Microcephaly, Growth Restriction, and Increased Sister Chromatid Exchange 2

Mendelian MONDO:0020628 Pathograph 11 Show in embeddings browser microcephaly, growth restriction and increased sister chromatid exchange chromosomal instability syndrome

Microcephaly, growth restriction, and increased sister chromatid exchange 2 (MGRISCE2) is an autosomal recessive Bloom syndrome-like microcephalic primordial dwarfism caused by biallelic hypomorphic variants in TOP3A, which encodes topoisomerase III alpha. TOP3A is the decatenase of the BLM-TOP3A-RMI1-RMI2 (BTRR) complex that dissolves double Holliday junctions without crossover. The index series described ten children from seven families with prenatal-onset growth restriction, microcephaly and short stature, multiple cafe-au-lait macules, and a 3- to 6-fold increase in sister chromatid exchanges in cultured cells. Unlike BLM-related Bloom syndrome, none had the photosensitive malar rash, and no malignancy had been reported, although all were children. Several affected children also had dilated or hypertrophic cardiomyopathy, and one had marked muscle mitochondrial DNA depletion, findings attributed to the separate mitochondrial function of TOP3A.

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1
Mappings
1
Inheritance
5
Pathophys.
14
Phenotypes
1
Gaps
11
Pathograph
1
Genes
2
Medical Actions
1
Deep Research
🔗

Mappings

MONDO
MONDO:0034991 intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome Not Yet Curated
skos:closeMatch MONDO
MONDO:0034991 is the Orphanet-derived (ORPHA:508512) phenotype-defined concept whose definition describes this clinical picture without naming a gene. It is kept as a closeMatch rather than an exactMatch because it is defined by phenotype and could include BTRR disorders other than the TOP3A-defined OMIM:618097 entity.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry biallelic TOP3A variants (homozygous in most families, compound heterozygous in one), and all tested parents were heterozygous carriers.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"All variants identified were validated by Sanger capillary sequencing, and all parents were confirmed to be heterozygous carriers."
Biallelic variants in affected children with heterozygous unaffected parents across the index families support autosomal recessive inheritance.
?

Discussions and Knowledge Gaps

1
Do all children with TOP3A Bloom-like disease have impaired mitochondrial DNA maintenance, and does it cause their cardiomyopathy?
KNOWLEDGE GAP mitochondrial_contribution_to_cardiomyopathy
Attached to
phenotypes#Dilated cardiomyopathy phenotypes#Hypertrophic cardiomyopathy phenotypes#Mitochondrial DNA depletion in muscle phenotypes#Hepatomegaly
TOP3A also has a mitochondrial isoform needed to separate replicated mtDNA. Cardiomyopathy is not a Bloom syndrome feature. It occurred in several TOP3A children, and one had 87% muscle mtDNA depletion. Two Bloom-like alleles only partially rescued mtDNA loss in cells, and patient-derived cells from a later family had a respiration defect that a missense allele failed to rescue. Muscle mtDNA was measured in only one index patient, and no study has measured mtDNA in the heart of a Bloom-like patient. The pathograph therefore has no mitochondrial node. These phenotypes are left unconnected until mtDNA maintenance is shown to fail in every case, or the cardiomyopathy is shown to follow from it.
Show evidence (4 references)
PMID:30057030 SUPPORT Human Clinical
"Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation."
The index study links the cardiac and mtDNA findings to the mitochondrial role, as an interpretation.
PMID:29290614 SUPPORT In Vitro
"We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex."
Establishes the mitochondrial decatenation function of TOP3A on which the hypothesis rests.
PMID:37013609 SUPPORT In Vitro
"Both of these Bloom syndrome-associated variants also showed only a limited capacity to ameliorate the mtDNA copy number loss and structural phenotypes associated with TOP3A depletion in rescue experiments."
Two Bloom-like alleles are defective for mtDNA maintenance in a cell rescue system.
+ 1 more reference
⚙

Pathophysiology

5
Biallelic Hypomorphic TOP3A Loss of Function
Most disease alleles are frameshifts expected to undergo nonsense-mediated decay, and patient fibroblasts show markedly reduced full-length topoisomerase III alpha. The index study interprets the alleles as severe hypomorphs rather than nulls, consistent with early embryonic lethality of complete Top3a loss in mice.
TOP3A hgnc:11992 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TOP3A (hgnc:11992). hgnc:11992 is a gene from the HUGO Gene Nomenclature Committee.
topoisomerase III alpha single-strand DNA decatenation activity GO:0003917 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased topoisomerase III alpha single-strand DNA decatenation activity, annotated with DNA topoisomerase type I (single strand cut, ATP-independent) activity (GO:0003917). GO:0003917 is a molecular function from the Gene Ontology.
Downstream
Impaired BTRR Double Holliday Junction Dissolution Reduced TOP3A abundance limits the decatenation step that the BTRR complex needs to dissolve double Holliday junctions.
Show evidence (4 references)
PMID:30057030 SUPPORT In Vitro
"Immunoblotting demonstrated that the amount of full-length TopIIIα was substantially lower in total cell lysates from all three individuals than in cell lines from unrelated control individuals and parents"
Patient-derived dermal fibroblasts (P1, P7, P8) directly show reduced TOP3A protein.
PMID:30057030 SUPPORT In Vitro
"we conclude that all of the identified mutations result in marked but most likely hypomorphic loss of function of TopIIIα as a result of a reduction in the cellular amount of the protein"
The authors' synthesis of the protein and biochemical data classifies the alleles as hypomorphic loss of function.
PMID:37013609 SUPPORT In Vitro
"variants that cause a severe loss of enzymatic activity result in a Bloom syndrome-like disorder with mitochondrial phenotypes in childhood"
Recombinant-enzyme and cellular rescue assays place the Bloom-like alleles at the severe end of TOP3A catalytic impairment.
+ 1 more reference
Impaired BTRR Double Holliday Junction Dissolution
TOP3A, with BLM, RMI1 and RMI2, converts double Holliday junctions into a hemicatenane and then decatenates it, giving only non-crossover products. Loss of TOP3A decatenase capacity leaves these joint molecules to be resolved by structure-specific nucleases or carried into mitosis.
double-strand break repair via homologous recombination GO:0000724 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal double-strand break repair via homologous recombination (GO:0000724). GO:0000724 is a biological process from the Gene Ontology.
Downstream
Excess Sister Chromatid Crossover Recombination Joint molecules that are not dissolved are resolved by nucleases that can generate crossovers between sister chromatids.
Persistent DNA Entanglements in Mitosis Undecatenated recombination or replication intermediates persist as sister-chromatid links into mitosis.
Show evidence (1 reference)
PMID:30057030 SUPPORT BACKGROUND In Vitro
"TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination."
Establishes the normal function of TOP3A that is lost in this disorder.
Excess Sister Chromatid Crossover Recombination
Patient cells undergo excessive crossover recombination between sister chromatids. Elevated sister chromatid exchange on BrdU differential staining is modelled as the cellular readout of this state.
mitotic recombination GO:0006312 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased mitotic recombination (GO:0006312). GO:0006312 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:30057030 SUPPORT In Vitro
"Therefore, excessive crossover recombination was evident in all tested individuals with TOP3A mutations"
SCE assays in patient fibroblasts and stimulated lymphocytes showed crossover hyper-recombination in every individual tested.
PMID:33631320 SUPPORT In Vitro
"TOP3A deficiency moderately increased sister chromatid exchanges and decreased cell proliferation compared with BLM or RMI2 deficiency"
An independent family's cellular studies replicate the SCE increase, while noting it is more moderate than in BLM deficiency.
Persistent DNA Entanglements in Mitosis
TOP3A-deficient patient fibroblasts show increased chromatin bridges, lagging chromatin, and PICH-positive ultrafine DNA bridges at anaphase, reflecting sister-chromatid links that were not removed before mitosis.
Downstream
Chromosome Segregation Errors and Genome Instability Entangled sister chromatids cause segregation errors, micronuclei, and DNA damage carried into the next cell cycle.
Show evidence (1 reference)
PMID:30057030 SUPPORT In Vitro
"Additionally, increased numbers of ultrafine DNA bridges (UFBs) were revealed by immunostaining for PICH on DAPI-negative regions"
Ultrafine bridges in P1 fibroblasts directly visualise persisting sister-chromatid entanglement in mitosis.
Chromosome Segregation Errors and Genome Instability
Patient fibroblasts show more micronucleated cells and more 53BP1 nuclear bodies in G1, markers of chromosome missegregation and of DNA damage transmitted between cell cycles. These measurements come from a single intensively studied patient cell line (P1).
chromosome segregation GO:0007059 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromosome segregation (GO:0007059). GO:0007059 is a biological process from the Gene Ontology.
Downstream
Prenatal growth restriction Genome instability is proposed to reduce cell viability during development, restricting fetal growth. The step from cellular genome instability to reduced developmental cell number has not been demonstrated in human tissue.
Microcephaly The same proposed loss of developmental cell viability is the favoured explanation for reduced head and brain growth; it is not directly demonstrated in developing human brain.
Short stature Postnatal short stature is the continuation of the global growth restriction attributed to genome instability.
Low body weight Postnatal low weight is part of the same global growth restriction.
Show evidence (1 reference)
PMID:30057030 SUPPORT In Vitro
"analysis of DAPI-stained cells demonstrated substantially more micronucleated cells in the P1 fibroblast cell line than in control and parental cell lines"
Micronuclei are a direct cellular consequence of chromosome segregation errors.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Microcephaly, Growth Restriction, and Increased Sister Chromatid Exchange 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Cardiovascular 2
Dilated cardiomyopathy FREQUENT HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30057030 SUPPORT Human Clinical
"P3 and P4 (family 2) had an additional diagnosis of dilated cardiomyopathy, which proved fatal in P4 at age 10 years."
Documents dilated cardiomyopathy, including a fatal case.
PMID:30057030 SUPPORT Human Clinical
"In P5 (family 3), a dilated cardiomyopathy was also reported, and skeletal muscle biopsy demonstrated 87% mitochondrial DNA depletion."
A third patient, from a different family, with dilated cardiomyopathy.
Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"P8 also had asymptomatic left ventricular dilatation noted on echocardiography, whereas P9 had hypertrophic cardiomyopathy."
Documents hypertrophic cardiomyopathy in one patient.
Digestive 2
Gastroesophageal reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"Gastroesophageal reflux | yes | NA | NA | NA | no | yes | no | NA | no | NA"
Table 3 row giving reflux in P1 and P6, with four patients not assessed.
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33631320 SUPPORT Human Clinical
"Beside the common clinical manifestations, our patients exhibited liver lipid storage with hepatomegaly."
Case report of two siblings with TOP3A Bloom-like disorder and hepatomegaly.
Head and Neck 1
Microcephaly VERY_FREQUENT 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:30057030 SUPPORT Human Clinical
"Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly."
Microcephaly is a defining feature of the index cohort.
Immune 1
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"Recurrent infections | yesc | NA | NA | NA | no | no | no | NA | yes | yesd"
Table 3 row giving recurrent infections in P1, P9 and P10.
Integument 2
Multiple cafe-au-lait macules VERY_FREQUENT Multiple cafe-au-lait spots HP:0007565 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple cafe-au-lait macules, annotated with Multiple cafe-au-lait spots (HP:0007565). HP:0007565 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30057030 SUPPORT Human Clinical
"Although multiple café-au-lait patches were present in some individuals with TOP3A mutations, the classical erythematous malar facial rash was not apparent"
Reports multiple cafe-au-lait patches and, as a distinguishing feature from Bloom syndrome, absence of the malar rash.
PMID:30057030 SUPPORT Human Clinical
"Café-au-lait macules | yes | yes | yes | yes | no | yes | no | yes | yes | yes"
Table 3 row giving 8 of 10 TOP3A patients (P1-P10) with cafe-au-lait macules.
Reduced subcutaneous adipose tissue FREQUENT HP:0003758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased subcutaneous fat, annotated with Reduced subcutaneous adipose tissue (HP:0003758). HP:0003758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"Decreased subcutaneous fat | no | no | no | no | no | no | yes | yes | no | yes"
Table 3 row giving decreased subcutaneous fat in P7, P8 and P10.
Nervous System 1
Developmental delay FREQUENT Neurodevelopmental delay HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild developmental delay, annotated with Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"Developmental delay | mild | no | no | no | no | milda | no | mild | no | mild"
Table 3 row giving mild delay in P1, P6 (speech only), P8 and P10.
Cellular 2
Increased sister chromatid exchange VERY_FREQUENT Increased susceptibility to spontaneous sister chromatid exchange HP:0010998 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased sister chromatid exchange, annotated with Increased susceptibility to spontaneous sister chromatid exchange (HP:0010998). HP:0010998 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30057030 SUPPORT In Vitro
"Cells from individuals with TOP3A mutations had substantially (3- to 6-fold) more SCEs, than cells from control individuals or heterozygous parents"
Directly documents the elevated SCE rate in patient cells.
Mitochondrial DNA depletion in muscle Depletion of mitochondrial DNA in muscle tissue HP:0009141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depletion of mitochondrial DNA in muscle tissue (HP:0009141). HP:0009141 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"In P5 (family 3), a dilated cardiomyopathy was also reported, and skeletal muscle biopsy demonstrated 87% mitochondrial DNA depletion."
Direct measurement of muscle mtDNA depletion in one patient.
Growth 3
Prenatal growth restriction VERY_FREQUENT Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prenatal growth restriction, annotated with Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"Prenatal growth restriction was evident from the substantially reduced birth weight in all individuals"
Prenatal-onset growth restriction was present in all ten TOP3A patients.
Short stature VERY_FREQUENT 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:30057030 SUPPORT Human Clinical
"Postnatally, weight (mean −4.8 ± 1.8 SD), height (mean −3.9 ± 1.0 SD), and occipital-frontal circumference (mean −4.0 ± 1.2 SD) were significantly reduced."
Mean postnatal height of -3.9 SD documents short stature across the cohort.
Low body weight VERY_FREQUENT Decreased body weight HP:0004325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low postnatal body weight, annotated with Decreased body weight (HP:0004325). HP:0004325 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"Postnatally, weight (mean −4.8 ± 1.8 SD), height (mean −3.9 ± 1.0 SD), and occipital-frontal circumference (mean −4.0 ± 1.2 SD) were significantly reduced."
Mean postnatal weight of -4.8 SD documents low body weight.
🧬

Genetic Associations

1
TOP3A (Biallelic hypomorphic loss of function)
Gene: TOP3A hgnc:11992 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TOP3A (hgnc:11992). hgnc:11992 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:30057030 SUPPORT Human Clinical
"In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs"
The index study establishes biallelic TOP3A variants as causal.
PMID:30057030 SUPPORT Human Clinical
"Notably, four of the families from the United Arab Emirates, Syria, and Saudi Arabia (F2, F4, F6, and F7), were homozygous for the same variant."
Documents the recurrent homozygous allele across four families.
PMID:33631320 SUPPORT Human Clinical
"We retrospectively studied the disease progression of two siblings with Bloom-like syndrome caused by two novel mutations of TOP3A, p.Q788* and p.D479G."
An independent family replicates TOP3A as the cause of the Bloom-like phenotype.
💊

Medical Actions

2
Heart transplantation
Action: heart transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is heart transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. Ontology label: Heart Transplantation NCIT:C15246
Platform: Surgery
One index patient with dilated cardiomyopathy underwent heart transplantation. This treats end-stage cardiac disease; it does not correct the genetic defect, and no outcome series exists for this disorder.
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"Dilated cardiomyopathy | no | no | yes | yes (severe, deceased) | yes (after heart transplant)"
Table 3 records P5's dilated cardiomyopathy as treated by heart transplantation.
Growth hormone therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: somatropin NCIT:C837 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses somatropin (NCIT:C837). NCIT:C837 is a therapeutic agent from the NCI Thesaurus.
Platform: Protein replacement
One index patient (P8) received growth hormone from age 4 years 3 months to 5 years 11 months without response. Growth hormone is not an established treatment for this disorder.
Show evidence (1 reference)
PMID:30057030 REFUTE Human Clinical
"Growth-hormone treatment from 4 years, 3 months of age to 5 years, 11 months of age showed no response."
A single treated patient showed no growth response, which counts against efficacy.
🔬

Diagnosis

2
Sister chromatid exchange analysis
BrdU differential staining of cultured lymphocytes or fibroblasts shows elevated SCE, as in BLM-related Bloom syndrome. An elevated SCE rate is therefore not specific to BLM and should prompt analysis of the other BTRR genes, including TOP3A.
cytogenetic analysis NCIT:C18280 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:30057030 SUPPORT Human Clinical
"indicating that diagnostic cytogenetic assessment of SCE levels is predictive of TOP3A mutations as well as BLM mutations"
States the diagnostic value of SCE testing for TOP3A disease.
PMID:30057030 SUPPORT Human Clinical
"Hence, analysis of other BTRR components is now warranted when elevated SCEs are detected."
Recommends testing the BTRR genes when SCE is elevated.
Exome sequencing
The causal TOP3A variants in the index families were found by whole-exome sequencing and confirmed by Sanger sequencing.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30057030 SUPPORT Human Clinical
"we subsequently ascertained a further nine individuals from seven families affected by biallelic deleterious TOP3A variants that had also been discovered by WES"
Exome sequencing identified the causal variants.
{ }

Source YAML

click to show 
name: Microcephaly, Growth Restriction, and Increased Sister Chromatid Exchange 2
creation_date: "2026-10-11T00:00:00Z"
category: Mendelian
parents:
- microcephaly, growth restriction and increased sister chromatid exchange
- chromosomal instability syndrome
description: >-
  Microcephaly, growth restriction, and increased sister chromatid exchange 2
  (MGRISCE2) is an autosomal recessive Bloom syndrome-like microcephalic
  primordial dwarfism caused by biallelic hypomorphic variants in TOP3A, which
  encodes topoisomerase III alpha. TOP3A is the decatenase of the
  BLM-TOP3A-RMI1-RMI2 (BTRR) complex that dissolves double Holliday junctions
  without crossover. The index series described ten children from seven
  families with prenatal-onset growth restriction, microcephaly and short
  stature, multiple cafe-au-lait macules, and a 3- to 6-fold increase in
  sister chromatid exchanges in cultured cells. Unlike BLM-related Bloom
  syndrome, none had the photosensitive malar rash, and no malignancy had been
  reported, although all were children. Several affected children also had
  dilated or hypertrophic cardiomyopathy, and one had marked muscle
  mitochondrial DNA depletion, findings attributed to the separate
  mitochondrial function of TOP3A.
disease_term:
  preferred_term: microcephaly, growth restriction, and increased sister chromatid exchange 2
  term:
    id: MONDO:0020628
    label: microcephaly, growth restriction, and increased sister chromatid exchange 2
synonyms:
- MGRISCE2
- TOP3A-related Bloom syndrome-like disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0034991
      label: intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0034991 is the Orphanet-derived (ORPHA:508512) phenotype-defined
      concept whose definition describes this clinical picture without naming
      a gene. It is kept as a closeMatch rather than an exactMatch because it is
      defined by phenotype and could include BTRR disorders other than the
      TOP3A-defined OMIM:618097 entity.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry biallelic TOP3A variants (homozygous in most
    families, compound heterozygous in one), and all tested parents were
    heterozygous carriers.
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All variants identified were validated by Sanger capillary sequencing, and all parents were confirmed to be heterozygous carriers."
    explanation: >-
      Biallelic variants in affected children with heterozygous unaffected
      parents across the index families support autosomal recessive
      inheritance.
pathophysiology:
- name: Biallelic Hypomorphic TOP3A Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Most disease alleles are frameshifts expected to undergo nonsense-mediated
    decay, and patient fibroblasts show markedly reduced full-length
    topoisomerase III alpha. The index study interprets the alleles as severe
    hypomorphs rather than nulls, consistent with early embryonic lethality of
    complete Top3a loss in mice.
  genes:
  - preferred_term: TOP3A
    term:
      id: hgnc:11992
      label: TOP3A
  molecular_functions:
  - preferred_term: topoisomerase III alpha single-strand DNA decatenation activity
    modifier: DECREASED
    term:
      id: GO:0003917
      label: DNA topoisomerase type I (single strand cut, ATP-independent) activity
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunoblotting demonstrated that the amount of full-length TopIIIα was substantially lower in total cell lysates from all three individuals than in cell lines from unrelated control individuals and parents"
    explanation: >-
      Patient-derived dermal fibroblasts (P1, P7, P8) directly show reduced
      TOP3A protein.
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we conclude that all of the identified mutations result in marked but most likely hypomorphic loss of function of TopIIIα as a result of a reduction in the cellular amount of the protein"
    explanation: >-
      The authors' synthesis of the protein and biochemical data classifies
      the alleles as hypomorphic loss of function.
  - reference: PMID:37013609
    reference_title: "Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "variants that cause a severe loss of enzymatic activity result in a Bloom syndrome-like disorder with mitochondrial phenotypes in childhood"
    explanation: >-
      Recombinant-enzyme and cellular rescue assays place the Bloom-like
      alleles at the severe end of TOP3A catalytic impairment.
  - reference: PMID:9448276
    reference_title: "Mammalian DNA topoisomerase IIIalpha is essential in early embryogenesis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "no viable top3alpha-/- homozygotes were found among over 100 progeny of top3alpha+/- intercrosses"
    explanation: >-
      Complete loss of Top3a is embryonic lethal in mice, which is why the
      surviving human genotypes are interpreted as hypomorphic rather than
      null.
  downstream:
  - target: Impaired BTRR Double Holliday Junction Dissolution
    description: >-
      Reduced TOP3A abundance limits the decatenation step that the BTRR
      complex needs to dissolve double Holliday junctions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30057030
      reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Therefore, these mutations would be predicted to severely compromise the decatenation activity of the BTRR complex in dHJ dissolution in vivo."
      explanation: >-
        The authors infer the dissolution defect from the protein loss and
        then test it with the SCE assay (next edge); the sentence itself is a
        prediction.
- name: Impaired BTRR Double Holliday Junction Dissolution
  biological_scale: MOLECULAR
  description: >-
    TOP3A, with BLM, RMI1 and RMI2, converts double Holliday junctions into a
    hemicatenane and then decatenates it, giving only non-crossover products.
    Loss of TOP3A decatenase capacity leaves these joint molecules to be
    resolved by structure-specific nucleases or carried into mitosis.
  biological_processes:
  - preferred_term: double-strand break repair via homologous recombination
    modifier: ABNORMAL
    term:
      id: GO:0000724
      label: double-strand break repair via homologous recombination
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: IN_VITRO
    snippet: "TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination."
    explanation: Establishes the normal function of TOP3A that is lost in this disorder.
  downstream:
  - target: Excess Sister Chromatid Crossover Recombination
    description: >-
      Joint molecules that are not dissolved are resolved by nucleases that
      can generate crossovers between sister chromatids.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30057030
      reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "dissolution by the BTRR complex yields non-crossover products only; second, resolution by endonucleases that cleave Holliday junctions generate both non-crossovers and crossover products that are visualized as SCEs"
      explanation: >-
        States why loss of dissolution shifts processing to a
        crossover-generating route that is read out as SCE.
  - target: Persistent DNA Entanglements in Mitosis
    description: >-
      Undecatenated recombination or replication intermediates persist as
      sister-chromatid links into mitosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30057030
      reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Impaired dHJ decatenation can result in persistently entangled sister chromatids that impede chromosome segregation at mitosis."
      explanation: Links the decatenation defect to persistent mitotic entanglement.
- name: Excess Sister Chromatid Crossover Recombination
  biological_scale: CELLULAR
  description: >-
    Patient cells undergo excessive crossover recombination between sister
    chromatids. Elevated sister chromatid exchange on BrdU differential
    staining is modelled as the cellular readout of this state.
  biological_processes:
  - preferred_term: mitotic recombination
    modifier: INCREASED
    term:
      id: GO:0006312
      label: mitotic recombination
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Therefore, excessive crossover recombination was evident in all tested individuals with TOP3A mutations"
    explanation: >-
      SCE assays in patient fibroblasts and stimulated lymphocytes showed
      crossover hyper-recombination in every individual tested.
  - reference: PMID:33631320
    reference_title: "Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TOP3A deficiency moderately increased sister chromatid exchanges and decreased cell proliferation compared with BLM or RMI2 deficiency"
    explanation: >-
      An independent family's cellular studies replicate the SCE increase,
      while noting it is more moderate than in BLM deficiency.
- name: Persistent DNA Entanglements in Mitosis
  biological_scale: CELLULAR
  description: >-
    TOP3A-deficient patient fibroblasts show increased chromatin bridges,
    lagging chromatin, and PICH-positive ultrafine DNA bridges at anaphase,
    reflecting sister-chromatid links that were not removed before mitosis.
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additionally, increased numbers of ultrafine DNA bridges (UFBs) were revealed by immunostaining for PICH on DAPI-negative regions"
    explanation: >-
      Ultrafine bridges in P1 fibroblasts directly visualise persisting
      sister-chromatid entanglement in mitosis.
  downstream:
  - target: Chromosome Segregation Errors and Genome Instability
    description: >-
      Entangled sister chromatids cause segregation errors, micronuclei, and
      DNA damage carried into the next cell cycle.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30057030
      reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Altogether, we conclude that impaired dHJ decatenation in TopIIIα-deficient cells results in both abnormal recombination and mitotic errors that lead to accumulation of DNA damage."
      explanation: The patient-cell study concludes that the mitotic errors lead to DNA damage accumulation.
- name: Chromosome Segregation Errors and Genome Instability
  biological_scale: CELLULAR
  description: >-
    Patient fibroblasts show more micronucleated cells and more 53BP1 nuclear
    bodies in G1, markers of chromosome missegregation and of DNA damage
    transmitted between cell cycles. These measurements come from a single
    intensively studied patient cell line (P1).
  biological_processes:
  - preferred_term: chromosome segregation
    modifier: ABNORMAL
    term:
      id: GO:0007059
      label: chromosome segregation
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "analysis of DAPI-stained cells demonstrated substantially more micronucleated cells in the P1 fibroblast cell line than in control and parental cell lines"
    explanation: Micronuclei are a direct cellular consequence of chromosome segregation errors.
  downstream:
  - target: Prenatal growth restriction
    description: >-
      Genome instability is proposed to reduce cell viability during
      development, restricting fetal growth. The step from cellular genome
      instability to reduced developmental cell number has not been
      demonstrated in human tissue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30057030
      reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "The resulting genome instability arising from persistent chromatin bridges40, 41 and micronuclei42 could therefore impair cell viability during development, causing microcephaly and global growth restriction."
      explanation: >-
        The authors propose, rather than demonstrate, that genome instability
        causes the growth restriction; the edge is marked as having unknown
        intermediates.
  - target: Microcephaly
    description: >-
      The same proposed loss of developmental cell viability is the favoured
      explanation for reduced head and brain growth; it is not directly
      demonstrated in developing human brain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30057030
      reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "The resulting genome instability arising from persistent chromatin bridges40, 41 and micronuclei42 could therefore impair cell viability during development, causing microcephaly and global growth restriction."
      explanation: The authors' proposed mechanism explicitly names microcephaly.
  - target: Short stature
    description: >-
      Postnatal short stature is the continuation of the global growth
      restriction attributed to genome instability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30057030
      reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome."
      explanation: >-
        The authors attribute the growth restriction, including the postnatal
        component, to genome instability, with an explicit hedge.
  - target: Low body weight
    description: >-
      Postnatal low weight is part of the same global growth restriction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30057030
      reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome."
      explanation: The authors attribute the global growth restriction to genome instability, with an explicit hedge.
phenotypes:
- name: Prenatal growth restriction
  category: Growth
  frequency: VERY_FREQUENT
  description: >-
    Birth weight was reduced in all ten index patients (mean -2.6 SD).
  phenotype_term:
    preferred_term: Prenatal growth restriction
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prenatal growth restriction was evident from the substantially reduced birth weight in all individuals"
    explanation: Prenatal-onset growth restriction was present in all ten TOP3A patients.
- name: Microcephaly
  category: Growth
  frequency: VERY_FREQUENT
  description: >-
    Postnatal occipital-frontal circumference averaged -4.0 SD in the index
    series.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly."
    explanation: Microcephaly is a defining feature of the index cohort.
- name: Short stature
  category: Growth
  frequency: VERY_FREQUENT
  description: >-
    Postnatal height averaged -3.9 SD in the index series, similar to Bloom
    syndrome. Growth hormone treatment in one child gave no response.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postnatally, weight (mean −4.8 ± 1.8 SD), height (mean −3.9 ± 1.0 SD), and occipital-frontal circumference (mean −4.0 ± 1.2 SD) were significantly reduced."
    explanation: Mean postnatal height of -3.9 SD documents short stature across the cohort.
- name: Low body weight
  category: Growth
  frequency: VERY_FREQUENT
  description: Postnatal weight averaged -4.8 SD in the index series.
  phenotype_term:
    preferred_term: Low postnatal body weight
    term:
      id: HP:0004325
      label: Decreased body weight
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postnatally, weight (mean −4.8 ± 1.8 SD), height (mean −3.9 ± 1.0 SD), and occipital-frontal circumference (mean −4.0 ± 1.2 SD) were significantly reduced."
    explanation: Mean postnatal weight of -4.8 SD documents low body weight.
- name: Increased sister chromatid exchange
  category: Cellular
  frequency: VERY_FREQUENT
  description: >-
    Cultured fibroblasts or stimulated lymphocytes from all seven tested index
    patients had 3- to 6-fold more sister chromatid exchanges than controls or
    heterozygous parents. Not tested in the other three.
  phenotype_term:
    preferred_term: Increased sister chromatid exchange
    term:
      id: HP:0010998
      label: Increased susceptibility to spontaneous sister chromatid exchange
  reports_on:
  - target: Excess Sister Chromatid Crossover Recombination
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated SCE on BrdU differential staining is the cytogenetic readout of
      crossover hyper-recombination, not a separate causal step.
    evidence:
    - reference: PMID:30057030
      reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cells from individuals with TOP3A mutations had substantially (3- to 6-fold) more SCEs, than cells from control individuals or heterozygous parents"
      explanation: The SCE assay is the measurement that reports the crossover state.
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cells from individuals with TOP3A mutations had substantially (3- to 6-fold) more SCEs, than cells from control individuals or heterozygous parents"
    explanation: Directly documents the elevated SCE rate in patient cells.
- name: Multiple cafe-au-lait macules
  category: Integument
  frequency: VERY_FREQUENT
  description: >-
    Multiple cafe-au-lait macules were recorded in 8 of 10 index patients.
  phenotype_term:
    preferred_term: Multiple cafe-au-lait macules
    term:
      id: HP:0007565
      label: Multiple cafe-au-lait spots
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although multiple café-au-lait patches were present in some individuals with TOP3A mutations, the classical erythematous malar facial rash was not apparent"
    explanation: >-
      Reports multiple cafe-au-lait patches and, as a distinguishing feature
      from Bloom syndrome, absence of the malar rash.
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Café-au-lait macules | yes | yes | yes | yes | no | yes | no | yes | yes | yes"
    explanation: Table 3 row giving 8 of 10 TOP3A patients (P1-P10) with cafe-au-lait macules.
- name: Developmental delay
  category: Neurological
  frequency: FREQUENT
  description: >-
    Mild developmental delay in 4 of 10 index patients; in one of these it was
    expressive speech delay only.
  phenotype_term:
    preferred_term: Mild developmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay | mild | no | no | no | no | milda | no | mild | no | mild"
    explanation: Table 3 row giving mild delay in P1, P6 (speech only), P8 and P10.
- name: Reduced subcutaneous adipose tissue
  category: Integument
  frequency: FREQUENT
  description: Decreased subcutaneous fat in 3 of 10 index patients.
  phenotype_term:
    preferred_term: Decreased subcutaneous fat
    term:
      id: HP:0003758
      label: Reduced subcutaneous adipose tissue
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased subcutaneous fat | no | no | no | no | no | no | yes | yes | no | yes"
    explanation: Table 3 row giving decreased subcutaneous fat in P7, P8 and P10.
- name: Gastroesophageal reflux
  category: Gastrointestinal
  description: >-
    Reported in 2 of the 6 index patients with an assessment recorded (P1 and
    P6); one (P1) also had a gastrostomy.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastroesophageal reflux | yes | NA | NA | NA | no | yes | no | NA | no | NA"
    explanation: Table 3 row giving reflux in P1 and P6, with four patients not assessed.
- name: Recurrent infections
  category: Immunological
  description: >-
    Reported in 3 index patients (P1, P9, P10): recurrent otitis media and
    tonsillitis, or recurrent upper respiratory tract infections and oral
    thrush. No immunodeficiency has been characterised.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent infections | yesc | NA | NA | NA | no | no | no | NA | yes | yesd"
    explanation: Table 3 row giving recurrent infections in P1, P9 and P10.
- name: Dilated cardiomyopathy
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Dilated cardiomyopathy in 3 of 10 index patients: fatal at age 10 in one,
    treated by heart transplantation in another. An affected brother of two of
    them, not genotyped in the series, died of cardiomyopathy at 13. A fourth
    patient had asymptomatic mild left-ventricular dilatation.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P3 and P4 (family 2) had an additional diagnosis of dilated cardiomyopathy, which proved fatal in P4 at age 10 years."
    explanation: Documents dilated cardiomyopathy, including a fatal case.
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In P5 (family 3), a dilated cardiomyopathy was also reported, and skeletal muscle biopsy demonstrated 87% mitochondrial DNA depletion."
    explanation: A third patient, from a different family, with dilated cardiomyopathy.
- name: Hypertrophic cardiomyopathy
  category: Cardiovascular
  description: Reported in one index patient (P9).
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P8 also had asymptomatic left ventricular dilatation noted on echocardiography, whereas P9 had hypertrophic cardiomyopathy."
    explanation: Documents hypertrophic cardiomyopathy in one patient.
- name: Mitochondrial DNA depletion in muscle
  category: Metabolic
  description: >-
    87% mtDNA depletion in the skeletal muscle of the one index patient
    biopsied (P5, who also had dilated cardiomyopathy). Muscle mtDNA was not
    measured in the other patients, so its frequency is unknown.
  phenotype_term:
    preferred_term: Depletion of mitochondrial DNA in muscle tissue
    term:
      id: HP:0009141
      label: Depletion of mitochondrial DNA in muscle tissue
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In P5 (family 3), a dilated cardiomyopathy was also reported, and skeletal muscle biopsy demonstrated 87% mitochondrial DNA depletion."
    explanation: Direct measurement of muscle mtDNA depletion in one patient.
- name: Hepatomegaly
  category: Gastrointestinal
  description: >-
    Hepatomegaly with hepatic lipid storage was reported in two siblings from
    a later family; it was not described in the index series.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:33631320
    reference_title: "Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Beside the common clinical manifestations, our patients exhibited liver lipid storage with hepatomegaly."
    explanation: Case report of two siblings with TOP3A Bloom-like disorder and hepatomegaly.
genetic:
- name: TOP3A
  association: Biallelic hypomorphic loss of function
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: TOP3A
    term:
      id: hgnc:11992
      label: TOP3A
  notes: >-
    Index alleles (NM_004618.4) were c.2271dup p.(Arg758GlnfsTer3), homozygous
    in four families from the United Arab Emirates, Syria and Saudi Arabia;
    c.2718del p.(Thr907LeufsTer101); c.2428del p.(Ser810LeufsTer2); and
    c.527C>T p.(Ala176Val) in trans with c.1072_1073dup. The original paper
    printed the allele of P9 and P10 as c.2771dup; an author correction
    (PMID:38701747, no quotable text retrieved) gives it as c.2271dup, the
    same recurrent allele. A later family carried p.Gln788Ter and p.Asp479Gly
    (PMID:33631320). No ClinGen gene-disease validity record for this pair
    was found in the local cache, so no validity tier is recorded.
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs"
    explanation: The index study establishes biallelic TOP3A variants as causal.
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, four of the families from the United Arab Emirates, Syria, and Saudi Arabia (F2, F4, F6, and F7), were homozygous for the same variant."
    explanation: Documents the recurrent homozygous allele across four families.
  - reference: PMID:33631320
    reference_title: "Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We retrospectively studied the disease progression of two siblings with Bloom-like syndrome caused by two novel mutations of TOP3A, p.Q788* and p.D479G."
    explanation: An independent family replicates TOP3A as the cause of the Bloom-like phenotype.
diagnosis:
- name: Sister chromatid exchange analysis
  description: >-
    BrdU differential staining of cultured lymphocytes or fibroblasts shows
    elevated SCE, as in BLM-related Bloom syndrome. An elevated SCE rate is
    therefore not specific to BLM and should prompt analysis of the other BTRR
    genes, including TOP3A.
  diagnosis_term:
    preferred_term: cytogenetic analysis
    term:
      id: NCIT:C18280
      label: Cytogenetic Analysis
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "indicating that diagnostic cytogenetic assessment of SCE levels is predictive of TOP3A mutations as well as BLM mutations"
    explanation: States the diagnostic value of SCE testing for TOP3A disease.
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hence, analysis of other BTRR components is now warranted when elevated SCEs are detected."
    explanation: Recommends testing the BTRR genes when SCE is elevated.
- name: Exome sequencing
  description: >-
    The causal TOP3A variants in the index families were found by whole-exome
    sequencing and confirmed by Sanger sequencing.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we subsequently ascertained a further nine individuals from seven families affected by biallelic deleterious TOP3A variants that had also been discovered by WES"
    explanation: Exome sequencing identified the causal variants.
treatments:
- name: Heart transplantation
  description: >-
    One index patient with dilated cardiomyopathy underwent heart
    transplantation. This treats end-stage cardiac disease; it does not
    correct the genetic defect, and no outcome series exists for this
    disorder.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dilated cardiomyopathy | no | no | yes | yes (severe, deceased) | yes (after heart transplant)"
    explanation: Table 3 records P5's dilated cardiomyopathy as treated by heart transplantation.
- name: Growth hormone therapy
  description: >-
    One index patient (P8) received growth hormone from age 4 years 3 months
    to 5 years 11 months without response. Growth hormone is not an
    established treatment for this disorder.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Growth-hormone treatment from 4 years, 3 months of age to 5 years, 11 months of age showed no response."
    explanation: A single treated patient showed no growth response, which counts against efficacy.
discussions:
- discussion_id: mitochondrial_contribution_to_cardiomyopathy
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Dilated cardiomyopathy
  - phenotypes#Hypertrophic cardiomyopathy
  - phenotypes#Mitochondrial DNA depletion in muscle
  - phenotypes#Hepatomegaly
  prompt: >-
    Do all children with TOP3A Bloom-like disease have impaired mitochondrial
    DNA maintenance, and does it cause their cardiomyopathy?
  rationale: >-
    TOP3A also has a mitochondrial isoform needed to separate replicated mtDNA.
    Cardiomyopathy is not a Bloom syndrome feature. It occurred in several
    TOP3A children, and one had 87% muscle mtDNA depletion. Two Bloom-like
    alleles only partially rescued mtDNA loss in cells, and patient-derived
    cells from a later family had a respiration defect that a missense allele
    failed to rescue. Muscle mtDNA was measured in only one index patient, and
    no study has measured mtDNA in the heart of a Bloom-like patient. The
    pathograph therefore has no mitochondrial node. These phenotypes are left
    unconnected until mtDNA maintenance is shown to fail in every case, or the
    cardiomyopathy is shown to follow from it.
  evidence:
  - reference: PMID:30057030
    reference_title: "Mutations in TOP3A Cause a Bloom Syndrome-like Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation."
    explanation: The index study links the cardiac and mtDNA findings to the mitochondrial role, as an interpretation.
  - reference: PMID:29290614
    reference_title: "Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex."
    explanation: Establishes the mitochondrial decatenation function of TOP3A on which the hypothesis rests.
  - reference: PMID:37013609
    reference_title: "Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both of these Bloom syndrome-associated variants also showed only a limited capacity to ameliorate the mtDNA copy number loss and structural phenotypes associated with TOP3A depletion in rescue experiments."
    explanation: Two Bloom-like alleles are defective for mtDNA maintenance in a cell rescue system.
  - reference: PMID:33631320
    reference_title: "Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, reduced mitochondrial ATP generation and oxygen consumption rates observed in TOP3A defective cells were rescued by over-expression of the wildtype TOP3A, but not TOP3A-D479G."
    explanation: Patient-cell respiration defect that a Bloom-like allele fails to rescue.
notes: >-
  Scope. This entry covers the childhood Bloom syndrome-like TOP3A disorder
  (OMIM:618097). It is kept separate from BLM-related Bloom syndrome
  (Bloom_Syndrome), which models the shared BTRR dissolution mechanism
  through BLM loss. Adult-onset TOP3A mitochondrial disease (ptosis, external
  ophthalmoplegia, myopathy, axonal neuropathy, multiple mtDNA deletions) has
  its own MONDO concept: MONDO:0020845, progressive external ophthalmoplegia
  with mitochondrial DNA deletions, autosomal recessive 5 (OMIM:618098). MONDO
  links TOP3A by RO:0004003 to both concepts, so that disease is not folded in
  here. The same applies to the childhood mitochondrial presentations without
  Bloom-like features (cardiomyopathy, Leigh-like disease, hearing loss)
  described by PMID:42478104, PMID:41075683 and PMID:42481970. EMBO Mol Med
  2023 (PMID:37013609) proposes that the Bloom-like presentation reflects more
  severe catalytic loss than the mitochondrial presentations. The
  mitochondrial phenotypes reported in Bloom-like patients (cardiomyopathy,
  muscle mtDNA depletion) are kept as phenotypes of this entry. They are not
  wired to a mechanism node; see the mitochondrial_contribution_to_cardiomyopathy
  discussion. No malignancy had been reported at publication, but all index
  patients were under 16 years old, and cancer risk is not established.
  No GeneReviews or StatPearls chapter names this disorder: `just
  check-genereviews --online` returned NO_CHAPTER for both against the
  2026-09-10 Bookshelf index and a live PubMed title search.
📚

References & Deep Research

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: Microcephaly, Growth Restriction, and Increased Sister Chromatid Exchange 2 · 2026-10-11T20:27:11Z · View source

New entry for MONDO:0020628 (OMIM:618097), the biallelic TOP3A Bloom syndrome-like disorder, curated from the Perplexity deep-research report (the only DR source; 20/20 references resolved, no unresolved terms) and primary papers. just preflight-dr returned PASS (TOP3A mentioned 44 times; OMIM 618097 matched). just check-genereviews --online returned NO_CHAPTER for GeneReviews and StatPearls. The full text of the index paper (PMID:30057030) and of PMID:37013609 was retrieved from PMC by a forced refetch; phenotype frequencies and several snippets are taken from the index paper's Table 3 rows and body text. Pathophysiology is a chain from hypomorphic TOP3A loss through impaired BTRR double Holliday junction dissolution to crossover hyper-recombination (read out as SCE) and persistent mitotic entanglement, chromosome segregation errors and genome instability, with edges to growth restriction, microcephaly, short stature and low weight marked INDIRECT_UNKNOWN_INTERMEDIATES because the source proposes rather than demonstrates that step. Scope decision: adult-onset TOP3A mitochondrial disease has its own MONDO concept (MONDO:0020845, PEOB5, OMIM:618098) and is not folded in; the childhood mitochondrial-only TOP3A presentations are also excluded. Cardiomyopathy, muscle mtDNA depletion and hepatomegaly are kept as phenotypes but are not wired to a mitochondrial mechanism node, because mtDNA maintenance failure is not shown for every case; a KNOWLEDGE_GAP discussion records the hypothesis and evidence. MONDO:0034991 (Orphanet 508512) is mapped as closeMatch. Not cited: the 2024 report of two Egyptian children (no PubMed record found; the DR-cached DOI abstract does not mention TOP3A) and PMID:38701747 (author correction, no quotable text retrieved; mentioned in genetic notes). PMID:40556620 was fetched by a search mistake, is unrelated, and was deleted. Validation: just validate passed with 47/47 snippets; validate-terms passed; count-verified-snippets 47/47; check-entity-refs, check-causal-targets, check-duplicate-keys and check-block-scalar-comments clean; 4/14 phenotypes causally connected (SCE is connected as a readout, which the metric does not count).

Perplexity ▸
Microcephaly, growth restriction, and increased sister chromatid exchange 2
sonar-deep-research 53 citations 2026-10-11T20:09:27.670472

Microcephaly, growth restriction, and increased sister chromatid exchange 2

MGRISCE2 (MONDO:0020628; OMIM:618097) is a rare, autosomal-recessive, TOP3A-related disorder of prenatal and postnatal growth and genome maintenance. Its defining combination is fetal growth restriction, persistent short stature and microcephaly, and increased sister-chromatid exchanges (SCEs) in tested cells. Some affected children also develop cardiomyopathy or other evidence of mitochondrial dysfunction. It resembles Bloom syndrome but is genetically distinct; the characteristic Bloom-syndrome malar rash was absent from the original TOP3A cohort. The foundational report described 10 affected people from seven families. [41][41][12]

Scope of evidence. Frequencies below describe small, clinically ascertained cohorts—not population frequencies. “MGRISCE2” is used here for the childhood Bloom-like TOP3A phenotype, not for the distinct, often adult-onset TOP3A-associated progressive external ophthalmoplegia/mitochondrial phenotype. Unless stated otherwise, findings are aggregated from publications and disease resources; they are not individual electronic health records. [41][50][12]

1. Disease information and identifiers

Identifier or name Value and interpretation
Preferred name Microcephaly, growth restriction, and increased sister chromatid exchange 2; abbreviation MGRISCE2. [12]
MONDO MONDO:0020628. [12][14]
OMIM phenotype / gene 618097 / TOP3A 601243, respectively. [41][107]
NCBI MedGen C4748176, UID 1648384. [12]
Orphanet OMIM lists ORPHA:508512 as a cross-reference. Orphanet calls the entry “intrauterine growth restriction–congenital multiple café-au-lait macules–increased sister chromatid exchange syndrome”; its broader phenotype-based description should not be treated as proof that every case has TOP3A-defined MGRISCE2. [41][221][256]
Alternative clinical name TOP3A-related Bloom syndrome-like disorder or Bloom-like microcephalic dwarfism; these are descriptive names, not Bloom syndrome caused by BLM. [41][59]
ICD-10/ICD-11 and MeSH No verified, disease-specific code or heading was established by the sources reviewed. Code the documented manifestations where required rather than inventing an MGRISCE2-specific code.

2. Etiology, risk, protection, and environment

Cause. Disease-associated biallelic germline TOP3A variants impair topoisomerase IIIα. Its nuclear activity helps the BLM–TOP3A–RMI1–RMI2 (BTRR) complex dissolve DNA-recombination intermediates without crossover; its mitochondrial activity helps separate replicated mitochondrial DNA (mtDNA). The original families showed segregation consistent with recessive inheritance. BLM, RMI1, and RMI2 cause overlapping disorders or are pathway partners; they are not additional established causal genes for the specifically TOP3A-defined OMIM:618097 entry. [41][50][41]

Risk factors. The established risk is inheriting pathogenic or likely pathogenic TOP3A alleles on both homologous chromosomes. A family history or parental consanguinity can increase the chance of such an inheritance pattern; neither establishes the diagnosis. The recurrent c.2271dup allele occurred in families from several Middle Eastern countries and later in two unrelated Egyptian children, but these observations do not establish a population-specific prevalence, carrier frequency, or proven founder effect. No validated susceptibility locus, modifier gene, protective variant, or sex-specific genetic risk has been demonstrated. [41][128][41]

Environmental and infectious factors. No toxin, infection, diet, smoking exposure, maternal age effect, or other environmental factor has been established as a cause of this Mendelian disorder; no protective diet, exposure, vaccine, or gene–environment interaction has been validated for it. Environmental causes of microcephaly or growth restriction in general must not be imported into this disease entry. Ordinary cardiac, nutritional, and infection care may still affect an individual’s complications. [41][41]

3. Phenotypes and their functional impact

The following frequencies use the original 10 TOP3A-affected individuals as the denominator unless specified. “Reported in n/10” is a count of positive reports, not an estimated penetrance: several features were not assessed or were marked unavailable. Ages at examination ranged from 5 months to 15 years. HPO codes are suggested annotation terms; a term’s presence in an ontology is not independent confirmation of frequency. [41]

Phenotype; type; suggested HPO Onset, severity, course, and evidence in affected people Likely day-to-day impact or qualification
Fetal growth restriction; prenatal clinical sign; HP:0001511 10/10 reported in the original series. Mean birth-weight Z score −2.6 ± 0.9; evident before birth. Later reports include two Egyptian children with strikingly different birth weights, illustrating variability. [41][128] Signals an early, persistent growth disorder; individual feeding and growth needs require assessment.
Decreased body weight and short stature; growth signs; HP:0004325, HP:0004322 Poor postnatal growth 10/10; mean weight −4.8 ± 1.8 SD, height −3.9 ± 1.0 SD in the original series. Chronic rather than episodic. [41] May affect nutrition, physical stamina, equipment sizing, and psychosocial well-being; disease-specific quality-of-life scores are unavailable.
Microcephaly; physical sign; HP:0000252 10/10 in the original series; mean occipital-frontal circumference −4.0 ± 1.2 SD at assessment. Generally apparent early, though measurements at birth were incomplete. [41] Calls for developmental assessment; head size alone does not establish cognitive outcome.
Increased spontaneous SCE; cytogenetic laboratory abnormality; HP:0010998 Present in all seven original patients tested; cultured patient cells had approximately 3–6 times control SCE rates. Not tested in the other three. The later Egyptian report did not provide individual SCE measurements. [41][128][130] Useful diagnostic evidence of cellular genome instability; generally not itself a symptom.
Multiple café-au-lait macules; skin sign; HP:0000957 Reported in 8/10 original patients; severity and evolution were not systematically quantified. Both subsequently reported Egyptian children also had multiple macules. [41][128][168] Visible skin finding; not diagnostic on its own.
Dilated cardiomyopathy; cardiac sign; HP:0001644 Reported in three original patients; one died at age 10 years with severe disease and another had undergone heart transplantation. A fourth had mild, asymptomatic left-ventricular dilatation, which should not automatically be coded as dilated cardiomyopathy. [41][170] Can dominate morbidity and survival; warrants individual cardiac assessment.
Hypertrophic cardiomyopathy; cardiac sign; HP:0001639 Reported in one original patient; it should not be merged with dilated cardiomyopathy. [41][134] Potential cardiac functional risk; longitudinal severity is unknown.
Mild developmental or expressive-speech delay; developmental/behavioral sign; HP:0001263 only when global delay is documented Four of 10 had mild delay; one was described as having expressive-speech delay only, for which a speech-specific HPO term is more accurate than global delay. No uniform progressive intellectual decline was established. [41][170] May affect communication or learning; standardized functional or quality-of-life scores were not reported.
Reduced subcutaneous adipose tissue; physical sign; HP:0003758 3/10 reported; distribution and progression were not established. [41][292] May contribute to appearance or nutritional concern; metabolic lipodystrophy should not be assumed.
Recurrent infections; clinical history; HP:0002719 Reported in three original patients, with assessment unavailable for others. Examples included otitis/tonsillitis and upper-respiratory infections/oral thrush. A primary human immunodeficiency has not been established. [41][171] Episodic illness and healthcare use where present.
Gastroesophageal reflux; symptom; HP:0002020 Reported in two original patients; others had missing or negative assessments. [41][290] May aggravate feeding difficulty or discomfort.
Muscle mtDNA depletion; laboratory/pathology abnormality; HP:0009141 Measured in one original MGRISCE2 patient: 87% depletion. It was not systematically tested across the cohort. [41][131] Supports mitochondrial involvement; neither universal nor sufficient alone for this diagnosis.
Feeding difficulty, atrial septal defect, pectus excavatum; later clinical observations; HP:0011968 for feeding difficulty The two Egyptian children had feeding difficulties and pectus excavatum; one had an atrial septal defect. These observations expand the reported findings but are too few to establish characteristic frequencies. [128][304] Feeding needs should be assessed; structural cardiac findings need their own clinical evaluation.
Hepatomegaly with hepatic lipid storage; later clinical/pathology observation Described in two additional siblings with a Bloom-like TOP3A disorder, not quantified in the original ten. [175] Possible hepatic involvement; not an established universal feature.
Absence of classic malar rash; useful differential feature 0/10 original TOP3A patients had the classic Bloom-syndrome malar rash. This is a cohort observation, not a guarantee of lifelong absence. A database listing “malar rash” as a positive MGRISCE2 feature conflicts with the primary clinical report. [41][41][139] Helps distinguish conditions clinically but cannot replace molecular testing.

Quality of life: No MGRISCE2-specific EQ-5D, SF-36, PROMIS, or validated natural-history quality-of-life estimates were identified. The impacts above are clinical interpretations of the reported impairments, not measured scores. [41]

4. Genetic and molecular information

TOP3A (HGNC:11992; NCBI Gene:7156; OMIM:601243) lies at 17p11.2. The principal disease-associated alleles are germline frameshifts or a missense variant paired with a frameshift. Transcript notation below follows NM_004618.4 as reported in the original paper; clinical laboratories should normalize against their stated transcript, such as NM_004618.5. Pathogenicity is variant-specific, and a variant of uncertain significance must not be promoted to pathogenic solely because it occurs in TOP3A. [14][238][41][50]

Reported disease-associated TOP3A variant or genotype Class, evidence, and interpretation
c.2271dup; p.Arg758GlnfsTer3, homozygous Recurrent frameshift in six original patients from four families; also homozygous in two unrelated Egyptian children reported online in December 2024. ClinVar Variation 560203 records a germline pathogenic aggregate classification. A ClinVar submitter reports gnomAD v2.1.1 overall frequency 0.005% and Finnish-subpopulation frequency 0.02%; these version-specific figures must not be treated as a current global carrier frequency. A 2024 correction clarifies that the original paper’s “c.2771dup” for patients P9/P10 was a typo: it is c.2271dup. [41][128][225][126]
c.2718del; p.Thr907LeufsTer101, homozygous C-terminal frameshift in one original patient. The original protein work found low abundance but retained activity when purified protein was supplied at equal concentration; later reanalysis detected a stable truncated protein, refining a simple “all protein absent” interpretation. [41][270]
c.2428del; p.Ser810LeufsTer2, homozygous Frameshift in two original siblings; associated with loss of the C-terminal region. The 2023 study found that a purified C-terminal truncation could retain single-stranded-DNA decatenation in one assay despite impaired cellular mitochondrial rescue: different assays probe different functions. [41][50]
c.[527C>T];[1072_1073dup]; p.[Ala176Val];[Tyr359GlyfsTer17], compound heterozygous One original patient. In 2023 assays p.Ala176Val bound DNA but had strongly impaired decatenation; 2025 biochemical testing of a different complex/assay found near-wild-type behavior and questioned whether this substitution is independently pathogenic. Record the genotype and conflicting functional evidence, rather than asserting a settled standalone ACMG classification for p.Ala176Val. [41][50][270]
p.Gln788Ter / p.Asp479Gly, reported together in two siblings Additional 2021 Bloom-like family. Patient-cell experiments separated partly preserved nuclear-genome readouts from defective mitochondrial respiration; detailed clinical ACMG classification should be checked against the individual variant records. [175]

The 2023 study’s 11 people from nine families with predominantly adult-onset mitochondrial disease are valuable genotype–function comparators, not 11 additional MGRISCE2 patients. The authors propose that more severe overall TOP3A defects tend toward childhood Bloom-like disease, whereas milder combinations can produce later mitochondrial disease. This is a model, not a validated severity predictor for a newly diagnosed child. [50]

Other molecular annotations. No disease-specific modifier allele, recurrent constitutional translocation/aneuploidy, diagnostic DNA-methylation signature, or established transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial, or multi-omics patient signature was identified. Mitotic missegregation and micronuclei are cellular consequences, not evidence of a defining constitutional karyotype. [41][41]

5. Environmental information

MGRISCE2 is not an infectious disease and has no demonstrated zoonotic, toxic-exposure, or lifestyle cause. The relevant non-genetic context is management of consequences—adequate nutrition, standard infection prevention and care, and monitoring of cardiac disease—rather than a demonstrated exposure that switches the TOP3A phenotype on or off. Specific chemicals should not be assigned a causal CHEBI disease annotation without such evidence. [41][41]

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic TOP3A lesions lead to reduced or altered topoisomerase IIIα activity in the nucleus and, for some genotypes, mitochondria. Protein abundance, C-terminal DNA binding, and catalytic defects differ by allele; complete enzyme absence is not established for every patient. Upstream lesion; demonstrated in patient material and biochemical studies. [41][50][270]
  2. Nuclear TOP3A dysfunction leads to less effective BTRR-mediated dissolution of double Holliday junctions and other linked DNA intermediates; alternative processing results in more crossover products, observed as elevated SCEs. Pathway demonstrated biochemically; patient SCE increase demonstrated. [41][59]
  3. Persistence of DNA links into mitosis leads to chromosome-segregation defects and DNA-damage markers: patient fibroblasts showed chromatin/ultrafine bridges, lagging chromosomes, micronuclei, and 53BP1 nuclear bodies. Demonstrated in cells from one intensively studied patient. [41]
  4. Accumulated genome instability is inferred to reduce developmental cell survival or proliferative capacity, leading to fetal growth restriction and microcephaly. The cellular abnormalities and clinical phenotype are observed; the precise causal cell-loss sequence in the developing human brain has not been directly demonstrated. [41]
  5. Mitochondrial branch: impaired mitochondrial TOP3A leads to defective decatenation/separation of replicated mtDNA, which can result in mtDNA depletion or instability and reduced mitochondrial energy production; this is a plausible contributor to cardiomyopathy and other organ findings, not a proven cause of every affected heart phenotype. Human muscle depletion and patient-cell respiration defects support this branch. [60][41][175]
  6. Additional experimentally induced branch—not established as the MGRISCE2 lesion: a self-trapping engineered TOP3A variant leads to trapped TOP3A–DNA cleavage complexes, fork-associated DNA damage, and repair through SPRTN–TDP2 or ATM–MRE11 pathways. These 2023 cell-model findings clarify TOP3A biology but must not be annotated as demonstrated in MGRISCE2 patient cells. [364]

Cellular and biochemical detail. BLM drives branch migration; TOP3A, assisted by RMI1/RMI2, performs the final DNA unlinking. SCE is an especially useful readout because normal dissolution favors non-crossover products. Mitochondrial TOP3A acts apart from the nuclear BTRR partners. In 2023, TOP3A knockdown in a cell-rescue experiment reduced mtDNA copy number by approximately 75%, reversible with wild-type TOP3A; the authors’ assays showed genotype-dependent differences in DNA binding, relaxation, decatenation, and mtDNA rescue. These are in-vitro findings, not a patient treatment response. [41][50]

Important 2025 refinement: an engineered C-terminally truncated mouse protein and reexamined human fibroblasts showed that some truncations produce detectable shortened protein, rather than necessarily undergoing complete nonsense-mediated decay. The C-terminal domain contributed to DNA binding; homozygous mutant mouse embryos developed profound mtDNA depletion and died early. This strengthens the mitochondrial-developmental hypothesis while demonstrating a significant human–mouse phenotype difference. [270][336]

Suggested mechanistic annotations: GO GO:0000724 (double-strand-break repair via homologous recombination), GO:0007059 (chromosome segregation), and GO:0006915 (apoptotic process; supported in the mutant-mouse model, not measured as a human-brain lesion). Candidate CL terms are CL:0000057 (fibroblast; directly studied), CL:0000746 (cardiac muscle cell; organ-level clinical involvement), and CL:0000047 (neuronal stem cell; inferred developmental target, not directly proven in patients). These are process/cell-type suggestions, not claims that a particular signaling cascade such as Wnt, MAPK, or mTOR has been established. [41][270][146][152][319]

7. Anatomical structures affected

Level Established observation and suggested annotation
Organs and systems Whole-body fetal/postnatal growth, head/central nervous system, heart, skin, and—in selected cases—skeletal muscle/mitochondrial function and gastrointestinal tract. Suggested UBERON: UBERON:0000948 heart, UBERON:0001134 skeletal muscle tissue. UBERON:0000956 cerebral cortex is a possible developmental site, not a demonstrated site of MGRISCE2-specific pathology. [41][147]
Tissues and cells Patient dermal fibroblasts and cultured blood cells provided direct evidence of genome instability; muscle biopsy provided one mtDNA result. Cardiomyocytes (CL:0000746), skeletal-muscle cells (CL:0000188), and neural stem cells (CL:0000047) are plausible tissues/cells for the corresponding manifestations, but were not all examined directly in affected humans. [41][325][152]
Subcellular Nucleus, GO:0005634 and mitochondrion, GO:0005739 are the functionally relevant TOP3A locations; chromosomes/mitotic DNA bridges and mitochondrial nucleoids are relevant structures. [50][324]
Laterality The growth and genome-instability findings are systemic; no characteristic unilateral or asymmetric brain lesion is established. The two Egyptian children were described as having asymmetry, without evidence that lateralization defines the disorder. [41][128]

8. Temporal development

Onset is prenatal and insidious, followed by chronic poor growth through childhood. There is no validated stage classification, typical remission, or measured rate of progression. Microcephaly and short stature persisted across the original 5-month-to-15-year age range, while cardiac disease varied substantially and could become life-threatening in childhood. The fetal period is the most clearly documented period of vulnerability; the benefit of any disease-specific intervention during a proposed “critical window” has not been tested. Do not substitute the decades-later onset pattern of TOP3A-associated ophthalmoplegia for MGRISCE2 natural history. [41][50]

9. Inheritance, epidemiology, and population

Inheritance is autosomal recessive: homozygous and compound-heterozygous affected genotypes were reported, with parents identified as carriers in the original families. If both parents carry a disease-causing allele, the conventional recessive risk per pregnancy is 25% affected, 50% carrier, and 25% neither familial allele. Penetrance, variant-specific expressivity, germline-mosaicism rates, anticipation, and a population carrier frequency have not been quantified; clinical expressivity is visibly variable, especially cardiac involvement. [41][41]

Prevalence and incidence per 100,000 are unknown. Ten affected individuals from seven families were reported in 2018, two further siblings in 2021, and two unrelated Egyptian children in a study published online in December 2024; these are published ascertainments, not a complete registry or an incidence numerator. Original patients came from multiple countries and ancestries. The original 7 female:3 male count is too small and selected to define a sex ratio. Recurrent c.2271dup is not proof of an exclusive ethnic distribution. [41][175][128][41]

10. Diagnostics

Practical diagnostic approach: document prenatal and postnatal growth parameters and head circumference; examine skin and development; assess cardiac symptoms and obtain echocardiography when clinically indicated or when establishing baseline involvement. If the phenotype suggests a chromosome-instability disorder, a laboratory experienced with SCE cytogenetics can test cultured blood cells or fibroblasts. Confirm the diagnosis with two pathogenic/likely pathogenic TOP3A variants in trans, interpreted with segregation, current variant standards, and the phenotype. Seven of seven original patients who had SCE testing showed elevation, but that small series does not establish test sensitivity. [41][41]

Genetic test selection: exome sequencing identified variants in the original families; genome sequencing found homozygous c.2271dup in the two Egyptian children after an initial work-up for an imprinting-disorder-like growth phenotype. A microcephaly/growth-failure or genome-instability panel including TOP3A and the differential genes BLM, RMI1, and RMI2, or exome/genome sequencing, is reasonable according to the clinical breadth. Targeted familial-variant testing is appropriate once both familial alleles are known. Chromosomal microarray, karyotyping, and FISH can investigate other suspected chromosomal diagnoses but do not substitute for sequencing the typical small TOP3A variants; mtDNA analysis may characterize selected muscle/cardiac presentations but does not replace nuclear-TOP3A testing. No validated disease-specific RNA-seq, proteomic, metabolomic, epigenomic, or liquid-biopsy diagnostic is established. [41][128][7][41]

Differential diagnosis: BLM-related Bloom syndrome shares growth failure and high SCE but classically has a photosensitive malar rash; RMI1/RMI2-related BTRR disorders can overlap; and other primordial-dwarfism, imprinting, or mitochondrial conditions can resemble individual components. High SCE is not BLM-specific. Conversely, adult-onset TOP3A mitochondrial disease can have normal stature and no elevated SCE, so a TOP3A result must be interpreted against its allele combination and clinical presentation. No formal MGRISCE2 diagnostic scoring criteria or population newborn screen was identified. [41][50][128]

11. Outcomes and prognosis

Prognosis is individually variable and not quantifiable as a survival rate. One of the original ten genetically described patients died from severe dilated cardiomyopathy at age 10; another affected brother was reported to have died of cardiomyopathy at age 13, but was not among the ten fully characterized cases. Another patient had received a heart transplant. The cohort is too small and young to calculate 5-year survival, life expectancy, or disease-attributable mortality rates. [41]

No malignancy had occurred among the original ten at publication, but they were all aged 15 or younger. Bloom syndrome raises a biologically relevant concern, not a measured MGRISCE2 cancer penetrance. A cervical cancer in the early 30s was noted in a 2023 TOP3A mitochondrial-disease cohort; it cannot establish a cancer rate for the childhood MGRISCE2 group. Long-term developmental disability rates, validated quality-of-life outcomes, recovery probabilities, and prognostic biomarkers are unavailable. Severe cardiomyopathy is an evident adverse clinical feature, but no validated risk model predicts it from genotype. [41][50]

12. Treatment and current clinical application

There is no established TOP3A-restoring drug or proven disease-modifying treatment for MGRISCE2. Management is coordinated, manifestation-directed care rather than a genotype-guided drug algorithm. The table separates observed interventions from reasonable clinical applications that have not been evaluated in MGRISCE2 trials. [41]

Intervention; suggested NCIT term Evidence and use
Cardiac evaluation and standard cardiomyopathy care; Echocardiography Test, NCIT:C16525 Cardiac involvement ranged from asymptomatic ventricular dilatation to fatal cardiomyopathy in the original cohort. The timing and choice of medicines or devices must follow the individual cardiac findings; no MGRISCE2-specific drug-response rate or pharmacogenomic rule exists. [41][360]
Heart transplantation; Heart Transplantation, NCIT:C15246 Observed in one original patient with dilated cardiomyopathy. This is treatment of severe organ disease, not correction of the genetic defect; no MGRISCE2 transplant response series is available. [41][360]
Growth and nutritional support; NCIT terminology to be selected for the actual nutrition intervention Individualized feeding assessment is reasonable for marked growth failure or reflux. One child received growth hormone from age 4 years 3 months to 5 years 11 months without response; growth hormone is not an established MGRISCE2 treatment. [41][128]
Developmental, speech, physical, or occupational support; intervention-specific NCIT terms as applicable Reasonable when delay or functional limitations are documented; the original cohort provides no controlled efficacy or adverse-event estimates for these interventions. [41]
Genetic counseling; NCIT:C15240 Explains biallelic inheritance, variant interpretation, cascade testing, and reproductive options. It is a clinical service, not a molecular cure. [41][350]

No MGRISCE2-specific approved gene, cell, RNA, targeted, or immune therapy—or disease-specific NCT-numbered interventional result—was established in the reviewed evidence. Research-cell rescue by introducing wild-type TOP3A is experimental functional evidence, not a treatment administered to patients. Drug classes, combination regimens, adverse-event rates, and pharmacogenomic recommendations cannot responsibly be specified as disease-specific without clinical studies. [175][50][41]

13. Prevention and screening

Primary prevention of a child’s inherited genotype is not achieved by vaccination, diet, or toxin avoidance. For a family with established pathogenic variants, genetic counseling (NCIT:C15240), carrier/cascade testing, and discussion of prenatal or preimplantation genetic testing offer reproductive risk assessment and options. These are options, not a claim that all families choose or have access to them. [41][350]

Secondary prevention means timely recognition of poor fetal/postnatal growth, diagnostic evaluation, developmental assessment, and attention to possible cardiac disease. Tertiary prevention is management of cardiomyopathy, feeding/reflux problems, and other individual complications. There is no established population newborn-screening program, MGRISCE2-specific vaccine, chemoprophylaxis, or validated cancer-surveillance schedule; extrapolation from Bloom syndrome should be discussed explicitly as extrapolation. [41][41]

14. Other species and naturally occurring disease

The human condition occurs in Homo sapiens (NCBI Taxon:9606). Orthologous Top3a/top3a genes have been studied in mouse (Mus musculus, 10090; mouse NCBI Gene 21975), zebrafish (Danio rerio, 7955), and fruit fly (Drosophila melanogaster, 7227). These are experimental models, not verified naturally occurring companion-animal or breed-associated MGRISCE2. No veterinary breed/VBO association or zoonotic transmission applies to the inherited human disorder. [381][247][384]

15. Model organisms and research uses

Model and evidence type Finding, degree of recapitulation, and limitation
Patient-derived fibroblasts and blood cells; human ex vivo, PMID 30057030 Low full-length TOP3A in tested cells, 3–6-fold elevated SCE, and, in one extensively examined fibroblast line, mitotic bridges/micronuclei. Directly models cellular features but not a developing human brain or full natural history. [41]
Patient-cell biochemical and engineered-cell rescue systems; in vitro, PMID 37013609 (2023) Distinguished nuclear and mitochondrial isoforms and tested allele-dependent DNA binding, relaxation, decatenation, and mtDNA rescue. Supports a severity-dependent genotype–phenotype hypothesis; engineered-cell responses are not clinical response rates. [50]
Top3a knockout mouse; induced mammalian model, PMID 9448276 Early embryonic lethality demonstrates essential developmental function. A complete knockout cannot reproduce the survival of affected humans with residual or altered TOP3A function. [204][387]
C-terminal-truncation Top3a mouse, created by CRISPR; induced mammalian model, PMID 40450688 (2025) Designed to mimic the consequence of common patient truncations. Homozygotes were small, accumulated DNA damage and apoptosis, had approximately 90% mtDNA depletion by embryonic day 6.5, and lost viability around day 7.5. It models the molecular/developmental insult but not the postnatal human phenotype. [270][270][225]
Zebrafish top3a deleterious alleles; induced vertebrate model, PMID 20623552 Revealed impaired developing thymocytes and a p53-dependent checkpoint, without an observed V(D)J-recombination defect. Useful for tissue sensitivity; it does not establish primary immunodeficiency in human MGRISCE2 or reproduce the whole syndrome. [237]
Fruit-fly top3α mutants and isoform-rescue experiments; induced invertebrate model, PMID 20308575 Null alleles caused delayed development and lethality; mitochondrial-function experiments demonstrated mtDNA maintenance and germ-line consequences. Conserves TOP3A biology but fly reproductive findings should not be assigned as human clinical phenotypes. [193][379]

Evidence interpretation and key abstract wording. The foundational human study states, “Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly” and reports that the mutations reduce cellular TopIIIα with elevated SCE (Martin et al., published July 26, 2018; PMID:30057030; https://pubmed.ncbi.nlm.nih.gov/30057030/). [59] The subsequent human/biochemical study describes “11 individuals from 9 families with an adult-onset mitochondrial disease” and proposes that the overall severity of catalytic impairment helps determine the distinct clinical outcomes (published April 4, 2023; PMID:37013609; https://pubmed.ncbi.nlm.nih.gov/37013609/). Those 11 are comparators, not MGRISCE2 prevalence data. [50][70] The corrected variant notation for original patients P9/P10 was published May 2, 2024; PMID:38701747 (https://pmc.ncbi.nlm.nih.gov/articles/PMC11080603/). [115][51]

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 20
Resolved 20
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 20
On topic 7
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 36
Resolved 30
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 6

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, ORPHA, Gene, Taxon.

30 of 36 terms resolved to a current term; the rest could not be looked up either way.