia and ventriculomegaly."
Brain MRI shows ventriculomegaly.
CNS hypomyelination HP:0003429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomyelination, annotated with CNS hypomyelination (HP:0003429). HP:0003429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination"
Hypomyelination is documented on neuroimaging.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39062862 SUPPORT Human Clinical
"non-febrile seizures, including status epilepticus"
Seizures including status epilepticus occurred in a severely affected patient.
Growth 2
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"The clinical features of these patients include failure to thrive, short stature, feeding difficulties"
Failure to thrive is a core clinical feature.
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)
PMID:32504085 SUPPORT Human Clinical
"The clinical features of these patients include failure to thrive, short stature, feeding difficulties"
Short stature is a core clinical feature.
Other 1
Renal thrombotic microangiopathy
Show evidence (1 reference)
PMID:39062862 SUPPORT Human Clinical
"associated with the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia, who developed renal TMA."
Documents renal thrombotic microangiopathy in a patient with CABAC syndrome.
🧬

Genetic Associations

1
EXOSC5 variants
Gene: EXOSC5 hgnc:24662 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EXOSC5 (hgnc:24662). hgnc:24662 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome."
Establishes EXOSC5 as the causative gene with a recessive, biallelic mechanism.
Variants (4)
p.Thr114Ile (c.341C>T)
Recurrent pathogenic missense variant (NM_020158.4:c.341C>T, p.Thr114Ile), seen compound heterozygous with an exon 5-6 deletion, with an early frameshift, and with p.Thr101Lys, and associated with cardiac conduction disease.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"NM_020158.4:c.341C > T (p.Thr114Ile; pathogenic, previously reported)"
Reports the recurrent pathogenic p.Thr114Ile allele.
p.Thr101Lys (c.302C>A)
Novel missense variant (NM_020158.4:c.302C>A, p.Thr101Lys) found in trans with p.Thr114Ile in two affected siblings.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"NM_020158.4:c.302C > A (p.Thr101Lys; novel variant)"
Reports the novel p.Thr101Lys allele.
Homozygous and null alleles
Additional biallelic genotypes include homozygous p.Leu206His, homozygous p.Met148Thr (via paternal chromosome 19 isodisomy), an exon 5-6 deletion and an early frameshift in trans with p.Thr114Ile.
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr."
Reports the homozygous missense, isodisomy, and null genotypes.
p.Glu77del (c.230_232del)
Homozygous in-frame single-codon deletion (NM_020158.4:c.230_232del, p.Glu77del) in the exoribonuclease phosphorolytic domain, reported in a consanguineous patient with CABAC syndrome and renal thrombotic microangiopathy.
Show evidence (1 reference)
PMID:39062862 SUPPORT Human Clinical
"Genetic diagnostics revealed a homozygous mutation in the EXOSC5 gene (c.230_232del and p.Glu77del)"
Reports the homozygous in-frame p.Glu77del allele.
💊

Medical Actions

3
Cardiac pacing / pacemaker implantation
Action: cardiac pacemaker implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cardiac pacemaker implantation, annotated with Pacemaker Procedure (NCIT:C99998), qualified as medical device cardiac pacemaker. NCIT:C99998 is a clinical intervention from the NCI Thesaurus. Ontology label: Pacemaker Procedure NCIT:C99998
Platform: Device
Permanent pacing is used for complete heart block and symptomatic conduction disease; proactive cardiac evaluation is advised given the risk of sudden cardiac death.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals"
A pacemaker is required for complete heart block in affected individuals.
Supportive 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, including feeding support, antiseizure treatment and multidisciplinary care. In the reported thrombotic microangiopathy case, recovery was attributed to supportive therapy and clearance of the viral infection.
Show evidence (1 reference)
PMID:39062862 SUPPORT Human Clinical
"the improvement in our patient was likely due to supporting therapy and elimination of the viral infection rather than to eculizumab therapy."
Supportive therapy, not eculizumab, drove recovery in the EXOSC5 TMA case.
🔬

Diagnosis

3
Brain MRI
Brain MRI NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:32504085 SUPPORT Human Clinical
"Brain MRI revealed cerebellar hypoplasia and ventriculomegaly."
Brain MRI demonstrates the characteristic cerebellar and ventricular findings.
Molecular genetic testing
Genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:39062862 SUPPORT Human Clinical
"Genetic diagnostics revealed a homozygous mutation in the EXOSC5 gene (c.230_232del and p.Glu77del)"
Diagnosis is confirmed by identifying biallelic EXOSC5 variants.
Cardiac conduction surveillance
Electrocardiography NCIT:C38053 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"argue for proactive screening due to potential risk of sudden cardiac death"
Proactive cardiac screening is advised given the conduction-disease risk; the specific ECG/Holter modality is inferred, as the quoted sentence calls for screening without naming the test.
📊

Prevalence

1
Worldwide (reported literature)
Cases In Literature Ultra Rare
About ten patients with an EXOSC5 mutation had been described in the literature at the time of the 2024 report; CABAC syndrome is ultra-rare.
Show evidence (1 reference)
PMID:39062862 SUPPORT Human Clinical
"Of the ten patients with an EXOSC5 mutation previously described in the literature, none showed kidney involvement"
Reports approximately ten EXOSC5 patients described in the literature.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from cerebellar ataxia, brain abnormalities, and cardiac conduction defects:

Pontocerebellar hypoplasia due to other RNA-exosome subunit genes (EXOSC3, EXOSC8, EXOSC9)
Overlapping Features Other RNA-exosome subunit disorders cause pontocerebellar hypoplasia with overlapping neurological features; they are distinguished by the causative gene and by the EXOSC5-specific cardiac conduction phenotype.
Show evidence (1 reference)
PMID:34089229 SUPPORT Human Clinical
"Several subunits are linked to Mendelian disorders, including pontocerebellar hypoplasia (EXOSC3, MIM #614678; EXOSC8, MIM #616081: and EXOSC9, MIM #618065)"
Names the other RNA-exosome subunit pontocerebellar hypoplasia disorders.
🐁

Animal Models

1
exosc5 loss-of-function zebrafish
Zebrafish exosc5 loss of function produces shortened and curved tails/bodies, reduced eye and head size and edema, used to test the requirement for EXOSC5 in development and brain growth.
Species
zebrafish
Publication
PMID:32504085
Pathograph links
Cerebellar and Pontine Hypoplasia partially recapitulates fidelity: low observes: organism Loss of exosc5 reduces head and eye size, modeling impaired brain growth; it does not reproduce the specific human cerebellar/pontine hypoplasia or the cardiac phenotype.
Limitations: Zebrafish crispants are mosaic and reflect acute knockdown rather than the constitutional biallelic hypomorphic state; the readout is a global reduction in head/eye size rather than isolated cerebellar or pontine hypoplasia, and no cardiac phenotype was reported.
Readouts
Head and eye size
Direction: DECREASED
Interpretation: Reduced head and eye size is the structural correlate of impaired brain growth in this model.
Show evidence (1 reference)
PMID:32504085 SUPPORT Model Organism
"Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema."
Reports the reduced head/eye size measured in the exosc5 loss-of-function model.
Show evidence (1 reference)
PMID:32504085 SUPPORT Model Organism
"Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema."
Supports treating the exosc5 zebrafish as informative for the requirement of EXOSC5 in brain development.
{ }

Source YAML

click to show 
name: cerebellar ataxia, brain abnormalities, and cardiac conduction defects
creation_date: "2026-10-12T13:10:00Z"
category: Mendelian
synonyms:
- CABAC syndrome
- EXOSC5-related disease
- EXOSC5-related neurodevelopmental disorder with or without thrombotic microangiopathy
- neurodevelopmental delay-hypotonia-cerebellar ataxia-cardiac conduction defects syndrome
disease_term:
  preferred_term: cerebellar ataxia, brain abnormalities, and cardiac conduction defects
  term:
    id: MONDO:0859200
    label: cerebellar ataxia, brain abnormalities, and cardiac conduction defects
parents:
- Mendelian neurodevelopmental disorder
- autosomal recessive cerebellar ataxia
- RNA exosomopathy
description: >-
  Cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC
  syndrome) is a rare autosomal recessive neurodevelopmental disorder caused by
  biallelic variants in EXOSC5, which encodes a structural subunit of the RNA
  exosome. Reported patients present in infancy with hypotonia, global
  developmental delay affecting motor skills, failure to thrive, short stature,
  feeding difficulties and esotropia, and brain MRI shows cerebellar hypoplasia
  or atrophy, pontocerebellar hypoplasia, ventriculomegaly and hypomyelination.
  A distinctive feature in a subset of patients is progressive cardiac
  conduction and rhythm disease (complete heart block, sinus node dysfunction,
  atrioventricular block and ventricular tachycardia) with a recognized risk of
  sudden cardiac death; cardiac involvement is variable and has been absent in
  some patients. Renal thrombotic microangiopathy after a viral trigger has
  been reported in one patient and is now recognized across RNA-exosome
  disorders. EXOSC5 is one of several RNA-exosome subunit genes (EXOSC2,
  EXOSC3, EXOSC8, EXOSC9) linked to Mendelian neurodegenerative disease, and
  the literature on CABAC remains small (about ten reported patients). Disease
  mechanism appears to vary with the specific pathogenic variant.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    CABAC syndrome is inherited in an autosomal recessive manner. Affected
    individuals carry biallelic EXOSC5 variants (homozygous in consanguineous
    families, or compound heterozygous), and unaffected parents are
    heterozygous carriers.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More recently, EXOSC5 (MIM *606492) was found to underlie an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies."
    explanation: States that EXOSC5-related disease is an autosomal recessive neurodevelopmental disorder.
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the parents were consanguineous (of Syrian descent) and both heterozygous carriers of this EXOSC5 variant."
    explanation: Documents recessive transmission with heterozygous carrier parents in a consanguineous family.
pathophysiology:
- name: EXOSC5 Subunit Dysfunction
  biological_scale: MOLECULAR
  description: >-
    Biallelic EXOSC5 variants (recurrent hypomorphic missense such as
    p.Thr114Ile plus null alleles including intragenic deletions and
    frameshifts) alter EXOSC5, a structural subunit of the RNA exosome. Some
    variants reduce RNA exosome function and alter interactions with other
    exosome subunits; the Slavotinek study concludes that disease mechanism
    varies with the specific variant. The nine-subunit exosome core (EXOSC1-9)
    is catalytically inactive and the 3' to 5' exoribonuclease activity is
    supplied by the associated DIS3 and EXOSC10 nucleases, so the GO:0000175
    binding here represents the activity of the whole complex that EXOSC5
    scaffolds rather than a catalytic function lost from EXOSC5 itself.
  genes:
  - preferred_term: EXOSC5
    term:
      id: hgnc:24662
      label: EXOSC5
  molecular_functions:
  - preferred_term: RNA exosome 3' to 5' exoribonuclease activity
    modifier: DECREASED
    term:
      id: GO:0000175
      label: 3'-5'-RNA exonuclease activity
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome."
    explanation: Establishes EXOSC5 as a structural RNA-exosome subunit altered by biallelic disease variants.
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits."
    explanation: Yeast and mammalian-cell modeling shows pathogenic variants impair exosome function and subunit interactions.
  downstream:
  - target: Impaired RNA Exosome-Mediated RNA Processing and Degradation
    causal_link_type: DIRECT
    description: >-
      Loss or reduction of the EXOSC5 structural subunit impairs the RNA
      exosome's 3' to 5' processing and degradation of coding and non-coding
      RNA.
    evidence:
    - reference: PMID:32504085
      reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits."
      explanation: Links the subunit defect to impaired RNA exosome function.
- name: Impaired RNA Exosome-Mediated RNA Processing and Degradation
  biological_scale: MOLECULAR
  description: >-
    The RNA exosome is an essential ribonuclease complex required for
    processing and degradation of coding and non-coding RNA; reduced EXOSC5
    function impairs this activity. The specific RNA targets and the basis for
    selective tissue vulnerability are not established.
  biological_processes:
  - preferred_term: RNA processing and degradation
    modifier: DECREASED
    term:
      id: GO:0006401
      label: RNA catabolic process
  cellular_components:
  - preferred_term: RNA exosome complex
    term:
      id: GO:0000178
      label: exosome (RNase complex)
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs."
    explanation: States the molecular function of the RNA exosome that EXOSC5 loss impairs.
  downstream:
  - target: Cerebellar and Pontine Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired RNA exosome function disrupts brain development, producing
      cerebellar and pontine hypoplasia; the mechanism of selective neural
      vulnerability is not established.
    evidence:
    - reference: PMID:32504085
      reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brain MRI revealed cerebellar hypoplasia and ventriculomegaly."
      explanation: Documents the cerebellar structural change that follows EXOSC5 dysfunction.
  - target: Ventriculomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Ventriculomegaly is part of the brain abnormality that follows impaired RNA exosome function.
    evidence:
    - reference: PMID:32504085
      reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brain MRI revealed cerebellar hypoplasia and ventriculomegaly."
      explanation: Ventriculomegaly accompanies the cerebellar structural change on MRI.
  - target: CNS hypomyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hypomyelination is part of the brain abnormality that follows impaired RNA exosome function.
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination"
      explanation: Hypomyelination is a reported brain abnormality in affected patients.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced brain growth manifests as microcephaly.
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "two siblings with microcephaly, developmental delay, cerebellar volume loss"
      explanation: Microcephaly reflects impaired brain growth in affected siblings.
  - target: Cardiac Conduction System Vulnerability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cardiac conduction tissue is vulnerable in a subset of patients; the
      mechanism linking RNA exosome dysfunction to conduction disease is not
      established and is inferred from the phenotype.
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An unusual feature of EXOSC5-related disease is the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals."
      explanation: Establishes cardiac conduction disease as part of the EXOSC5 disease spectrum.
  - target: Impaired Ribosome Assembly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      An intact RNA exosome is required for ribosome assembly, so exosome
      dysfunction is proposed to impair ribosome production.
    evidence:
    - reference: PMID:39062862
      reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "an intact RNA exosome is essential for the assembly of the ribosome"
      explanation: States the exosome's role in ribosome assembly underlying the proposed TMA mechanism.
- name: Cerebellar and Pontine Hypoplasia
  biological_scale: TISSUE
  description: >-
    Hypoplasia and progressive atrophy of the cerebellum and pons, with
    ventriculomegaly and hypomyelination, are the core brain abnormalities and
    drive the neurological phenotype.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  - preferred_term: pons
    term:
      id: UBERON:0000988
      label: pons
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination"
    explanation: Documents cerebellar volume loss and hypomyelination in affected siblings.
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cerebral MRI showed pontocerebellar hypoplasia, an immature gyral pattern, and a small aspect of the neurocranium with a small biparietal diameter."
    explanation: Documents pontocerebellar hypoplasia on brain MRI.
  downstream:
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cerebellar hypoplasia and atrophy underlie the cerebellar ataxia that names the syndrome.
    evidence:
    - reference: PMID:39062862
      reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia"
      explanation: Names cerebellar ataxia as a cardinal feature of the pontocerebellar phenotype.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities"
      explanation: Links the cerebellar/brain phenotype with hypotonia in the disease description.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities"
      explanation: Developmental delay accompanies the brain abnormalities.
  - target: Motor delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32504085
      reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "developmental delays that affect motor skills"
      explanation: Motor-skill delay is a core neurological feature.
  - target: Cerebellar hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cerebellar hypoplasia is the imaging manifestation of this structural node.
    evidence:
    - reference: PMID:32504085
      reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Brain MRI revealed cerebellar hypoplasia and ventriculomegaly."
      explanation: Cerebellar hypoplasia is seen on brain MRI.
  - target: Cerebellar atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Progressive cerebellar volume loss is the atrophic manifestation of this structural node.
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination"
      explanation: Progressive cerebellar volume loss manifests this node.
  - target: Hypoplasia of the pons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Pontine hypoplasia is the brainstem manifestation of this structural node.
    evidence:
    - reference: PMID:39062862
      reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The cerebral MRI showed pontocerebellar hypoplasia, an immature gyral pattern, and a small aspect of the neurocranium with a small biparietal diameter."
      explanation: Pontocerebellar hypoplasia includes hypoplasia of the pons.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The brain malformation underlies seizures in a severely affected patient.
    evidence:
    - reference: PMID:39062862
      reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "non-febrile seizures, including status epilepticus"
      explanation: Seizures occurred in a patient with the brain malformation.
  - target: Feeding difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Feeding difficulty arises from neurological coordinative problems and axial hypotonia.
    evidence:
    - reference: PMID:39062862
      reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Her feeding difficulties were likely due to a combination of neurological coordinative problems, axial hypotonia, mild respiratory distress, and her mucosal stasis due to facial dysmorphic features."
      explanation: The source attributes feeding difficulty to neurological coordination problems and axial hypotonia.
- name: Cardiac Conduction System Vulnerability
  biological_scale: TISSUE
  description: >-
    Progressive disease of the cardiac conduction system occurs in a subset of
    patients and can include complete heart block, sinus node dysfunction,
    atrioventricular block and ventricular tachycardia, with a risk of sudden
    cardiac death. Cardiac involvement is variable and has been absent on
    repeated evaluation in some patients.
  locations:
  - preferred_term: cardiac conduction system
    term:
      id: UBERON:0002350
      label: conducting system of heart
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT)"
    explanation: Enumerates the conduction and rhythm abnormalities arising in the conduction system.
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeated cardiac evaluations were performed because of previously described severe cardiac conduction problems, but showed no significant abnormalities"
    explanation: Documents that cardiac conduction involvement is variable and may be absent.
  downstream:
  - target: Atrioventricular block
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An unusual feature of EXOSC5-related disease is the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals."
      explanation: Complete heart block (third-degree atrioventricular block) occurs in a subset of patients.
  - target: Sinus node dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT)"
      explanation: Sinus node dysfunction is part of the reported conduction phenotype.
  - target: Ventricular tachycardia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "atrioventricular block, and ventricular tachycardia (VT)"
      explanation: Ventricular tachycardia is part of the reported rhythm phenotype.
  - target: Intraventricular conduction delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT)"
      explanation: Intraventricular conduction delay is part of the reported conduction phenotype.
- name: Impaired Ribosome Assembly
  biological_scale: CELLULAR
  description: >-
    Because the RNA exosome is required for ribosome assembly, exosome
    dysfunction is proposed to impair ribosome production; altered ribosome
    production could lead to cell cycle arrest and apoptosis. This step is
    hypothesized rather than demonstrated in affected tissue.
  biological_processes:
  - preferred_term: ribosome biogenesis
    modifier: DECREASED
    term:
      id: GO:0042254
      label: ribosome biogenesis
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Alterations in ribosome production could ultimately lead to cell cycle arrest and apoptosis"
    explanation: States the proposed link from impaired ribosome production to apoptosis.
  downstream:
  - target: Endothelial Cell Apoptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      It is hypothesized that defective processing of RNA induces ribosomal
      dysfunction in endothelial cells, leading to apoptosis.
    evidence:
    - reference: PMID:39062862
      reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "It is hypothesized that infection causes an accumulation of viral RNA or defective processing of (viral) RNA in the cell, inducing ribosomal dysfunction in the endothelial cells resulting in apoptosis, and consequently leading to the cascade resulting in TMA"
      explanation: States the hypothesized endothelial mechanism linking the RNA exosome defect to endothelial apoptosis.
- name: Endothelial Cell Apoptosis
  biological_scale: CELLULAR
  description: >-
    Proposed endothelial injury: ribosomal dysfunction in endothelial cells
    leads to apoptosis, the cellular event upstream of the thrombotic
    microangiopathy cascade. Observed consequence in one EXOSC5 patient who
    developed renal thrombotic microangiopathy after a rotavirus infection; the
    mechanism is hypothesized and complement-independent.
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "It is hypothesized that infection causes an accumulation of viral RNA or defective processing of (viral) RNA in the cell, inducing ribosomal dysfunction in the endothelial cells resulting in apoptosis, and consequently leading to the cascade resulting in TMA"
    explanation: States the hypothesized endothelial-cell apoptosis mechanism that this node represents.
  downstream:
  - target: Renal thrombotic microangiopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39062862
      reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "associated with the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia, who developed renal TMA."
      explanation: The hypothesized endothelial injury manifests as renal thrombotic microangiopathy in the EXOSC5 patient.
phenotypes:
- name: Ataxia
  category: Neurologic
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia"
    explanation: Cerebellar ataxia is the cardinal neurological feature naming the syndrome.
- name: Hypotonia
  category: Neurologic
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delays that affect motor skills, hypotonia and esotropia"
    explanation: Hypotonia is a core clinical feature.
- name: Global developmental delay
  category: Neurologic
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an autosomal recessive neurodevelopmental disorder characterized by developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies."
    explanation: Developmental delay is a defining feature of EXOSC5-related disease.
- name: Motor delay
  category: Neurologic
  phenotype_term:
    preferred_term: Motor developmental delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delays that affect motor skills"
    explanation: Developmental delay affecting motor skills is reported in the patients.
- name: Cerebellar hypoplasia
  category: Neurologic
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed cerebellar hypoplasia and ventriculomegaly."
    explanation: Brain MRI shows cerebellar hypoplasia.
- name: Cerebellar atrophy
  category: Neurologic
  phenotype_term:
    preferred_term: Cerebellar volume loss
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination"
    explanation: Progressive cerebellar volume loss is documented in affected siblings.
- name: Hypoplasia of the pons
  category: Neurologic
  phenotype_term:
    preferred_term: Pontocerebellar hypoplasia
    term:
      id: HP:0012110
      label: Hypoplasia of the pons
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cerebral MRI showed pontocerebellar hypoplasia, an immature gyral pattern, and a small aspect of the neurocranium with a small biparietal diameter."
    explanation: MRI shows pontocerebellar hypoplasia, i.e. hypoplasia of the pons and cerebellum.
- name: Ventriculomegaly
  category: Neurologic
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed cerebellar hypoplasia and ventriculomegaly."
    explanation: Brain MRI shows ventriculomegaly.
- name: CNS hypomyelination
  category: Neurologic
  phenotype_term:
    preferred_term: Hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with microcephaly, developmental delay, cerebellar volume loss, hypomyelination"
    explanation: Hypomyelination is documented on neuroimaging.
- name: Microcephaly
  category: Neurologic
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with microcephaly, developmental delay, cerebellar volume loss"
    explanation: Microcephaly is reported in affected siblings.
- name: Seizure
  category: Neurologic
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "non-febrile seizures, including status epilepticus"
    explanation: Seizures including status epilepticus occurred in a severely affected patient.
- name: Failure to thrive
  category: Growth
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of these patients include failure to thrive, short stature, feeding difficulties"
    explanation: Failure to thrive is a core clinical feature.
- name: Short stature
  category: Growth
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of these patients include failure to thrive, short stature, feeding difficulties"
    explanation: Short stature is a core clinical feature.
- name: Feeding difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of these patients include failure to thrive, short stature, feeding difficulties"
    explanation: Feeding difficulty is a core clinical feature.
- name: Esotropia
  category: Ophthalmologic
  phenotype_term:
    preferred_term: Esotropia
    term:
      id: HP:0000565
      label: Esotropia
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delays that affect motor skills, hypotonia and esotropia"
    explanation: Esotropia is reported among the clinical features.
- name: Abnormal facial shape
  category: Craniofacial
  phenotype_term:
    preferred_term: Dysmorphic facies
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay, hypotonia, cerebellar abnormalities, and dysmorphic facies."
    explanation: Dysmorphic facies is part of the clinical description.
- name: Mixed hearing impairment
  category: Auditory
  description: Reported in a single patient.
  phenotype_term:
    preferred_term: Mixed conductive and sensorineural hearing loss
    term:
      id: HP:0000410
      label: Mixed hearing impairment
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An audiological examination at five weeks revealed mixed (conductive and sensorineural) hearing loss in both ears."
    explanation: Mixed hearing loss was found in one patient.
- name: Atrioventricular block
  category: Cardiovascular
  phenotype_term:
    preferred_term: Complete heart block
    term:
      id: HP:0001709
      label: Third degree atrioventricular block
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An unusual feature of EXOSC5-related disease is the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals."
    explanation: Complete heart block (third-degree atrioventricular block) occurs in a subset of patients.
- name: Sinus node dysfunction
  category: Cardiovascular
  phenotype_term:
    preferred_term: Sinus node dysfunction
    term:
      id: HP:0011704
      label: Sick sinus syndrome
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac conduction and rhythm abnormalities including sinus node dysfunction"
    explanation: Sinus node dysfunction is reported among the conduction abnormalities.
- name: Ventricular tachycardia
  category: Cardiovascular
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "atrioventricular block, and ventricular tachycardia (VT)"
    explanation: Ventricular tachycardia is reported among the rhythm abnormalities.
- name: Intraventricular conduction delay
  category: Cardiovascular
  description: >-
    Reported among the conduction abnormalities. On the ECG an intraventricular
    conduction delay appears as QRS prolongation without a typical
    bundle-branch-block pattern, so it is bound to Prolonged QRS complex.
  phenotype_term:
    preferred_term: Intraventricular conduction delay
    term:
      id: HP:0006677
      label: Prolonged QRS complex
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiac conduction and rhythm abnormalities including sinus node dysfunction, intraventricular conduction delay, atrioventricular block, and ventricular tachycardia (VT)"
    explanation: Intraventricular conduction delay is listed among the reported conduction abnormalities.
- name: Renal thrombotic microangiopathy
  category: Renal
  description: >-
    Renal thrombotic microangiopathy after a viral trigger has been reported in
    one EXOSC5 patient and is now recognized across RNA-exosome disorders; no
    standard HP term exists for thrombotic microangiopathy, so this phenotype
    is left unbound.
  phenotype_term:
    preferred_term: Renal thrombotic microangiopathy
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "associated with the clinical phenotype known as CABAC syndrome (cerebellar ataxia, brain abnormalities, and cardiac conduction defects), including pontocerebellar hypoplasia, who developed renal TMA."
    explanation: Documents renal thrombotic microangiopathy in a patient with CABAC syndrome.
genetic:
- name: EXOSC5 variants
  gene_term:
    preferred_term: EXOSC5
    term:
      id: hgnc:24662
      label: EXOSC5
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Biallelic EXOSC5 variants cause CABAC syndrome. The recurrent missense
    allele p.Thr114Ile (c.341C>T, NM_020158.4) is carried by most patients with
    conduction disease and is seen compound heterozygous with null alleles or
    with other missense variants; homozygous missense (p.Leu206His,
    p.Met148Thr), an in-frame single-codon deletion (p.Glu77del) and null
    alleles (an exon 5-6 deletion and an early frameshift) are also reported.
    Slavotinek et al. conclude that disease mechanism varies with the specific
    variant. No ClinGen gene-disease validity (CGGV) record for EXOSC5 is cached
    in this repository, so gene_disease_validity is omitted; GenCC lists the
    gene-disease relationship as Strong (autosomal recessive).
  variants:
  - name: p.Thr114Ile (c.341C>T)
    description: >-
      Recurrent pathogenic missense variant (NM_020158.4:c.341C>T, p.Thr114Ile),
      seen compound heterozygous with an exon 5-6 deletion, with an early
      frameshift, and with p.Thr101Lys, and associated with cardiac conduction
      disease.
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "NM_020158.4:c.341C > T (p.Thr114Ile; pathogenic, previously reported)"
      explanation: Reports the recurrent pathogenic p.Thr114Ile allele.
  - name: p.Thr101Lys (c.302C>A)
    description: Novel missense variant (NM_020158.4:c.302C>A, p.Thr101Lys) found in trans with p.Thr114Ile in two affected siblings.
    evidence:
    - reference: PMID:34089229
      reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "NM_020158.4:c.302C > A (p.Thr101Lys; novel variant)"
      explanation: Reports the novel p.Thr101Lys allele.
  - name: Homozygous and null alleles
    description: >-
      Additional biallelic genotypes include homozygous p.Leu206His, homozygous
      p.Met148Thr (via paternal chromosome 19 isodisomy), an exon 5-6 deletion
      and an early frameshift in trans with p.Thr114Ile.
    evidence:
    - reference: PMID:32504085
      reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr."
      explanation: Reports the homozygous missense, isodisomy, and null genotypes.
  - name: p.Glu77del (c.230_232del)
    description: >-
      Homozygous in-frame single-codon deletion (NM_020158.4:c.230_232del,
      p.Glu77del) in the exoribonuclease phosphorolytic domain, reported in a
      consanguineous patient with CABAC syndrome and renal thrombotic
      microangiopathy.
    evidence:
    - reference: PMID:39062862
      reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic diagnostics revealed a homozygous mutation in the EXOSC5 gene (c.230_232del and p.Glu77del)"
      explanation: Reports the homozygous in-frame p.Glu77del allele.
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome."
    explanation: Establishes EXOSC5 as the causative gene with a recessive, biallelic mechanism.
prevalence:
- population: Worldwide (reported literature)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    About ten patients with an EXOSC5 mutation had been described in the
    literature at the time of the 2024 report; CABAC syndrome is ultra-rare.
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the ten patients with an EXOSC5 mutation previously described in the literature, none showed kidney involvement"
    explanation: Reports approximately ten EXOSC5 patients described in the literature.
diagnosis:
- name: Brain MRI
  diagnosis_term:
    preferred_term: Brain MRI
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:32504085
    reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed cerebellar hypoplasia and ventriculomegaly."
    explanation: Brain MRI demonstrates the characteristic cerebellar and ventricular findings.
- name: Molecular genetic testing
  diagnosis_term:
    preferred_term: Genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic diagnostics revealed a homozygous mutation in the EXOSC5 gene (c.230_232del and p.Glu77del)"
    explanation: Diagnosis is confirmed by identifying biallelic EXOSC5 variants.
- name: Cardiac conduction surveillance
  diagnosis_term:
    preferred_term: Electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "argue for proactive screening due to potential risk of sudden cardiac death"
    explanation: >-
      Proactive cardiac screening is advised given the conduction-disease risk;
      the specific ECG/Holter modality is inferred, as the quoted sentence calls
      for screening without naming the test.
treatments:
- name: Cardiac pacing / pacemaker implantation
  description: >-
    Permanent pacing is used for complete heart block and symptomatic
    conduction disease; proactive cardiac evaluation is advised given the risk
    of sudden cardiac death.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cardiac pacemaker implantation
    term:
      id: NCIT:C99998
      label: Pacemaker Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cardiac pacemaker
        term:
          id: NCIT:C94198
          label: Cardiac Pacemaker
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the occurrence of complete heart block requiring a pacemaker in a subset of affected individuals"
    explanation: A pacemaker is required for complete heart block in affected individuals.
- name: Supportive care
  description: >-
    Management is supportive, including feeding support, antiseizure treatment
    and multidisciplinary care. In the reported thrombotic microangiopathy
    case, recovery was attributed to supportive therapy and clearance of the
    viral infection.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the improvement in our patient was likely due to supporting therapy and elimination of the viral infection rather than to eculizumab therapy."
    explanation: Supportive therapy, not eculizumab, drove recovery in the EXOSC5 TMA case.
- name: Eculizumab (not recommended for EXOSC-related TMA)
  description: >-
    C5 complement inhibition with eculizumab was tried for the renal thrombotic
    microangiopathy but is not beneficial, because the TMA in EXOSC3/EXOSC5
    disease is not linked to complement dysregulation.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: eculizumab
      term:
        id: CHEBI:749604
        label: eculizumab
  evidence:
  - reference: PMID:39062862
    reference_title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "these patients are unlikely to benefit from eculizumab therapy"
    explanation: The source concludes eculizumab is unlikely to benefit EXOSC-related, complement-independent TMA.
animal_models:
- name: exosc5 loss-of-function zebrafish
  species: zebrafish
  description: >-
    Zebrafish exosc5 loss of function produces shortened and curved
    tails/bodies, reduced eye and head size and edema, used to test the
    requirement for EXOSC5 in development and brain growth.
  publication: PMID:32504085
  modeled_mechanisms:
  - target: Cerebellar and Pontine Hypoplasia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Loss of exosc5 reduces head and eye size, modeling impaired brain growth;
      it does not reproduce the specific human cerebellar/pontine hypoplasia or
      the cardiac phenotype.
    limitations: >-
      Zebrafish crispants are mosaic and reflect acute knockdown rather than the
      constitutional biallelic hypomorphic state; the readout is a global
      reduction in head/eye size rather than isolated cerebellar or pontine
      hypoplasia, and no cardiac phenotype was reported.
    readouts:
    - name: Head and eye size
      target: Cerebellar and Pontine Hypoplasia
      direction: DECREASED
      interpretation: Reduced head and eye size is the structural correlate of impaired brain growth in this model.
      evidence:
      - reference: PMID:32504085
        reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema."
        explanation: Reports the reduced head/eye size measured in the exosc5 loss-of-function model.
    evidence:
    - reference: PMID:32504085
      reference_title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema."
      explanation: Supports treating the exosc5 zebrafish as informative for the requirement of EXOSC5 in brain development.
differential_diagnoses:
- name: Pontocerebellar hypoplasia due to other RNA-exosome subunit genes (EXOSC3, EXOSC8, EXOSC9)
  description: >-
    Other RNA-exosome subunit disorders cause pontocerebellar hypoplasia with
    overlapping neurological features; they are distinguished by the causative
    gene and by the EXOSC5-specific cardiac conduction phenotype.
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several subunits are linked to Mendelian disorders, including pontocerebellar hypoplasia (EXOSC3, MIM #614678; EXOSC8, MIM #616081: and EXOSC9, MIM #618065)"
    explanation: Names the other RNA-exosome subunit pontocerebellar hypoplasia disorders.
- name: EXOSC2-related short stature, hearing loss, retinitis pigmentosa and distinctive facies
  description: >-
    EXOSC2 disease is another RNA-exosome subunit disorder with a distinct,
    non-pontocerebellar presentation.
  evidence:
  - reference: PMID:34089229
    reference_title: Risk of sudden cardiac death in EXOSC5-related disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short stature, hearing loss, retinitis pigmentosa, and distinctive facies (EXOSC2, MIM #617763)"
    explanation: Names the distinct EXOSC2-related RNA-exosome disorder.
references:
- reference: PMID:32504085
  title: "Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness."
- reference: PMID:34089229
  title: Risk of sudden cardiac death in EXOSC5-related disease.
- reference: PMID:39062862
  title: Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
notes: >-
  CABAC syndrome is a single-gene (EXOSC5) autosomal recessive RNA
  exosomopathy and is curated as one leaf disease with a single conserved
  pathograph; the EXOSC2/EXOSC3/EXOSC8/EXOSC9 disorders are distinct diseases
  kept as differentials rather than lumped. Cardiac conduction disease is a
  distinctive but variable feature (absent on repeated evaluation in the
  EXOSC5 thrombotic-microangiopathy patient). Renal thrombotic microangiopathy
  and the ribosome/endothelial-apoptosis mechanism are hypothesized from a
  single case and background exosome biology, and are marked as inferred.
📚

References & Deep Research

References

3
PMID:32504085
Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness.
No top-level findings curated for this source.
PMID:34089229
Risk of sudden cardiac death in EXOSC5-related disease.
No top-level findings curated for this source.
PMID:39062862
Mutations in Genes Encoding Subunits of the RNA Exosome as a Potential Novel Cause of Thrombotic Microangiopathy.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Cerebellar_Ataxia_Brain_Abnormalities_And_Cardiac_Conduction_Defects · 2026-10-12T14:44:40Z · View source

De-novo curation of CABAC syndrome (EXOSC5-related RNA exosomopathy, MONDO:0859200). Primary sources quoted from cached abstracts/full text: Slavotinek 2020 (PMID:32504085), Calame 2021 (PMID:34089229), Wijnsma 2024 (PMID:39062862, full text, adds renal TMA and p.Glu77del). Deep-research report used as leads only; all PMIDs and CURIEs verified by lookup (HGNC EXOSC5 hgnc:24662; GO/HP/CL/UBERON/NCIT via OLS). EXOSC5 node grounded with GO:0000175. Single-gene leaf disease; EXOSC2/3/8/9 disorders kept as differentials. Validation: validate-disorders clean, 70/70 snippets verified, validate-terms passed, gene-activity-grounding OK against origin/main, no GeneReviews chapter exists.

Claude Code ▸
Research report: cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC)
claude-haiku-5-5, claude-sonnet-5-5 8 citations 2026-10-12T14:12:20.542458

Let me get the primary papers' details.

Research report: cerebellar ataxia, brain abnormalities, and cardiac conduction defects (CABAC)

Evidence status. This report rests on a limited number of fetched sources: the Calame 2021 full text (PMC8382094), part of the Slavotinek 2020 full text, and secondary aggregators (MedGen, MalaCards, KEGG, GenCC, PanelApp, GeneCards). I did not confirm OMIM, Orphanet, MONDO or MeSH identifiers directly, because OMIM, PubMed and MalaCards blocked fetches. Items marked [unverified] come from aggregator summaries or my own recall, and need a lookup before they go into the KB. All ontology IDs below are suggestions and must be looked up with runoak or OLS before binding.

The literature is small: about 10 reported patients, and the recurrent variant p.Thr114Ile accounts for most conduction disease.

1. Disease information

  • Overview. CABAC is a rare autosomal recessive neurodevelopmental disorder caused by biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. It features hypotonia, developmental delay, ataxic gait, cerebellar hypoplasia or atrophy, and progressive cardiac conduction disease with arrhythmia.
  • Identifiers. OMIM #619576 (per MedGen and GenCC summaries). Other identifiers I did not retrieve: MONDO (unknown), Orphanet, ICD-10/11, MeSH. KEGG has an entry, H02549.
  • Synonyms. CABAC; EXOSC5-related disease; EXOSC5-related neurodevelopmental disorder.
  • Related earlier description. Zaki et al. 2011 described a family with bradycardia and second-degree heart block ("Zaki-Gleeson syndrome"). Calame 2021 lists it as a possibly related family with unknown locus.
  • Data source. The data come from individual patient case reports and small series, not from EHR or population resources.

2. Etiology

  • Cause. Biallelic loss or hypomorphic variants in EXOSC5. GenCC lists the gene-disease relationship as "Strong" and autosomal recessive (GenCC SGC-178553.1). Genomics England PanelApp notes a caveat: all of the first three families shared p.Thr114Ile (PanelApp EXOSC5).
  • Risk factors. Consanguinity (see Section 9). No environmental risk factors, protective factors or gene-environment interactions are reported. The report does not state this; it is an absence of data.
  • Modifier genes. None reported.

3. Phenotypes

Sources: Slavotinek 2020 (HMG 29:2218, DOI 10.1093/hmg/ddaa108, PMID 32504085 per GenCC) and Calame 2021 (PMC8382094, PMID 34089229). Frequencies are not computable from about 10 patients. Counts below are per reported patients.

Phenotype Notes Suggested HPO (verify)
Global developmental delay / intellectual disability All patients with data. Calame P1 was mild; her brother was profound and nonverbal. HP:0001263; HP:0001249
Hypotonia Infantile onset (Slavotinek P2; GeneCards summary). HP:0001252
Cerebellar ataxia / ataxic gait, dysmetria Slavotinek P1; Calame P1. HP:0001251; HP:0002070
Cerebellar hypoplasia / atrophy Slavotinek P1, P4, P5 (hypoplasia); Calame P1 and P2 show progressive volume loss. HP:0001321; HP:0001272
Brainstem or pons hypoplasia Slavotinek P1, P2, P4, P5. HP:0007366 (lead; check the exact brainstem term)
Ventriculomegaly Slavotinek P2, P3, P4. HP:0002119
Hypomyelination or delayed myelination Slavotinek P2; Calame P1 and P2. HP:0003429 (lead)
Thin corpus callosum Calame P2 (severe by age 20); Slavotinek P2. HP:0033725 (lead)
Microcephaly Calame P1 (OFC Z −2.77). HP:0000252
Short stature / failure to thrive Several patients. HP:0004322; HP:0001508
Feeding difficulty Slavotinek P2 (gastrostomy). HP:0011968
Esotropia, nystagmus Slavotinek P1 and P2. HP:0000565; HP:0000639
Cone-rod dystrophy Slavotinek P1 only. HP:0000548
Optic atrophy Calame P2. HP:0000648
Myoclonic epilepsy, spasticity, scoliosis Calame P2 (severe). HP:0032794 (check); HP:0001257; HP:0002650
Complete AV block Slavotinek P1 (syncope at age 2, pacemaker). HP:0001678
Right bundle branch block, bradycardia Iranian siblings, adolescent onset (Beheshtian 2019 via Calame). HP:0011712; HP:0001662
Sinus node dysfunction Calame P1 and P2. HP:0011704
Intraventricular conduction delay, trifascicular block Calame P1 and P2. HP:0011705 (lead); HP:0011707 (lead)
Ventricular tachycardia Calame P1 and P2. HP:0004756
Sudden cardiac death Reported in secondary sources [unverified in primary papers]. HP:0001645
  • Variable or single-patient findings. Hypospadias, tethered cord, metopic craniosynostosis, OCD and coronary fistula appear in single Slavotinek patients and may not be core features.
  • Onset and progression. Neurological features start in infancy. Cardiac conduction disease appears in infancy to adolescence and is progressive. Calame reports that both siblings showed intermittent complete heart block and profound sinus node dysfunction at ICD implantation. Brain MRI shows progressive cerebellar and cerebral atrophy over time.
  • Quality of life. No data are available.

4. Genetic and molecular information

  • Gene. EXOSC5 (hgnc ID not verified; look it up with runoak or HGNC). Transcript NM_020158.4.
  • Variants reported.
Variant Genotype and patients Source
c.341C>T p.Thr114Ile Recurrent. Compound heterozygous with a 1,023 bp exon 5–6 deletion (Slavotinek P1). Compound heterozygous with an early frameshift (P4, P5). Compound heterozygous with p.Thr101Lys (Calame siblings). Homozygous in 3 Iranian siblings (Beheshtian 2019). Slavotinek 2020; Calame 2021
c.617T>A p.Leu206His Homozygous, first-cousin parents (Slavotinek P2). Slavotinek 2020
c.443T>C p.Met148Thr Homozygous through paternal chromosome 19 isodisomy (Slavotinek P3). Slavotinek 2020
c.302C>A p.Thr101Lys Novel, in trans with p.Thr114Ile. Both variants are in exon 3. Calame 2021
Exon 5–6 deletion, early frameshift Null alleles, in trans with p.Thr114Ile. Slavotinek 2020
  • Functional consequence. Most variants are hypomorphic missense. The abstract of Slavotinek 2020 concludes that "different EXOSC5 variants may act through different disease mechanisms" (paraphrased by the fetch tool, not a verified verbatim quote). Allele frequencies in gnomAD were not retrieved. Calame 2021 calls both missense alleles ultra-rare.
  • Genotype-phenotype pattern. Calame 2021 states that six of ten reported patients have conduction abnormalities, and that all six carry p.Thr114Ile. The paper's introduction gives a different count (four of eight) and the article does not reconcile the two. The Slavotinek P2 (p.Leu206His) and P3 (p.Met148Thr) patients, with homozygous alleles that are not p.Thr114Ile, had no documented conduction disease, though their cardiac work-up was limited. Treat this pattern as suggestive.
  • Epigenetic or chromosomal. Segmental uniparental disomy (chr19 isodisomy) is documented in one patient. No other epigenetic data are available.

5. Environmental information

None reported. No infectious, toxic or lifestyle contribution is documented.

6. Mechanism and pathophysiology

Causal chain (steps 1–3 are demonstrated or inferred from the molecular data. Steps 4–6 are inferred, not demonstrated):

  1. Biallelic EXOSC5 variants (mostly hypomorphic missense, plus rare null alleles) alter the Rrp46 subunit (EXOSC5) of the RNA exosome. Demonstrated by genetics.
  2. This impairs RNA exosome function. In yeast, the allele equivalent to p.Leu206His (rrp46-L191H) caused growth defects at 30°C and 37°C. The equivalents of p.Thr114Ile and p.Met148Thr (rrp46-Q86I, L127T) showed no growth defect in the fetched content. The Thr114 equivalent was not clearly identified in the text I read, so I do not link the yeast result to that variant.
  3. This leads to reduced exosome-mediated 3'→5' RNA processing and decay. The specific RNA targets in affected cells are not identified in the sources read. Inferred from exosome biology.
  4. Neural tissue is selectively vulnerable. This is inferred from the pattern in other exosomopathies (EXOSC3, 8, 9: pontocerebellar hypoplasia, motor neuronopathy), and the mechanism of selectivity is unknown.
  5. This leads to cerebellar and brainstem hypoplasia or atrophy, hypomyelination and ventriculomegaly, causing hypotonia, ataxia and developmental delay.

  6. In the heart, the mechanism is unknown. Conduction tissue (sinus node, AV node, His-Purkinje) appears vulnerable, leading to AV block, bundle branch block, VT and a risk of sudden cardiac death. Inferred from phenotype only.

  7. Branch. Missense alleles may differ in mechanism. Slavotinek 2020 reports that mutant EXOSC5 protein levels were not significantly altered in mammalian cells, while neuronal cells showed differences in interactions with other exosome subunits. This part was truncated in the fetched text.

  8. Suggested terms. GO: RNA catabolic process (GO:0006401 lead); nuclear RNA surveillance; exosome (RNase complex) (GO:0000178 lead). CL: Purkinje cell (CL:0000121), cardiac muscle cell, cardiac pacemaker cell (verify). All to be looked up.
  9. Not available. Transcriptomics, proteomics, single-cell data and CRISPR screens for CABAC were not found.

7. Anatomical structures affected

  • Primary. Cerebellum, brainstem and pons, cerebral white matter, corpus callosum, and the cardiac conduction system (sinus node, AV node, His-Purkinje) (UBERON: cerebellum UBERON:0002037; pons; corpus callosum; heart; verify).
  • Secondary. Eye (retina, extraocular muscles, optic nerve), skeletal system (short stature, scoliosis), and swallowing function.
  • Subcellular. The RNA exosome in nucleus and cytoplasm.
  • Lateralization. Bilateral.

8. Temporal development

  • Onset. Congenital or infantile for neurological features. Cardiac onset ranges from age 2 (syncope, complete heart block) to adolescence (RBBB, bradycardia). One patient died at 11 months of respiratory disease (Slavotinek P2).
  • Progression. Progressive cerebellar atrophy on serial MRI, and progressive conduction disease.
  • Critical period. Cardiac surveillance before and through adolescence.

9. Inheritance and population

  • Inheritance. Autosomal recessive (HP:0000007).
  • Parents. Obligate carriers are unaffected. Calame's family had unrelated parents and three unaffected siblings.
  • Consanguinity. Present in some families (first-cousin parents in Slavotinek P2; the Iranian siblings).
  • Founder effect. p.Thr114Ile is recurrent across different populations. Founder status is not established.
  • Prevalence, incidence, carrier frequency, sex ratio. Not available. Ten or fewer reported patients.

10. Diagnostics

  • Genetic testing. Exome or genome sequencing, or a panel (EXOSC5 is on the Genomics England ataxia and cerebellar anomalies panel). Include copy-number analysis, because a 1,023 bp intragenic deletion was found. Consider UPD when a homozygous variant is found with a single carrier parent (Slavotinek P3).
  • Imaging. Brain MRI: cerebellar hypoplasia or atrophy, small brainstem or pons, ventriculomegaly, hypomyelination, thin corpus callosum.
  • Electrophysiology and cardiac. ECG and Holter. Calame found the Holter showed bradycardia, AV block and monomorphic VT. Echocardiograms were normal in both siblings, so a normal echocardiogram does not exclude conduction disease.
  • Differential diagnosis. Pontocerebellar hypoplasia types due to EXOSC3, EXOSC8, EXOSC9 and EXOSC1, and other recessive cerebellar ataxias with cardiac involvement.
  • Screening. No established program. Calame recommends proactive cardiac screening.

11. Outcome and prognosis

  • Survival. Not systematically characterized. Early death (11 months) was reported in one patient. Sudden cardiac death has been reported in this and other exosome disorders in secondary sources [unverified in primary papers]. Calame notes sudden unexplained death in a 10-year-old with EXOSC9 disease.
  • Morbidity. Developmental disability ranges from mild to profound; the severe brother in Calame had no walking or speech, epilepsy and spasticity.
  • Prognostic factors. The p.Thr114Ile allele is associated with conduction disease in reported cases. No validated prognostic model exists.

12. Treatment

No disease-specific therapy exists. Management is supportive and cardiac.

  • Cardiac devices. Pacemaker (Slavotinek P1; Iranian siblings). Dual-chamber ICD in both Calame siblings (NCIT: Cardiac Pacemaker Implantation / Implantable Cardioverter Defibrillator Placement, to be looked up). Calame recommends considering a pacemaker or ICD when conduction disease or arrhythmia is found.
  • Supportive. Physical, occupational and speech therapy, feeding support (gastrostomy), antiseizure treatment and ophthalmologic care. Suggested NCIT: Physical Therapy NCIT:C15302; Supportive Care NCIT:C15747; Genetic Counseling NCIT:C15240.
  • Experimental. No trials, gene therapy, RNA therapy or pharmacogenomic data were found. I did not search ClinicalTrials.gov.

13. Prevention

  • Genetic counseling and carrier testing for at-risk relatives. Prenatal or preimplantation diagnosis is possible for known familial variants.
  • Cascade testing of siblings.
  • Calame recommends periodic ECG and Holter surveillance for conduction defects and arrhythmias, and suggests that cardiac evaluation may also be prudent for people with variants in other exosome genes.

14. Other species and natural disease

No naturally occurring disease in other species was found. I did not check OMIA, so this is an absence of retrieved data, not a confirmed negative.

15. Model organisms

  • Zebrafish. Slavotinek 2020 made exosc5 crispants, which showed shortened and curved tails and bodies, reduced eye and head size, edema, fin defects, increased ventricle size and reduced brain size. Reporter lines (mnx1:EGFP motor neuron, NBT:dsRed pan-neuronal) showed reduced fluorescence and abnormal brain morphology in severe larvae. qRT-PCR showed reduced exosc5 expression in abnormal larvae. This is partial, crispant-level evidence, and cardiac phenotypes were not reported in the text I read.
  • Budding yeast. Rrp46 variants modeling patient alleles. Only the p.Leu206His equivalent caused a growth defect (doubling time about 64–69% longer).
  • Mouse. A mouse knockout resource appeared in search results for a different gene (a mousephenotype.org page); I did not verify an Exosc5 mouse model.
  • Limitations. Crispants are mosaic and acute. Yeast has no heart or cerebellum, so the cardiac phenotype is not modeled by any retrieved system.

Open items before curation

  1. Look up the MONDO ID, Orphanet and ICD entries, and confirm OMIM #619576 and its clinical synopsis.
  2. Confirm PMIDs. Slavotinek 2020 = 32504085 (from GenCC, not independently confirmed) and Calame 2021 = 34089229 (from search result). The Beheshtian 2019 PMID is unknown. GenCC lists PMID 29302074 as "Hu et al., 2019", which I could not tie to Beheshtian, so do not use it for that paper without checking.
  3. Run just fetch-reference for each PMID before quoting snippets. All snippets must be copied from the cached text; I have not supplied verbatim quotes.
  4. Check for newer EXOSC5 cases after 2021. The search returned none, but it was not exhaustive.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 5
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 38
Resolved 38
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 12
Terms named correctly 0
Terms named as a different term 12

Terms the report names something else

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

  • HP:0001252 (1 mention) - the report calls it "Infantile onset (Slavotinek P2; GeneCards summary)"; HP calls it Hypotonia
  • HP:0007366 (1 mention) - the report calls it "lead; check the exact brainstem term"; HP calls it Atrophy/Degeneration affecting the brainstem
  • HP:0002119 (1 mention) - the report calls it "Slavotinek P2, P3, P4"; HP calls it Ventriculomegaly
  • HP:0003429 (1 mention) - the report calls it "lead"; HP calls it CNS hypomyelination
  • HP:0033725 (1 mention) - the report calls it "lead"; HP calls it Thin corpus callosum
  • HP:0000252 (1 mention) - the report calls it "Calame P1 (OFC Z −2.77)"; HP calls it Microcephaly
  • HP:0011968 (1 mention) - the report calls it "Slavotinek P2 (gastrostomy)"; HP calls it Feeding difficulties
  • HP:0000548 (1 mention) - the report calls it "Slavotinek P1 only"; HP calls it Cone/cone-rod dystrophy
  • HP:0000648 (1 mention) - the report calls it "Calame P2"; HP calls it Optic atrophy
  • HP:0001678 (1 mention) - the report calls it "Slavotinek P1 (syncope at age 2, pacemaker)"; HP calls it Atrioventricular block
  • HP:0011704 (1 mention) - the report calls it "Calame P1 and P2"; HP calls it Sick sinus syndrome
  • HP:0004756 (1 mention) - the report calls it "Calame P1 and P2"; HP calls it Ventricular tachycardia