Mosaic Variegated Aneuploidy Syndrome

Mendelian MONDO:0000141 Pathograph 16 chromosomal disorder hereditary neoplastic syndrome

Mosaic variegated aneuploidy syndrome is a rare chromosomal instability disorder in which pathogenic germline variants in mitotic checkpoint or centrosome-associated genes impair faithful chromosome segregation. The resulting constitutional mosaic aneuploidy causes antenatal or neonatal-onset growth and neurodevelopmental abnormalities, variable congenital anomalies, and cancer predisposition, especially Wilms tumor and rhabdomyosarcoma in spindle-assembly-checkpoint-defective forms.

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1
Mappings
1
Definitions
2
Inheritance
6
Pathophys.
25
Phenotypes
16
Pathograph
5
Genes
3
Treatments
3
Subtypes
1
Deep Research
🔗

Mappings

MONDO
MONDO:0000141 mosaic variegated aneuploidy syndrome
skos:exactMatch Orphanet ORPHA:1052
Orphanet ORPHA:1052 lists MONDO:0000141 as an exact cross-reference for Mosaic variegated aneuploidy syndrome.
📘

Definitions

1
Orphanet Mosaic variegated aneuploidy syndrome definition
A rare chromosomal anomaly syndrome characterized by multiple mosaic aneuploidies, variable congenital and neurodevelopmental abnormalities, and cancer predisposition.
OTHER
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal anomaly characterized by multiple mosaic aneuploidies that leads to a variety of phenotypic abnormalities and cancer predisposition."
Orphanet defines the core chromosomal, clinical, and cancer-predisposition features.
👪

Inheritance

2
Autosomal recessive inheritance HP:0000007
Most molecularly characterized MVA forms are autosomal recessive, including biallelic BUB1B-, CEP57-, and TRIP13-related disease.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance for MVA syndrome.
PMID:15475955 SUPPORT Human Clinical
"Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses."
The BUB1B gene-discovery paper directly describes MVA as a recessive condition.
Autosomal dominant inheritance HP:0000006
Orphanet also records an autosomal dominant inheritance mode, reflecting rarer dominant chromosomal-instability presentations grouped under the MVA syndrome record.
Autosomal dominant inheritance
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance for the MVA syndrome record.
◆

Subtypes

3
BUB1B-related mosaic variegated aneuploidy
Spindle-assembly-checkpoint-defective MVA caused by BUB1B pathogenic variants, with constitutional mosaic aneuploidy and increased embryonal and gastrointestinal tumor risk.
Show evidence (1 reference)
PMID:15475955 SUPPORT Human Clinical
"In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B"
The original report identifies BUB1B mutations in MVA families.
CEP57-related mosaic variegated aneuploidy syndrome 2
CEP57-related MVA is associated with growth retardation, facial features, endocrine, cardiovascular, and skeletal abnormalities; reported cohorts have not shown the same embryonal-tumor enrichment as BUB1B or TRIP13 disease.
Show evidence (1 reference)
PMID:34500087 SUPPORT Human Clinical
"Mosaic Variegated Aneuploidy Syndrome 2 (MVA2; MIM 614114) is a rare autosomal recessive disorder, characterized by mosaic aneuploidies involving multiple chromosomes and tissues, caused by biallelic pathogenic variants in the CEP57 gene."
This review defines the CEP57-related MVA2 subtype.
TRIP13-related mosaic variegated aneuploidy
TRIP13-related MVA has severe spindle-assembly-checkpoint impairment and a high Wilms tumor risk in reported biallelic loss-of-function cases.
Show evidence (1 reference)
PMID:28553959 SUPPORT Human Clinical
"Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor."
This paper identifies TRIP13-related MVA with Wilms tumor predisposition.
⚙

Pathophysiology

6
Mitotic checkpoint gene disruption
MVA syndrome is caused by disease-causing germline variants in genes that support the spindle assembly checkpoint, centrosome function, or faithful chromosome segregation, including BUB1B, CEP57, TRIP13, BUB1, and BUB3.
BUB1 link BUB1B link BUB3 link CEP57 link TRIP13 link
mitotic spindle assembly checkpoint signaling link ↓ DECREASED
Downstream
Spindle assembly checkpoint impairment Mutations in checkpoint genes reduce checkpoint activity and kinetochore-associated control of mitosis.
CEP57 centrosomal kinetochore attachment defects CEP57-related MVA acts through centrosomal and kinetochore-attachment biology rather than severe SAC impairment.
Show evidence (4 references)
ORPHA:1052 SUPPORT Other
"BUB1B | BUB1 mitotic checkpoint serine/threonine kinase B | hgnc:1149 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline BUB1B mutations in MVA syndrome.
ORPHA:1052 SUPPORT Other
"CEP57 | centrosomal protein 57 | hgnc:30794 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline CEP57 mutations in MVA syndrome.
PMID:32884756 SUPPORT Human Clinical
"Mosaic variegated aneuploidy (MVA) is a rare genetic disorder caused by mutations in BUB1B, CEP57, or TRIP13."
This clinical case report summarizes the three established MVA genes at the time.
+ 1 more reference
Spindle assembly checkpoint impairment
BUB1B and TRIP13 pathogenic variants reduce spindle assembly checkpoint proficiency, disrupt chromosome alignment or kinetochore-microtubule attachment, and permit chromosome missegregation during mitosis.
mitotic spindle assembly checkpoint signaling link ↓ DECREASED attachment of spindle microtubules to kinetochore link ⚠ ABNORMAL
Downstream
Chromosome segregation errors and mosaic aneuploidy Checkpoint impairment permits chromosome missegregation, producing constitutional mosaic gains and losses.
Show evidence (2 references)
PMID:20516114 SUPPORT In Vitro
"Ectopic expression of BUBR1 restored mitotic checkpoint activity, proving that BUBR1 dysfunction causes chromosome segregation errors in the patients."
Rescue of patient-cell checkpoint activity by BUBR1 expression supports checkpoint impairment as causal.
PMID:28553959 SUPPORT In Vitro
"TRIP13-mutant patient cells have no detectable TRIP13 and have substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation."
TRIP13-mutant patient cells directly show SAC impairment leading to missegregation.
CEP57 centrosomal kinetochore attachment defects
CEP57-related MVA involves a centrosomal protein required for kinetochore attachment. Reported CEP57 patient cells show minimal SAC deficiency compared with BUB1B- or TRIP13-mutant cells, supporting a distinct centrosomal and kinetochore-attachment route to chromosome missegregation.
CEP57 link
attachment of spindle microtubules to kinetochore link ⚠ ABNORMAL
Downstream
Chromosome segregation errors and mosaic aneuploidy Kinetochore-attachment defects compromise faithful chromosome segregation and contribute to mosaic aneuploidy.
Show evidence (2 references)
PMID:28553959 SUPPORT Human Clinical
"More recently we identified biallelic mutations in CEP57, which encodes a centrosomal protein involved in kinetochore attachment, in four individuals with MVA, none of whom have developed cancer"
The paper defines CEP57-related MVA as a centrosomal kinetochore-attachment disorder.
PMID:28553959 SUPPORT In Vitro
"severe SAC impairment was observed in TRIP13-mutant and BUB1B-mutant patient cells but not in cells from patients with CEP57 mutations"
Patient-cell data support CEP57-related disease as mechanistically distinct from the severe SAC-defective BUB1B/TRIP13 forms.
Chromosome segregation errors and mosaic aneuploidy
Failed mitotic fidelity produces multiple aneuploid cell lines involving different chromosomes and tissues; cytogenetic studies may show premature chromatid separation and repeated mosaic trisomies or monosomies.
chromosome segregation link ⚠ ABNORMAL
Downstream
Growth and neurodevelopmental abnormalities Constitutional chromosomal mosaicism is associated with prenatal growth restriction, microcephaly, developmental delay, and brain malformations.
Cancer predisposition Aneuploidy and checkpoint defects create a constitutional tumor-predisposition state.
Show evidence (3 references)
ORPHA:1052 SUPPORT Other
"Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal anomaly characterized by multiple mosaic aneuploidies"
Orphanet identifies multiple mosaic aneuploidies as the defining chromosomal abnormality.
PMID:16059936 SUPPORT Human Clinical
"The MVA syndrome is associated with mosaicism for several different aneuploidies involving many different chromosomes with or without premature centromere division (PCD)."
This clinical report describes the diagnostic pattern of several different aneuploidies.
PMID:25696020 SUPPORT Human Clinical
"Repeat amniocentesis at 21 weeks' gestation consistently showed the presence of multiple mosaic autosomal variegated aneuploidies."
Prenatal testing directly documented multiple mosaic autosomal variegated aneuploidies.
Growth and neurodevelopmental abnormalities
Constitutional mosaic aneuploidy manifests with prenatal and postnatal growth restriction, microcephaly or other brain anomalies, developmental delay, intellectual disability, seizures, and variable ocular and craniofacial abnormalities.
Downstream
Microcephaly MVA commonly includes reduced head size.
Global developmental delay MVA commonly includes developmental delay.
Dandy-Walker malformation MVA can include posterior fossa developmental brain malformations.
Show evidence (2 references)
PMID:25696020 SUPPORT Human Clinical
"The phenotype of MVA syndrome includes severe microcephaly and growth deficiency, central nervous system anomalies, mental retardation, mild physical anomalies, and predisposition to cancer."
This literature review supports the core growth and neurodevelopmental phenotype group.
PMID:32861809 SUPPORT Human Clinical
"Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy."
The CEP57 report supports the recurrent growth, craniofacial, developmental, cancer, and epilepsy features.
Cancer predisposition
MVA confers cancer predisposition. BUB1B- and TRIP13-related disease is especially associated with embryonal tumors such as Wilms tumor and rhabdomyosarcoma, while adult gastrointestinal cancers have also been reported in BUB1B-related disease.
Downstream
Nephroblastoma Wilms tumor is a characteristic embryonal tumor risk in TRIP13- and BUB1B-related MVA.
Rhabdomyosarcoma Embryonal rhabdomyosarcoma was present in BUB1B-related MVA families.
Show evidence (3 references)
ORPHA:1052 SUPPORT Other
"cancer predisposition."
Orphanet includes cancer predisposition in the disease definition.
PMID:28553959 SUPPORT Human Clinical
"Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors"
The TRIP13 paper supports high embryonal tumor risk for TRIP13- and BUB1B-related MVA.
PMID:21190457 SUPPORT Human Clinical
"Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers"
This case extends BUB1B-related MVA tumor predisposition to adult-onset gastrointestinal cancers.
⬡

Pathograph

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

Phenotypes

25
Digestive 1
Ascites VERY_FREQUENT Ascites (HP:0001541)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0001541 | Ascites | Very frequent (99-80%)"
Orphanet records ascites as very frequent in MVA syndrome.
Eye 4
Cataract VERY_FREQUENT Cataract (HP:0000518)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0000518 | Cataract | Very frequent (99-80%)"
Orphanet records cataract as very frequent in MVA syndrome.
Microphthalmia VERY_FREQUENT Microphthalmia (HP:0000568)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0000568 | Microphthalmia | Very frequent (99-80%)"
Orphanet records microphthalmia as very frequent in MVA syndrome.
Glaucoma VERY_FREQUENT Glaucoma (HP:0000501)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0000501 | Glaucoma | Very frequent (99-80%)"
Orphanet records glaucoma as very frequent in MVA syndrome.
Corneal opacity VERY_FREQUENT Corneal opacity (HP:0007957)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0007957 | Corneal opacity | Very frequent (99-80%)"
Orphanet records corneal opacity as very frequent in MVA syndrome.
Genitourinary 1
Nephroblastoma OCCASIONAL Nephroblastoma (HP:0002667)
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"HP:0002667 | Nephroblastoma | Occasional (29-5%)"
Orphanet records nephroblastoma as occasional in MVA syndrome.
PMID:28553959 SUPPORT Human Clinical
"Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor."
This case series directly supports Wilms tumor predisposition in TRIP13-related MVA.
Head and Neck 4
Epicanthus VERY_FREQUENT Epicanthus (HP:0000286)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0000286 | Epicanthus | Very frequent (99-80%)"
Orphanet records epicanthus as very frequent in MVA syndrome.
Micrognathia VERY_FREQUENT Micrognathia (HP:0000347)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0000347 | Micrognathia | Very frequent (99-80%)"
Orphanet records micrognathia as very frequent in MVA syndrome.
Triangular face FREQUENT Triangular face (HP:0000325)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0000325 | Triangular face | Frequent (79-30%)"
Orphanet records triangular face as frequent in MVA syndrome.
Microcephaly FREQUENT Microcephaly (HP:0000252)
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"HP:0000252 | Microcephaly | Frequent (79-30%)"
Orphanet records microcephaly as frequent in MVA syndrome.
PMID:16059936 SUPPORT Human Clinical
"From this case report, we suggest that microcephaly is not mandatory for the diagnosis of MVA syndrome."
This report supports microcephaly as common but not required.
Musculoskeletal 1
Muscular dystrophy VERY_FREQUENT Muscular dystrophy (HP:0003560)
Retained because ORPHA:1052 lists HP:0003560 as very frequent, but this frequency is not corroborated by the primary MVA literature cited in this entry and should be treated as an Orphanet assertion requiring future verification.
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0003560 | Muscular dystrophy | Very frequent (99-80%)"
Orphanet records muscular dystrophy as very frequent in MVA syndrome.
Nervous System 4
Global developmental delay FREQUENT Global developmental delay (HP:0001263)
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"HP:0001263 | Global developmental delay | Frequent (79-30%)"
Orphanet records global developmental delay as frequent in MVA syndrome.
PMID:32861809 SUPPORT Human Clinical
"Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy."
The CEP57 report supports developmental delay as part of the typical MVA phenotype.
Intellectual disability FREQUENT Intellectual disability (HP:0001249)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0001249 | Intellectual disability | Frequent (79-30%)"
Orphanet records intellectual disability as frequent in MVA syndrome.
Ventriculomegaly VERY_FREQUENT Ventriculomegaly (HP:0002119)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0002119 | Ventriculomegaly | Very frequent (99-80%)"
Orphanet records ventriculomegaly as very frequent in MVA syndrome.
Seizure OCCASIONAL Seizure (HP:0001250)
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"HP:0001250 | Seizure | Occasional (29-5%)"
Orphanet records seizures as occasional in MVA syndrome.
PMID:23916859 SUPPORT Human Clinical
"Clinical features also include prenatal-onset growth retardation, microcephaly, mild dysmorphism, feeding difficulty, hypotonia, seizures, and developmental delay."
This neurologic case report lists seizures among MVA clinical features.
Prenatal and Birth 1
Polyhydramnios VERY_FREQUENT Polyhydramnios (HP:0001561)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0001561 | Polyhydramnios | Very frequent (99-80%)"
Orphanet records polyhydramnios as very frequent in MVA syndrome.
Growth 2
Short stature VERY_FREQUENT Short stature (HP:0004322)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0004322 | Short stature | Very frequent (99-80%)"
Orphanet records short stature as very frequent in MVA syndrome.
Intrauterine growth retardation OCCASIONAL Intrauterine growth retardation (HP:0001511)
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"HP:0001511 | Intrauterine growth retardation | Occasional (29-5%)"
Orphanet records intrauterine growth retardation as occasional in MVA syndrome.
PMID:32861809 SUPPORT Human Clinical
"Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy."
The CEP57 report supports intrauterine and postnatal growth retardation in MVA.
Neoplasm 1
Neoplasm OCCASIONAL Neoplasm (HP:0002664)
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"HP:0002664 | Neoplasm | Occasional (29-5%)"
Orphanet records neoplasm as occasional in MVA syndrome.
PMID:15475955 SUPPORT Human Clinical
"Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses."
The BUB1B gene-discovery paper identifies childhood cancer as part of the syndrome.
Other 6
Dandy-Walker malformation VERY_FREQUENT Dandy-Walker malformation (HP:0001305)
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"HP:0001305 | Dandy-Walker malformation | Very frequent (99-80%)"
Orphanet records Dandy-Walker malformation as very frequent in MVA syndrome.
PMID:25696020 SUPPORT Human Clinical
"Ultrasonography at 21 weeks' gestation revealed relatively small head circumference for gestational age (<3%) and vermis defect, suggesting that the fetus would have microcephaly and Dandy-Walker malformation."
Prenatal ultrasound in this MVA fetus supported Dandy-Walker malformation.
Ocular abnormalities FREQUENT Abnormality of the eye (HP:0000478)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0000478 | Abnormality of the eye | Frequent (79-30%)"
Orphanet records abnormality of the eye as frequent in MVA syndrome.
Abnormality of vision FREQUENT Abnormality of vision (HP:0000504)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0000504 | Abnormality of vision | Frequent (79-30%)"
Orphanet records abnormality of vision as frequent in MVA syndrome.
Increased nuchal translucency VERY_FREQUENT Increased nuchal translucency (HP:0010880)
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"HP:0010880 | Increased nuchal translucency | Very frequent (99-80%)"
Orphanet records increased nuchal translucency as very frequent in MVA syndrome.
Rhabdomyosarcoma OCCASIONAL Rhabdomyosarcoma (HP:0002859)
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"HP:0002859 | Rhabdomyosarcoma | Occasional (29-5%)"
Orphanet records rhabdomyosarcoma as occasional in MVA syndrome.
PMID:15475955 SUPPORT Human Clinical
"In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B"
The BUB1B gene-discovery paper reports embryonal rhabdomyosarcoma in two MVA families.
Acute lymphoblastic leukemia OCCASIONAL Acute lymphoblastic leukemia (HP:0006721)
Show evidence (3 references)
ORPHA:1052 SUPPORT Other
"HP:0006721 | Acute lymphoblastic leukemia | Occasional (29-5%)"
Orphanet records acute lymphoblastic leukemia as occasional in MVA syndrome.
PMID:20516114 SUPPORT Human Clinical
"37% of patients develop cancers including rhadomyosarcoma, Wilms tumor and leukemia, mostly within the first 3 years of life"
This review of MVA patients reports leukemia among early-onset cancers.
PMID:32884756 SUPPORT Human Clinical
"Wilms tumor, rhabdomyosarcoma, leukemia and granulosa cell tumor of the ovary."
This clinical management discussion lists leukemia among BUB1B-associated MVA tumors.
🧬

Genetic Associations

5
BUB1B germline pathogenic variants
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"BUB1B | BUB1 mitotic checkpoint serine/threonine kinase B | hgnc:1149 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline BUB1B mutations.
PMID:15475955 SUPPORT Human Clinical
"we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint."
This gene-discovery paper identifies BUB1B/BUBR1 mutations in MVA.
CEP57 germline pathogenic variants
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"CEP57 | centrosomal protein 57 | hgnc:30794 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline CEP57 mutations.
PMID:34500087 SUPPORT Human Clinical
"Mosaic Variegated Aneuploidy Syndrome 2 (MVA2; MIM 614114) is a rare autosomal recessive disorder, characterized by mosaic aneuploidies involving multiple chromosomes and tissues, caused by biallelic pathogenic variants in the CEP57 gene."
This review identifies biallelic CEP57 pathogenic variants as causal for MVA2.
TRIP13 germline pathogenic variants
Show evidence (2 references)
ORPHA:1052 SUPPORT Other
"TRIP13 | thyroid hormone receptor interactor 13 | hgnc:12307 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline TRIP13 mutations.
PMID:28553959 SUPPORT Human Clinical
"Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor."
This study identifies biallelic TRIP13 loss-of-function mutations in affected individuals.
BUB1 germline pathogenic variants
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"BUB1 | BUB1 mitotic checkpoint serine/threonine kinase | hgnc:1148 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline BUB1 mutations in MVA syndrome.
BUB3 germline pathogenic variants
Show evidence (1 reference)
ORPHA:1052 SUPPORT Other
"BUB3 | BUB3 mitotic checkpoint protein | hgnc:1151 | Disease-causing germline mutation(s) in"
Orphanet records disease-causing germline BUB3 mutations in MVA syndrome.
💊

Treatments

3
Symptomatic supportive care
Action: supportive care MAXO:0000950
Management is supportive and tailored to the patient's developmental, neurologic, endocrine, skeletal, ocular, and congenital-anomaly burden.
Show evidence (1 reference)
PMID:32884756 SUPPORT Human Clinical
"Clinical management of patients with MVA syndrome includes symptomatic support and tumor surveillance, particularly for BUB1B subtype."
The long-term follow-up report supports symptomatic supportive care as part of clinical management.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling is indicated because MVA is usually inherited, may be detected prenatally, and has recurrence-risk implications for families.
Show evidence (1 reference)
PMID:23916859 SUPPORT Human Clinical
"Awareness of this disorder is important not only for proper diagnosis but also for genetic counseling of the family."
This case report explicitly supports genetic counseling as part of MVA management.
Cancer surveillance
Action: clinical assessment MAXO:0000487
Longitudinal tumor surveillance is biologically and clinically justified in checkpoint-defective MVA, especially for Wilms tumor and rhabdomyosarcoma in BUB1B- or TRIP13-related disease.
Show evidence (2 references)
PMID:28553959 SUPPORT Human Clinical
"Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors"
High embryonal tumor risk supports subtype-aware cancer surveillance.
PMID:32884756 SUPPORT Human Clinical
"Clinical management of patients with MVA syndrome includes symptomatic support and tumor surveillance, particularly for BUB1B subtype."
This clinical management statement directly supports tumor surveillance, especially for BUB1B-related MVA.
{ }

Source YAML

click to show 
name: Mosaic Variegated Aneuploidy Syndrome
creation_date: '2026-05-11T15:52:05Z'
updated_date: '2026-05-11T15:52:05Z'
category: Mendelian
description: >
  Mosaic variegated aneuploidy syndrome is a rare chromosomal instability
  disorder in which pathogenic germline variants in mitotic checkpoint or
  centrosome-associated genes impair faithful chromosome segregation. The
  resulting constitutional mosaic aneuploidy causes antenatal or neonatal-onset
  growth and neurodevelopmental abnormalities, variable congenital anomalies,
  and cancer predisposition, especially Wilms tumor and rhabdomyosarcoma in
  spindle-assembly-checkpoint-defective forms.
disease_term:
  preferred_term: Mosaic variegated aneuploidy syndrome
  term:
    id: MONDO:0000141
    label: mosaic variegated aneuploidy syndrome
parents:
- chromosomal disorder
- hereditary neoplastic syndrome
synonyms:
- MVA syndrome
- Warburton-Anyane-Yeboa syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0000141
      label: mosaic variegated aneuploidy syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:1052
    mapping_justification: >
      Orphanet ORPHA:1052 lists MONDO:0000141 as an exact cross-reference for
      Mosaic variegated aneuploidy syndrome.
external_assertions:
- name: Orphanet Mosaic variegated aneuploidy syndrome record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:1052
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=1052
  description: >
    Orphanet's ORPHA:1052 structured record provides the disease definition,
    inheritance, onset, epidemiology, disease-gene assertions, MONDO and OMIM
    mappings, and HPO phenotype rows used in this curation.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0000141 | Exact"
    explanation: Orphanet maps ORPHA:1052 exactly to the MONDO identifier used here.
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:257300 | Exact"
    explanation: Orphanet maps ORPHA:1052 exactly to the classic OMIM MVA syndrome record.
definitions:
- name: Orphanet Mosaic variegated aneuploidy syndrome definition
  definition_type: OTHER
  description: >
    A rare chromosomal anomaly syndrome characterized by multiple mosaic
    aneuploidies, variable congenital and neurodevelopmental abnormalities, and
    cancer predisposition.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal anomaly characterized by multiple mosaic aneuploidies that leads to a variety of phenotypic abnormalities and cancer predisposition."
    explanation: Orphanet defines the core chromosomal, clinical, and cancer-predisposition features.
inheritance:
- name: Autosomal recessive inheritance
  description: >
    Most molecularly characterized MVA forms are autosomal recessive, including
    biallelic BUB1B-, CEP57-, and TRIP13-related disease.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance for MVA syndrome.
  - reference: PMID:15475955
    reference_title: "Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses."
    explanation: The BUB1B gene-discovery paper directly describes MVA as a recessive condition.
- name: Autosomal dominant inheritance
  description: >
    Orphanet also records an autosomal dominant inheritance mode, reflecting
    rarer dominant chromosomal-instability presentations grouped under the MVA
    syndrome record.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for the MVA syndrome record.
prevalence:
- population: Worldwide
  percentage: <1 per 1,000,000
  notes: Orphanet records point prevalence below one per million worldwide.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet records worldwide point prevalence below one per million.
progression:
- phase: Antenatal to neonatal onset
  age_range: Antenatal to neonatal
  notes: >
    Growth restriction, brain malformations, or multiple mosaic aneuploidies can
    be detected prenatally, while neurodevelopmental and tumor-predisposition
    manifestations require longitudinal care.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Antenatal"
    explanation: Orphanet records antenatal onset.
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset.
has_subtypes:
- name: BUB1B-related MVA
  display_name: BUB1B-related mosaic variegated aneuploidy
  description: >
    Spindle-assembly-checkpoint-defective MVA caused by BUB1B pathogenic
    variants, with constitutional mosaic aneuploidy and increased embryonal and
    gastrointestinal tumor risk.
  evidence:
  - reference: PMID:15475955
    reference_title: "Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B"
    explanation: The original report identifies BUB1B mutations in MVA families.
- name: CEP57-related MVA
  display_name: CEP57-related mosaic variegated aneuploidy syndrome 2
  description: >
    CEP57-related MVA is associated with growth retardation, facial features,
    endocrine, cardiovascular, and skeletal abnormalities; reported cohorts have
    not shown the same embryonal-tumor enrichment as BUB1B or TRIP13 disease.
  evidence:
  - reference: PMID:34500087
    reference_title: "Mosaic Variegated Aneuploidy syndrome 2 caused by biallelic variants in CEP57, two new cases and review of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mosaic Variegated Aneuploidy Syndrome 2 (MVA2; MIM 614114) is a rare autosomal recessive disorder, characterized by mosaic aneuploidies involving multiple chromosomes and tissues, caused by biallelic pathogenic variants in the CEP57 gene."
    explanation: This review defines the CEP57-related MVA2 subtype.
- name: TRIP13-related MVA
  display_name: TRIP13-related mosaic variegated aneuploidy
  description: >
    TRIP13-related MVA has severe spindle-assembly-checkpoint impairment and a
    high Wilms tumor risk in reported biallelic loss-of-function cases.
  evidence:
  - reference: PMID:28553959
    reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor."
    explanation: This paper identifies TRIP13-related MVA with Wilms tumor predisposition.
pathophysiology:
- name: Mitotic checkpoint gene disruption
  description: >
    MVA syndrome is caused by disease-causing germline variants in genes that
    support the spindle assembly checkpoint, centrosome function, or faithful
    chromosome segregation, including BUB1B, CEP57, TRIP13, BUB1, and BUB3.
  genes:
  - preferred_term: BUB1
    term:
      id: hgnc:1148
      label: BUB1
  - preferred_term: BUB1B
    term:
      id: hgnc:1149
      label: BUB1B
  - preferred_term: BUB3
    term:
      id: hgnc:1151
      label: BUB3
  - preferred_term: CEP57
    term:
      id: hgnc:30794
      label: CEP57
  - preferred_term: TRIP13
    term:
      id: hgnc:12307
      label: TRIP13
  biological_processes:
  - preferred_term: mitotic spindle assembly checkpoint signaling
    modifier: DECREASED
    term:
      id: GO:0007094
      label: mitotic spindle assembly checkpoint signaling
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BUB1B | BUB1 mitotic checkpoint serine/threonine kinase B | hgnc:1149 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline BUB1B mutations in MVA syndrome.
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CEP57 | centrosomal protein 57 | hgnc:30794 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline CEP57 mutations in MVA syndrome.
  - reference: PMID:32884756
    reference_title: "Prenatal diagnosis and long-term follow-up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mosaic variegated aneuploidy (MVA) is a rare genetic disorder caused by mutations in BUB1B, CEP57, or TRIP13."
    explanation: This clinical case report summarizes the three established MVA genes at the time.
  - reference: PMID:32884756
    reference_title: "Prenatal diagnosis and long-term follow-up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in BUB1B, CEP57, and TRIP13 genes, which are involved in mitotic spindle and microtubule stabilization, are responsible for the molecular pathogenesis of MVA."
    explanation: Asta retrieval highlighted this full-text passage, which directly links the core genes to mitotic spindle and microtubule biology.
  downstream:
  - target: Spindle assembly checkpoint impairment
    description: Mutations in checkpoint genes reduce checkpoint activity and kinetochore-associated control of mitosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20516114
      reference_title: "Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "cell lines derived from MVA patients with biallelic mutations have an impaired mitotic checkpoint, chromosome alignment defects, and low overall BUBR1 abundance."
      explanation: Patient-derived cell lines show impaired mitotic checkpoint function downstream of BUBR1/BUB1B dysfunction.
  - target: CEP57 centrosomal kinetochore attachment defects
    description: CEP57-related MVA acts through centrosomal and kinetochore-attachment biology rather than severe SAC impairment.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28553959
      reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "More recently we identified biallelic mutations in CEP57, which encodes a centrosomal protein involved in kinetochore attachment, in four individuals with MVA, none of whom have developed cancer"
      explanation: This establishes CEP57-related MVA as a centrosomal kinetochore-attachment subtype distinct from the severe SAC-defective tumor-predisposition forms.
- name: Spindle assembly checkpoint impairment
  description: >
    BUB1B and TRIP13 pathogenic variants reduce spindle assembly checkpoint
    proficiency, disrupt chromosome alignment or kinetochore-microtubule
    attachment, and permit chromosome missegregation during mitosis.
  biological_processes:
  - preferred_term: mitotic spindle assembly checkpoint signaling
    modifier: DECREASED
    term:
      id: GO:0007094
      label: mitotic spindle assembly checkpoint signaling
  - preferred_term: attachment of spindle microtubules to kinetochore
    modifier: ABNORMAL
    term:
      id: GO:0008608
      label: attachment of spindle microtubules to kinetochore
  evidence:
  - reference: PMID:20516114
    reference_title: "Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ectopic expression of BUBR1 restored mitotic checkpoint activity, proving that BUBR1 dysfunction causes chromosome segregation errors in the patients."
    explanation: Rescue of patient-cell checkpoint activity by BUBR1 expression supports checkpoint impairment as causal.
  - reference: PMID:28553959
    reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TRIP13-mutant patient cells have no detectable TRIP13 and have substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation."
    explanation: TRIP13-mutant patient cells directly show SAC impairment leading to missegregation.
  downstream:
  - target: Chromosome segregation errors and mosaic aneuploidy
    description: Checkpoint impairment permits chromosome missegregation, producing constitutional mosaic gains and losses.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28553959
      reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Accurate segregation, as well as SAC proficiency, is rescued by restoring TRIP13 function."
      explanation: Restoration of TRIP13 rescues chromosome segregation in patient cells, supporting this causal edge.
- name: CEP57 centrosomal kinetochore attachment defects
  description: >
    CEP57-related MVA involves a centrosomal protein required for kinetochore
    attachment. Reported CEP57 patient cells show minimal SAC deficiency compared
    with BUB1B- or TRIP13-mutant cells, supporting a distinct centrosomal and
    kinetochore-attachment route to chromosome missegregation.
  genes:
  - preferred_term: CEP57
    term:
      id: hgnc:30794
      label: CEP57
  biological_processes:
  - preferred_term: attachment of spindle microtubules to kinetochore
    modifier: ABNORMAL
    term:
      id: GO:0008608
      label: attachment of spindle microtubules to kinetochore
  evidence:
  - reference: PMID:28553959
    reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More recently we identified biallelic mutations in CEP57, which encodes a centrosomal protein involved in kinetochore attachment, in four individuals with MVA, none of whom have developed cancer"
    explanation: The paper defines CEP57-related MVA as a centrosomal kinetochore-attachment disorder.
  - reference: PMID:28553959
    reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "severe SAC impairment was observed in TRIP13-mutant and BUB1B-mutant patient cells but not in cells from patients with CEP57 mutations"
    explanation: Patient-cell data support CEP57-related disease as mechanistically distinct from the severe SAC-defective BUB1B/TRIP13 forms.
  downstream:
  - target: Chromosome segregation errors and mosaic aneuploidy
    description: Kinetochore-attachment defects compromise faithful chromosome segregation and contribute to mosaic aneuploidy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28553959
      reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Many biological processes, including spindle assembly, chromatid-spindle attachment, attachment error-correction, and the spindle assembly checkpoint (SAC) are involved in ensuring chromosome segregation proceeds flawlessly and that aneuploidy is prevented"
      explanation: This mechanistic overview links chromatid-spindle attachment and error correction to prevention of aneuploidy.
- name: Chromosome segregation errors and mosaic aneuploidy
  description: >
    Failed mitotic fidelity produces multiple aneuploid cell lines involving
    different chromosomes and tissues; cytogenetic studies may show premature
    chromatid separation and repeated mosaic trisomies or monosomies.
  biological_processes:
  - preferred_term: chromosome segregation
    modifier: ABNORMAL
    term:
      id: GO:0007059
      label: chromosome segregation
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal anomaly characterized by multiple mosaic aneuploidies"
    explanation: Orphanet identifies multiple mosaic aneuploidies as the defining chromosomal abnormality.
  - reference: PMID:16059936
    reference_title: "Microcephaly is not mandatory for the diagnosis of mosaic variegated aneuploidy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The MVA syndrome is associated with mosaicism for several different aneuploidies involving many different chromosomes with or without premature centromere division (PCD)."
    explanation: This clinical report describes the diagnostic pattern of several different aneuploidies.
  - reference: PMID:25696020
    reference_title: "A case report of a fetus with mosaic autosomal variegated aneuploidies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeat amniocentesis at 21 weeks' gestation consistently showed the presence of multiple mosaic autosomal variegated aneuploidies."
    explanation: Prenatal testing directly documented multiple mosaic autosomal variegated aneuploidies.
  downstream:
  - target: Growth and neurodevelopmental abnormalities
    description: Constitutional chromosomal mosaicism is associated with prenatal growth restriction, microcephaly, developmental delay, and brain malformations.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25696020
      reference_title: "A case report of a fetus with mosaic autosomal variegated aneuploidies and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The phenotype of MVA syndrome includes severe microcephaly and growth deficiency, central nervous system anomalies, mental retardation, mild physical anomalies, and predisposition to cancer."
      explanation: This review connects MVA chromosomal mosaicism to growth, brain, developmental, and cancer phenotypes.
  - target: Cancer predisposition
    description: Aneuploidy and checkpoint defects create a constitutional tumor-predisposition state.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15475955
      reference_title: "Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These data are the first to relate germline mutations in a spindle checkpoint gene with a human disorder and strongly support a causal link between aneuploidy and cancer development."
      explanation: The gene-discovery paper links the aneuploidy mechanism to cancer development.
- name: Growth and neurodevelopmental abnormalities
  description: >
    Constitutional mosaic aneuploidy manifests with prenatal and postnatal
    growth restriction, microcephaly or other brain anomalies, developmental
    delay, intellectual disability, seizures, and variable ocular and
    craniofacial abnormalities.
  evidence:
  - reference: PMID:25696020
    reference_title: "A case report of a fetus with mosaic autosomal variegated aneuploidies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype of MVA syndrome includes severe microcephaly and growth deficiency, central nervous system anomalies, mental retardation, mild physical anomalies, and predisposition to cancer."
    explanation: This literature review supports the core growth and neurodevelopmental phenotype group.
  - reference: PMID:32861809
    reference_title: "Follow-up of two adult brothers with homozygous CEP57 pathogenic variants expands the phenotype of Mosaic Variegated Aneuploidy Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy."
    explanation: The CEP57 report supports the recurrent growth, craniofacial, developmental, cancer, and epilepsy features.
  downstream:
  - target: Microcephaly
    causal_link_type: DIRECT
    description: MVA commonly includes reduced head size.
  - target: Global developmental delay
    causal_link_type: DIRECT
    description: MVA commonly includes developmental delay.
  - target: Dandy-Walker malformation
    causal_link_type: DIRECT
    description: MVA can include posterior fossa developmental brain malformations.
- name: Cancer predisposition
  description: >
    MVA confers cancer predisposition. BUB1B- and TRIP13-related disease is
    especially associated with embryonal tumors such as Wilms tumor and
    rhabdomyosarcoma, while adult gastrointestinal cancers have also been
    reported in BUB1B-related disease.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cancer predisposition."
    explanation: Orphanet includes cancer predisposition in the disease definition.
  - reference: PMID:28553959
    reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors"
    explanation: The TRIP13 paper supports high embryonal tumor risk for TRIP13- and BUB1B-related MVA.
  - reference: PMID:21190457
    reference_title: "Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers"
    explanation: This case extends BUB1B-related MVA tumor predisposition to adult-onset gastrointestinal cancers.
  downstream:
  - target: Nephroblastoma
    causal_link_type: DIRECT
    description: Wilms tumor is a characteristic embryonal tumor risk in TRIP13- and BUB1B-related MVA.
    evidence:
    - reference: PMID:28553959
      reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor."
      explanation: All six reported TRIP13 biallelic loss-of-function cases developed Wilms tumor.
  - target: Rhabdomyosarcoma
    causal_link_type: DIRECT
    description: Embryonal rhabdomyosarcoma was present in BUB1B-related MVA families.
    evidence:
    - reference: PMID:15475955
      reference_title: "Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B"
      explanation: The BUB1B discovery paper reports embryonal rhabdomyosarcoma in MVA families.
phenotypes:
- name: Epicanthus
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Epicanthus is a very frequent craniofacial feature in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000286 | Epicanthus | Very frequent (99-80%)"
    explanation: Orphanet records epicanthus as very frequent in MVA syndrome.
- name: Micrognathia
  category: Craniofacial
  frequency: VERY_FREQUENT
  description: Micrognathia is a very frequent craniofacial feature in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000347 | Micrognathia | Very frequent (99-80%)"
    explanation: Orphanet records micrognathia as very frequent in MVA syndrome.
- name: Triangular face
  category: Craniofacial
  frequency: FREQUENT
  description: Triangular face is a frequent craniofacial feature in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000325 | Triangular face | Frequent (79-30%)"
    explanation: Orphanet records triangular face as frequent in MVA syndrome.
- name: Microcephaly
  category: Neurologic
  frequency: FREQUENT
  description: Microcephaly is frequent but not mandatory for diagnosis.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000252 | Microcephaly | Frequent (79-30%)"
    explanation: Orphanet records microcephaly as frequent in MVA syndrome.
  - reference: PMID:16059936
    reference_title: "Microcephaly is not mandatory for the diagnosis of mosaic variegated aneuploidy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From this case report, we suggest that microcephaly is not mandatory for the diagnosis of MVA syndrome."
    explanation: This report supports microcephaly as common but not required.
- name: Global developmental delay
  category: Neurodevelopmental
  frequency: FREQUENT
  description: Developmental delay is frequent in MVA syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001263 | Global developmental delay | Frequent (79-30%)"
    explanation: Orphanet records global developmental delay as frequent in MVA syndrome.
  - reference: PMID:32861809
    reference_title: "Follow-up of two adult brothers with homozygous CEP57 pathogenic variants expands the phenotype of Mosaic Variegated Aneuploidy Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy."
    explanation: The CEP57 report supports developmental delay as part of the typical MVA phenotype.
- name: Intellectual disability
  category: Neurodevelopmental
  frequency: FREQUENT
  description: Intellectual disability is frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Frequent (79-30%)"
    explanation: Orphanet records intellectual disability as frequent in MVA syndrome.
- name: Dandy-Walker malformation
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Dandy-Walker malformation is a very frequent brain malformation in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Dandy-Walker malformation
    term:
      id: HP:0001305
      label: Dandy-Walker malformation
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001305 | Dandy-Walker malformation | Very frequent (99-80%)"
    explanation: Orphanet records Dandy-Walker malformation as very frequent in MVA syndrome.
  - reference: PMID:25696020
    reference_title: "A case report of a fetus with mosaic autosomal variegated aneuploidies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrasonography at 21 weeks' gestation revealed relatively small head circumference for gestational age (<3%) and vermis defect, suggesting that the fetus would have microcephaly and Dandy-Walker malformation."
    explanation: Prenatal ultrasound in this MVA fetus supported Dandy-Walker malformation.
- name: Ventriculomegaly
  category: Neurologic
  frequency: VERY_FREQUENT
  description: Ventriculomegaly is very frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002119 | Ventriculomegaly | Very frequent (99-80%)"
    explanation: Orphanet records ventriculomegaly as very frequent in MVA syndrome.
- name: Seizure
  category: Neurologic
  frequency: OCCASIONAL
  description: Seizures occur in some patients and may be refractory in severe cases.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
    explanation: Orphanet records seizures as occasional in MVA syndrome.
  - reference: PMID:23916859
    reference_title: "Refractory infantile spasms associated with mosaic variegated aneuploidy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features also include prenatal-onset growth retardation, microcephaly, mild dysmorphism, feeding difficulty, hypotonia, seizures, and developmental delay."
    explanation: This neurologic case report lists seizures among MVA clinical features.
- name: Short stature
  category: Growth
  frequency: VERY_FREQUENT
  description: Short stature is very frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004322 | Short stature | Very frequent (99-80%)"
    explanation: Orphanet records short stature as very frequent in MVA syndrome.
- name: Intrauterine growth retardation
  category: Growth
  frequency: OCCASIONAL
  description: Prenatal growth restriction is a reported MVA manifestation.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001511 | Intrauterine growth retardation | Occasional (29-5%)"
    explanation: Orphanet records intrauterine growth retardation as occasional in MVA syndrome.
  - reference: PMID:32861809
    reference_title: "Follow-up of two adult brothers with homozygous CEP57 pathogenic variants expands the phenotype of Mosaic Variegated Aneuploidy Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals typically present with severe intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, developmental delay and predisposition to cancer and epilepsy."
    explanation: The CEP57 report supports intrauterine and postnatal growth retardation in MVA.
- name: Cataract
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  description: Cataract is very frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000518 | Cataract | Very frequent (99-80%)"
    explanation: Orphanet records cataract as very frequent in MVA syndrome.
- name: Microphthalmia
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  description: Microphthalmia is very frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000568 | Microphthalmia | Very frequent (99-80%)"
    explanation: Orphanet records microphthalmia as very frequent in MVA syndrome.
- name: Glaucoma
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  description: Glaucoma is very frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000501 | Glaucoma | Very frequent (99-80%)"
    explanation: Orphanet records glaucoma as very frequent in MVA syndrome.
- name: Ocular abnormalities
  category: Ophthalmologic
  frequency: FREQUENT
  description: Ocular abnormalities are frequent and include cataract, glaucoma, microphthalmia, corneal opacity, and visual impairment.
  phenotype_term:
    preferred_term: Ocular abnormalities
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000478 | Abnormality of the eye | Frequent (79-30%)"
    explanation: Orphanet records abnormality of the eye as frequent in MVA syndrome.
- name: Abnormality of vision
  category: Ophthalmologic
  frequency: FREQUENT
  description: Vision abnormalities are frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Abnormality of vision
    term:
      id: HP:0000504
      label: Abnormality of vision
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000504 | Abnormality of vision | Frequent (79-30%)"
    explanation: Orphanet records abnormality of vision as frequent in MVA syndrome.
- name: Corneal opacity
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  description: Corneal opacity is very frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Corneal opacity
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007957 | Corneal opacity | Very frequent (99-80%)"
    explanation: Orphanet records corneal opacity as very frequent in MVA syndrome.
- name: Polyhydramnios
  category: Prenatal
  frequency: VERY_FREQUENT
  description: Polyhydramnios is very frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001561 | Polyhydramnios | Very frequent (99-80%)"
    explanation: Orphanet records polyhydramnios as very frequent in MVA syndrome.
- name: Increased nuchal translucency
  category: Prenatal
  frequency: VERY_FREQUENT
  description: Increased nuchal translucency is very frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Increased nuchal translucency
    term:
      id: HP:0010880
      label: Increased nuchal translucency
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010880 | Increased nuchal translucency | Very frequent (99-80%)"
    explanation: Orphanet records increased nuchal translucency as very frequent in MVA syndrome.
- name: Ascites
  category: Prenatal
  frequency: VERY_FREQUENT
  description: Ascites is very frequent in the Orphanet MVA record.
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001541 | Ascites | Very frequent (99-80%)"
    explanation: Orphanet records ascites as very frequent in MVA syndrome.
- name: Muscular dystrophy
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  description: Muscular dystrophy is listed as very frequent in the Orphanet MVA phenotype table.
  notes: >
    Retained because ORPHA:1052 lists HP:0003560 as very frequent, but this
    frequency is not corroborated by the primary MVA literature cited in this
    entry and should be treated as an Orphanet assertion requiring future
    verification.
  phenotype_term:
    preferred_term: Muscular dystrophy
    term:
      id: HP:0003560
      label: Muscular dystrophy
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003560 | Muscular dystrophy | Very frequent (99-80%)"
    explanation: Orphanet records muscular dystrophy as very frequent in MVA syndrome.
- name: Neoplasm
  category: Neoplastic
  frequency: OCCASIONAL
  description: MVA is a cancer-predisposition syndrome with variable benign or malignant neoplasms.
  phenotype_term:
    preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002664 | Neoplasm | Occasional (29-5%)"
    explanation: Orphanet records neoplasm as occasional in MVA syndrome.
  - reference: PMID:15475955
    reference_title: "Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mosaic variegated aneuploidy is a rare recessive condition characterized by growth retardation, microcephaly, childhood cancer and constitutional mosaicism for chromosomal gains and losses."
    explanation: The BUB1B gene-discovery paper identifies childhood cancer as part of the syndrome.
- name: Nephroblastoma
  category: Neoplastic
  frequency: OCCASIONAL
  description: Wilms tumor is a recurrent embryonal tumor in MVA, particularly TRIP13- and BUB1B-related forms.
  phenotype_term:
    preferred_term: Wilms tumor
    term:
      id: HP:0002667
      label: Nephroblastoma
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002667 | Nephroblastoma | Occasional (29-5%)"
    explanation: Orphanet records nephroblastoma as occasional in MVA syndrome.
  - reference: PMID:28553959
    reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor."
    explanation: This case series directly supports Wilms tumor predisposition in TRIP13-related MVA.
- name: Rhabdomyosarcoma
  category: Neoplastic
  frequency: OCCASIONAL
  description: Rhabdomyosarcoma is an occasional embryonal tumor manifestation in MVA syndrome.
  phenotype_term:
    preferred_term: Rhabdomyosarcoma
    term:
      id: HP:0002859
      label: Rhabdomyosarcoma
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002859 | Rhabdomyosarcoma | Occasional (29-5%)"
    explanation: Orphanet records rhabdomyosarcoma as occasional in MVA syndrome.
  - reference: PMID:15475955
    reference_title: "Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In five families with mosaic variegated aneuploidy, including two with embryonal rhabdomyosarcoma, we identified truncating and missense mutations of BUB1B"
    explanation: The BUB1B gene-discovery paper reports embryonal rhabdomyosarcoma in two MVA families.
- name: Acute lymphoblastic leukemia
  category: Neoplastic
  frequency: OCCASIONAL
  description: Acute lymphoblastic leukemia is an occasional neoplastic manifestation in the Orphanet MVA phenotype table, and leukemia is reported among MVA-associated tumors.
  phenotype_term:
    preferred_term: Acute lymphoblastic leukemia
    term:
      id: HP:0006721
      label: Acute lymphoblastic leukemia
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006721 | Acute lymphoblastic leukemia | Occasional (29-5%)"
    explanation: Orphanet records acute lymphoblastic leukemia as occasional in MVA syndrome.
  - reference: PMID:20516114
    reference_title: "Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "37% of patients develop cancers including rhadomyosarcoma, Wilms tumor and leukemia, mostly within the first 3 years of life"
    explanation: This review of MVA patients reports leukemia among early-onset cancers.
  - reference: PMID:32884756
    reference_title: "Prenatal diagnosis and long-term follow-up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wilms tumor, rhabdomyosarcoma, leukemia and granulosa cell tumor of the ovary."
    explanation: This clinical management discussion lists leukemia among BUB1B-associated MVA tumors.
genetic:
- name: BUB1B germline pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: BUB1B
    term:
      id: hgnc:1149
      label: BUB1B
  notes: >
    BUB1B encodes BUBR1, a spindle assembly checkpoint protein. Biallelic or
    functionally severe BUB1B defects are a classic molecular cause of MVA.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BUB1B | BUB1 mitotic checkpoint serine/threonine kinase B | hgnc:1149 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline BUB1B mutations.
  - reference: PMID:15475955
    reference_title: "Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified truncating and missense mutations of BUB1B, which encodes BUBR1, a key protein in the mitotic spindle checkpoint."
    explanation: This gene-discovery paper identifies BUB1B/BUBR1 mutations in MVA.
- name: CEP57 germline pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: CEP57
    term:
      id: hgnc:30794
      label: CEP57
  notes: >
    Biallelic CEP57 pathogenic variants cause MVA syndrome 2, often with short
    stature, microcephaly, facial, skeletal, endocrine, and cardiovascular
    abnormalities.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CEP57 | centrosomal protein 57 | hgnc:30794 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline CEP57 mutations.
  - reference: PMID:34500087
    reference_title: "Mosaic Variegated Aneuploidy syndrome 2 caused by biallelic variants in CEP57, two new cases and review of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mosaic Variegated Aneuploidy Syndrome 2 (MVA2; MIM 614114) is a rare autosomal recessive disorder, characterized by mosaic aneuploidies involving multiple chromosomes and tissues, caused by biallelic pathogenic variants in the CEP57 gene."
    explanation: This review identifies biallelic CEP57 pathogenic variants as causal for MVA2.
- name: TRIP13 germline pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: TRIP13
    term:
      id: hgnc:12307
      label: TRIP13
  notes: >
    Biallelic TRIP13 loss-of-function causes a spindle-checkpoint-defective MVA
    subtype with high Wilms tumor risk.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TRIP13 | thyroid hormone receptor interactor 13 | hgnc:12307 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline TRIP13 mutations.
  - reference: PMID:28553959
    reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor."
    explanation: This study identifies biallelic TRIP13 loss-of-function mutations in affected individuals.
- name: BUB1 germline pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: BUB1
    term:
      id: hgnc:1148
      label: BUB1
  notes: Orphanet records BUB1 among disease-causing germline genes for MVA syndrome.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BUB1 | BUB1 mitotic checkpoint serine/threonine kinase | hgnc:1148 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline BUB1 mutations in MVA syndrome.
- name: BUB3 germline pathogenic variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: BUB3
    term:
      id: hgnc:1151
      label: BUB3
  notes: Orphanet records BUB3 among disease-causing germline genes for MVA syndrome.
  evidence:
  - reference: ORPHA:1052
    reference_title: "Mosaic variegated aneuploidy syndrome (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BUB3 | BUB3 mitotic checkpoint protein | hgnc:1151 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records disease-causing germline BUB3 mutations in MVA syndrome.
diagnosis:
- name: Cytogenetic detection of mosaic aneuploidies
  description: >
    Conventional karyotyping or cytogenetic studies can detect multiple mosaic
    trisomies or monosomies, sometimes with premature chromatid separation, in
    blood, amniocytes, fibroblasts, or other tissues.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: PMID:16059936
    reference_title: "Microcephaly is not mandatory for the diagnosis of mosaic variegated aneuploidy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cytogenetics analyses and FISH studies showed multiple aneuploidy with trisomy 18, 19, and 8, respectively in blood lymphocyte and fibroblasts without PCD."
    explanation: This case report supports cytogenetic/FISH detection of multiple aneuploidies.
  - reference: PMID:25696020
    reference_title: "A case report of a fetus with mosaic autosomal variegated aneuploidies and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repeat amniocentesis at 21 weeks' gestation consistently showed the presence of multiple mosaic autosomal variegated aneuploidies."
    explanation: Repeat prenatal cytogenetic testing documented persistent mosaic variegated aneuploidies.
- name: Molecular genetic testing
  description: >
    Sequencing and copy-number analysis of MVA genes, especially BUB1B, CEP57,
    and TRIP13, supports molecular confirmation, recurrence-risk counseling, and
    subtype-aware tumor-risk assessment.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:32884756
    reference_title: "Prenatal diagnosis and long-term follow-up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe the prenatal diagnosis, molecular characterization, and clinical management of a long-lived patient with BUB1B-related MVA."
    explanation: This case report supports molecular characterization after prenatal diagnosis.
  - reference: PMID:40555658
    reference_title: "Genetic analysis of two fetuses with Mosaic variegated aneuploidy syndrome caused by compound heterozygous variants in BUB1B and its upstream regulatory elements and a literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing (WES) was performed on both fetuses, followed by Sanger sequencing for familial validation and pathogenicity analysis of candidate variants."
    explanation: This prenatal family report supports WES and Sanger confirmation for MVA molecular diagnosis.
treatments:
- name: Symptomatic supportive care
  description: >
    Management is supportive and tailored to the patient's developmental,
    neurologic, endocrine, skeletal, ocular, and congenital-anomaly burden.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:32884756
    reference_title: "Prenatal diagnosis and long-term follow-up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical management of patients with MVA syndrome includes symptomatic support and tumor surveillance, particularly for BUB1B subtype."
    explanation: The long-term follow-up report supports symptomatic supportive care as part of clinical management.
- name: Genetic counseling
  description: >
    Genetic counseling is indicated because MVA is usually inherited, may be
    detected prenatally, and has recurrence-risk implications for families.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:23916859
    reference_title: "Refractory infantile spasms associated with mosaic variegated aneuploidy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Awareness of this disorder is important not only for proper diagnosis but also for genetic counseling of the family."
    explanation: This case report explicitly supports genetic counseling as part of MVA management.
- name: Cancer surveillance
  description: >
    Longitudinal tumor surveillance is biologically and clinically justified in
    checkpoint-defective MVA, especially for Wilms tumor and rhabdomyosarcoma in
    BUB1B- or TRIP13-related disease.
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:28553959
    reference_title: "Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors"
    explanation: High embryonal tumor risk supports subtype-aware cancer surveillance.
  - reference: PMID:32884756
    reference_title: "Prenatal diagnosis and long-term follow-up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical management of patients with MVA syndrome includes symptomatic support and tumor surveillance, particularly for BUB1B subtype."
    explanation: This clinical management statement directly supports tumor surveillance, especially for BUB1B-related MVA.
📚

References & Deep Research

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Mosaic Variegated Aneuploidy Syndrome. Core disease mechanisms, molecular...
Asta Scientific Corpus Retrieval 19 citations 2026-05-11T09:13:18.401448

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Mosaic Variegated Aneuploidy Syndrome. Core disease mechanisms, molecular...

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

  • Papers retrieved: 19
  • Snippets retrieved: 20

Relevant Papers

[1] Prenatal diagnosis of mosaic chromosomal aneuploidy and uniparental disomy and clinical outcomes evaluation of four fetuses

  • Authors: Shengfang Qin, Xueyan Wang, Jin Wang, Na Xi, Mengjia Yan et al.
  • Year: 2023
  • Venue: Molecular Cytogenetics
  • URL: https://www.semanticscholar.org/paper/a66093d2bab75ff7942c5f7b22f8f815300af7cf
  • DOI: 10.1186/s13039-023-00667-9
  • PMID: 38057902
  • PMCID: 10701935
  • Citations: 3
  • Summary: Fetal clinical outcomes were related to the affected chromosomes aneuploidy and UPD, mosaic levels and tissues, methylation status, and homozygous variation of recessive genes on the UPD chromosome.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > The effects of mosaic chromosomal aneuploidy and UPD on fetuses are related to different chromosomes, mosaic levels, and mosaic tissues, which affect the intrauterine phenotype and clinical outcome. The four fetuses in this study had low-level mosaic chromosomes of T2, T15, monosomy X, and T20, respectively. The clinical influence of UPD is directly related to the gene content and size of the affected chromosomal region. If imprinted genes were involved, UPD could cause imprinted diseases, such as Beckwith-Wiedemann syndrome (BWS, patUPD11), Kagami-ogata syndrome (KOS, patUPD14), Angelman syndrome (AS, patUPD15)/PWS (PWS, matUPD15), pseudohypoparathyroidism (patUPD20) /Mulchandani-Bhoj-Conlin syndrome (MBCS, matUPD20) [15]. In addition, UPD events also increase the risk of recessive genetic disorders. The UPD of this study involved chr2, chr15, chr20, and the whole genome. In utero, fetuses usually have less visible phenotypes. However, when the prenatal imaging of the fetus is consistent with typical UPD manifestations of the KOS and BWS, chromosomal or genetic abnormalities should be validated by laboratory methods [16]. > In our four cases, we found more than two adverse genetic events happened in succession during their meiosis and mitosis as in previous reports [17] and proposed a possible formation mechanism of mosaic chromosomal aneuploidy and UPD. See Fig. 4 for details. We speculate multiple events might occur continuously on chromosome 2, including homologous recombination in prophase I, no separation in meiosis II, and rescue of trisomy and monosomy during mitosis. The chr2 consisted of normal cells, trisomy, and maternal UPD cells.
  • Snippet 2 (score: 0.388) > Background Few co-occurrence cases of mosaic aneuploidy and uniparental disomy (UPD) chromosomes have been reported in prenatal periods. It is a big challenge for us to predict fetal clinical outcomes with these chromosome abnormalities because of their highly heterogeneous clinical manifestations and limited phenotype attainable by ultrasound. Methods Amniotic fluid samples were collected from four cases. Karyotype, chromosome microarray analysis, short tandem repeats, and whole exome sequencing were adopted to analyze fetal chromosomal aneuploidy, UPD, and gene variation. Meanwhile, CNVseq analysis proceeded for cultured and uncultured amniocytes in case 2 and case 4 and MS-MLPA for chr11 and chr15 in case 3. Results All four fetuses showed mosaic chromosomal aneuploidy and UPD simultaneously. The results were: Case 1: T2(7%) and UPD(2)mat(12%). Case 2: T15(60%) and UPD(15)mat(40%). Case 3: 45,X(13%) and genome-wide paternal UPD(20%). Case 4: <10% of T20 and > 90% UPD(20)mat in uncultured amniocyte. By analyzing their formation mechanism of mosaic chromosomal aneuploidy and UPD, at least two adverse genetic events happened during their meiosis and mitosis. The fetus of case 1 presented a benign with a normal intrauterine phenotype, consistent with a low proportion of trisomy cells. However, the other three fetuses had adverse pregnancy outcomes, resulting from the UPD chromosomes with imprinted regions involved or a higher level of mosaic aneuploidy. Conclusion UPD is often present with mosaic aneuploidy. It is necessary to analyze them simultaneously using a whole battery of analyses for these cases when their chromosomes with imprinted regions are involved or known carriers of a recessive allele. Fetal clinical outcomes were related to the affected chromosomes aneuploidy and UPD, mosaic levels and tissues, methylation status, and homozygous variation of recessive genes on the UPD chromosome. Genetic counseling for pregnant

[2] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 4
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[3] Turner’s syndrome mosaicism in girls with neurodevelopmental disorders: a cohort study and hypothesis

  • Authors: S. Vorsanova, A. D. Kolotii, O. S. Kurinnaia, V. Kravets, I. Demidova et al.
  • Year: 2021
  • Venue: Molecular Cytogenetics
  • URL: https://www.semanticscholar.org/paper/9769a11d85d603b4437db8112bfd3695202f1abf
  • DOI: 10.1186/s13039-021-00529-2
  • PMID: 33573679
  • PMCID: 7879607
  • Citations: 14
  • Influential citations: 1
  • Summary: It appears that molecular cytogenetic monitoring of TSM, which is a likely risk factor/biomarker for adult-onset multifactorial diseases, is required and may be an element of pathogenic cascades in brain diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > Turner's syndrome represents a common chromosomal (gonosomal) syndrome (newborn prevalence: 5.9/1000) [24]. So far, this is the sole syndrome associated with non-mosaic monosomy in human [5,6]. However, it is systematically hypothesized that liveborn children with non-mosaic 45,X karyotype are tissue-specific mosaics [6,25,26]. Recently, analyses of multiple tissues repeatedly supported this idea [27]. Since mosaicism is an important biomarker in Turner's syndrome, high attention is paid to mosaic cases. Moreover, studies of TSM in clinical cohorts are a broad area of medical genetic research. This may be explained by the fact that gonosomal mosaicism is a phenomenon with global relevance to biomedicine [28]. Mostly, these studies are performed for cohorts of patients with reproductive problems or for children without specific clinical features [8,[29][30][31]. Surprisingly, despite of the presence of neurobehavioral and psychiatric endophenotypes in the clinical picture of Turner's syndrome, analyses of TSM are exclusive in neurodevelopmental cohorts [32,33]. The present study fills this gap providing a comprehensive analysis of TSM among females with neurodevelopmental disorders. Thus, this mosaicism type is involved in 1.9% of cases among neurodevelopmental disorders, i.e. such a phenotypically variable group of patients. Somatic gonosomal mosaicism manifesting as aneuploidy is a contributor to the pathogenesis of numerous diseases [7,[34][35][36][37]. Here, we have shown that 1.2% of females with neurodevelopmental disorders are affected by mosaic X chromosome loss alone. Therefore, one can suggest that mosaicism for monosomy of chromosome X is a highly probable and relatively common mechanism of brain diseases in females. Supernumerary marker chromosomes derived from gonosomes have extremely variable phenotypic outcomes from asymptomatic carriage to irritant medical problems [38,39].

[4] Prenatal diagnosis and long‐term follow‐up of a Chinese patient with mosaic variegated aneuploidy and its molecular analysis

  • Authors: S. Lin, H. Luk, I. Lo, Wai-Keung Tam, K. Y. Chan et al.
  • Year: 2020
  • Venue: Clinical Case Reports
  • URL: https://www.semanticscholar.org/paper/55c0cf44e588c85d20a72365efc433be7b3b4219
  • DOI: 10.1002/ccr3.2802
  • PMID: 32884756
  • PMCID: 7455400
  • Citations: 4
  • Summary: The prenatal diagnosis, molecular characterization, and clinical management of a long‐lived patient with BUB1B‐related MVA are described.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > Mosaic variegated aneuploidy (MVA, OMIM 257300) is a congenital autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies, and monosomies, involving multiple chromosomes and tissues. 1 Mutations in BUB1B, CEP57, and TRIP13 genes, which are involved in mitotic spindle and microtubule stabilization, are responsible for the molecular pathogenesis of MVA. The clinical features of MVA syndrome include severe pre/postnatal growth retardation, microcephaly, central nervous system anomalies, intellectual disability, minor congenital malformation, and predisposition to malignancy. There is some genotype-phenotype correlation (Table 1). Intellectual disability, microcephaly, brain malformations, epilepsy, and cancer predisposition are more common in BUB1B subtype. Rhizomelic shortening of the upper limbs, skull anomalies with conserved head circumference, and absence of malignancy are more common in CEP57 subtype. In addition, TRIP13 subtype has growth retardation with microcephaly and developmental delay, but there is no other structural abnormality and dysmorphic facial feature as in BUB1B subtype. > Several cases of MVA were diagnosed in prenatal period, 2 followed by the termination of pregnancy. Here we reported a Chinese patient with the longest survival in literature, with cytogenetic and antenatal findings together with her longterm postnatal course and molecular finding.

[5] The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.

  • Authors: S. Silva, G. Arno, A. Robson, A. Fakin, Nikolas Pontikos et al.
  • Year: 2020
  • Venue: Progress in retinal and eye research
  • URL: https://www.semanticscholar.org/paper/0002f4d18faa348181db81ac27fed490c9ddb569
  • DOI: 10.1016/j.preteyeres.2020.100898
  • PMID: 32860923
  • Citations: 127
  • Influential citations: 7
  • Summary: An algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy is presented, current experimental therapeutic approaches are summarised, and questions for future research are considered.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > Inherited retinal diseases are a frequent cause of blindness in paediatric and working age populations in many countries Rahman et al., 2020;Solebo and Rahi, 2014;Solebo et al., 2017). > The X-linked retinopathies represent an important, diverse subgroup, including both progressive and stationary conditions, and disorders with and without syndromic features. They display a number of different pathogenic mechanisms, thereby yielding important and wide-ranging insights into key aspects of retinal physiology and pathophysiology. A significant number are also the subject of novel therapeutic trials. > Pathogenic variants usually cause disease by loss of protein function; hence these conditions are particularly attractive for gene-replacement strategies. There is a carrier phenotype in several of these conditions, which can help clinicians narrow the differential diagnosis and thereby mode of inheritance, and which may also reveal valuable information regarding patterns of X inactivation, normal retinal cellular development and migration, and mechanisms of disease. Carrier females are often asymptomatic, but may infrequently be as severely affected as males, which may result in inheritance being incorrectly classified as autosomal dominant. Some of the disorders also illustrate ways in which variants in the same gene can generate a number of phenotypes, and potential limitations in current genetic sequencing methods; awareness of the latter is particularly relevant as we enter the era of widely available whole genome sequencing and gene therapy. > In this article, X-inactivation and patterns of X-linked inheritance will be reviewed briefly. We then explore the burden of disease attributable to X-linked genes in a large clinically and genetically characterised inherited retinal disease cohort, highlighting the most frequently implicated genes, and investigating correlation between gene transcript length and numbers of affected families. Subsequently, we provide a list of X-linked genes involved in a number of non-syndromic and syndromic retinopathies, together with key clinical features, and a schematic showing sites of expression or impairment in the retina. We then discuss several genes in more detail as specified in the abstract. For several conditions, disease mechanisms, clinical features, carrier phenotypes, electrophysiological findings, and novel experimental therapies, where applicable, are considered. A comprehensive, detailed discussion of

[6] Total Hemi-overgrowth in Pigmentary Mosaicism of the (Hypomelanosis of) Ito Type

  • Authors: V. Pavone, S. Signorelli, A. Praticò, G. Corsello, S. Savasta et al.
  • Year: 2016
  • Venue: Medicine
  • URL: https://www.semanticscholar.org/paper/d3902c737bb463b877dc93ccf49c3a144415d82e
  • DOI: 10.1097/MD.0000000000002705
  • PMID: 26962770
  • PMCID: 4998851
  • Citations: 40
  • Summary: The present study, which includes children and adults with the longest follow-up so far recorded, confirms the association between pigmentary mosaicism of the Ito type and HOG lowering previous estimates (7% vs 16%) for HOG in the context of mosaic hypopigmentation.
  • Evidence snippets:
  • Snippet 1 (score: 0.389) > The systemic form of ND in its unilateral form may be difficult to differentiate from pigmentary mosaicism, but it is usually not associated with systemic manifestations. > Regarding the likely role of pigmentary genes in the occurrence of mosaic phenomena of hypopigmentation (along the lines of Blaschko) either as isolated traits or as syndromic patterns, Taibjee et al 19 reported several ranges of mosaic chromosomal abnormalities, including diploidy, triploidy, aneuploidy, chromosomal deletions, insertions, and translocations (of basically all chromosomes) in about 50% of affected individuals with hypopigmentation along the lines of Blaschko: cross-comparison of these cytogenetic abnormalities and one or more pigmentary genes showed significant (ie, >70%) overlaps. The claimed familial occurrence and the number of reported pedigrees inferring Mendelian inheritance in pigmentary mosaicism of the Ito type have not been proven at a clinical level. 20 It has been hypothesized that the pigmentary pattern that follows Blaschko's lines is the result of the migration of 2 different clones of cells during embryogenesis, and the clinical findings of pigmentary mosaicism (of the Ito type) is a nonspecific manifestation (ie, a phenotype) reflecting genetic mosaicism, which likely disrupts expression or function of pigmentary genes. 19,21 The pigmentary anomalies are the results of an interaction between 2 different cellular populations as it happens with the mosaicism. 7,9 The current term of pigmentary mosaicism along the lines of Blaschko (or of the Ito type) (or linear hypomelanosis in narrow bands, according to the system of archetypical patterns of cutaneous mosaicism) 9,10 thus reflects the anatomical distribution of the abnormal skin patterning over the body and the assumed pathogenesis of the disorder: that is, somatic mosaicism for a yet undiscovered gene or genes responsible for pigmentation in humans. 5,9

[7] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

  • Authors: M. M. Wong, L. Watson, Esther B. E. Becker
  • Year: 2017
  • Venue: Journal of neurology & neuromedicine
  • URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
  • DOI: 10.29245/2572.942X/2017/7.1134
  • PMID: 28825058
  • PMCID: 5558869
  • Citations: 10
  • Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
  • Evidence snippets:
  • Snippet 1 (score: 0.388) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[8] Consequences of aneuploidy in human fibroblasts with trisomy 21

  • Authors: Sunyoung Hwang, Paola Cavaliere, Rui Li, L. Zhu, Noah E. Dephoure et al.
  • Year: 2020
  • Venue: Proceedings of the National Academy of Sciences of the United States of America
  • URL: https://www.semanticscholar.org/paper/5ae9f7792cd2e4a8e2d6178f5a322da9f96ba3ac
  • DOI: 10.1101/2020.08.14.251082
  • PMID: 33526671
  • PMCID: 8017964
  • Citations: 57
  • Influential citations: 6
  • Summary: It is shown that several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and increased dependency on serine-driven lipid synthesis, and the lack of evidence for widespread dosage compensation or dysregulation of chromosomal domains in human autosomes is supported.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Significance An abnormal number of chromosomes or aneuploidy accounts for most spontaneous abortions, as missegregation of a single chromosome during development is often lethal. Only individuals with trisomy 21, which causes Down syndrome, can live to adulthood but show cognitive disabilities, increased risk for leukemias, autoimmune disorders, and clinical symptoms associated with premature aging. The mechanisms by which aneuploidy affects cellular function to cause Down syndrome are not understood. Our studies revealed that aneuploidy causes several defects in cells from individuals with Down syndrome. These include increased gene and protein expression, lower viability, and increased dependency on serine to proliferate. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21. An extra copy of chromosome 21 causes Down syndrome, the most common genetic disease in humans. The mechanisms contributing to aneuploidy-related pathologies in this syndrome, independent of the identity of the triplicated genes, are not well defined. To characterize aneuploidy-driven phenotypes in trisomy 21 cells, we performed global transcriptome, proteome, and phenotypic analyses of primary human fibroblasts from individuals with Patau (trisomy 13), Edwards (trisomy 18), or Down syndromes. On average, mRNA and protein levels were increased by 1.5-fold in all trisomies, with a subset of proteins enriched for subunits of macromolecular complexes showing signs of posttranscriptional regulation. These results support the lack of evidence for widespread dosage compensation or dysregulation of chromosomal domains in human autosomes. Furthermore, we show that several aneuploidy-associated phenotypes are present in trisomy 21 cells, including lower viability and increased dependency on serine-driven lipid synthesis. Our studies establish a critical role of aneuploidy, independent of triplicated gene identity, in driving cellular defects associated with trisomy 21.

[9] VEXAS Syndrome: Genetics, Gender Differences, Clinical Insights, Diagnostic Pitfalls, and Emerging Therapies

  • Authors: S. Corrao, Marta Moschetti, S. Scibetta, L. Calvo, Annarita Giardina et al.
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/a4a8629aace3ad297f6f1c4d45022fd3e2f64e79
  • DOI: 10.3390/ijms26167931
  • PMID: 40869252
  • PMCID: 12386336
  • Summary: This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies.
  • Evidence snippets:
  • Snippet 1 (score: 0.383) > VEXAS syndrome, caused by somatic mutations in the UBA1 gene, leads to severe inflammatory conditions that manifest in adulthood. Its genetic origin, linked to the X chromosome, highlights a significant clinical impact even in female patients, who remain underrepresented in research due to a frequently milder disease course influenced by lyonization. The primary manifestations include systemic inflammation and hematologic abnormalities. However, the clinical phenotype is broad and complex, often resulting in misdiagnosis, diagnostic delays, and initially inappropriate treatments. A deeper understanding of the molecular mechanisms underlying this syndrome could pave the way for precision therapeutic strategies that target the disease at its core. One promising avenue is the longitudinal study of UBA1 mutations through genomic sequencing and functional assays, which will be essential for elucidating the impact of different variants on disease progression and treatment response. Another potential approach is to disrupt the inflammatory cascade associated with the disease by targeting the ubiquitination pathway. Additionally, restoring UBA1 function could represent a significant therapeutic breakthrough in re-establishing cellular homeostasis. With these strategies, we aim to provide clinicians with concrete tools to enhance the recognition and management of VEXAS syndrome, ensuring timely diagnosis and personalized care. The role of mosaicism and lyonization in female patients further underscores the complexity of the disease and the necessity for refined diagnostic approaches to detect milder cases. Future studies should concentrate on unraveling the impact of mosaicism in women, seeking to identify subtle clinical manifestations and optimize patient outcomes. A deeper understanding of these mechanisms could ultimately elevate quality of life and improve prognosis for individuals affected by this complex and potentially life-threatening condition. > This remains a significant challenge owing to the involvement of multiple organ systems, the variability in clinical manifestations, the common co-occurrence with hematologic malignancies, the reliance on glucocorticoids, and the limited response to standard immunosuppressive treatments.

[10] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.383) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[11] An Overview of Oxidative Stress in Sex Chromosome Aneuploidies in Pediatric Populations

  • Authors: R. Paparella, Fabiola Panvino, F. Tarani, Benedetto D'Agostino, Lucia Leonardi et al.
  • Year: 2025
  • Venue: Antioxidants
  • URL: https://www.semanticscholar.org/paper/da1e94b42aa80ca885e2c884a219ccb4d8688d81
  • DOI: 10.3390/antiox14050531
  • PMID: 40427413
  • PMCID: 12108347
  • Citations: 3
  • Summary: Early, tailored antioxidant strategies, integrated with syndrome-specific hormonal therapies, could reduce long-term complications and improve patient outcomes and future research should focus on standardizing protocols to optimize these interventions for pediatric patients with SCAs.
  • Evidence snippets:
  • Snippet 1 (score: 0.378) > Sex chromosome aneuploidies (SCAs) are among the most common chromosomal abnormalities, affecting approximately 1 in 500 live births, with the prevalence varying based on the specific condition [1][2][3]. The most frequent SCAs include Klinefelter syndrome (KS), Turner syndrome (TS), 47,XXX syndrome, and 47,XYY syndrome, along with less common variants and mosaicism forms [4,5]. > SCAs are associated with a wide spectrum of clinical manifestations, including developmental delay, cognitive impairment, dysmorphic features, gonadal dysfunction, cardiovascular anomalies, and metabolic disturbances [6,7]. The variability in phenotypic presentation is influenced by the specific aneuploidy, mosaicism degree, and dosage effects of sex chromosome-linked genes [8]. Advances in prenatal diagnostic techniques and improved clinical management have contributed to earlier detection and better outcomes, emphasizing the need for a deeper understanding of underlying pathophysiological mechanisms [9][10][11]. > Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defense mechanisms, has been implicated in the pathogenesis of numerous pediatric disorders [12,13]. Emerging evidence suggests that SCAs may also involve oxidative stress, contributing to the development of associated comorbidities such as cardiovascular disease, diabetes, and neurodevelopmental disorders [14][15][16][17]. Notably, oxidative stress has been extensively studied in autosomal aneuploidies such as trisomy 21, where altered redox homeostasis plays a critical role in phenotypic manifestations [18,19]. The role of oxidative stress in SCAs, however, remains underexplored. Specific genes located on sex chromosomes, such as those regulating oxidative balance and mitochondrial function, as well as autosomal genes, may contribute to increased ROS production and decreased antioxidant capacity [20][21][22][23][24][25]. Understanding these mechanisms could illuminate the etiology of SCA-related complications and inform therapeutic strategies targeting oxidative stress.

[12] Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience

  • Authors: Cecelia R. Miller, Kristy Lee, R. Pfau, S. Reshmi, Don Corsmeier et al.
  • Year: 2020
  • Venue: Cold Spring Harbor Molecular Case Studies
  • URL: https://www.semanticscholar.org/paper/ab0fc796600e188cc823d77a1ae52db443027255
  • DOI: 10.1101/mcs.a005231
  • PMID: 32371413
  • PMCID: 7304353
  • Citations: 21
  • Summary: The potential and importance of detecting mosaicism in ES is highlighted, particularly with increased sequence depth attainable from ES, as well as the need to assess diagnostic yield and characteristics of causal variants.
  • Evidence snippets:
  • Snippet 1 (score: 0.374) > Pathogenic variants at very low VAF in affected tissue can be sufficient to cause disease. For example, in diseases such as Sturge-Weber or vascular anomalies with overgrowth (e.g., Proteus syndrome or PIK3CA-related overgrowth spectrum [PROS]), the VAF of pathogenic variants in affected tissue has been reported as low as 1% (Lindhurst et al. 2011;Shirley et al. 2013;Hucthagowder et al. 2016). > Among unselected clinical exome cohort studies of pediatric, and combined pediatric and adult populations, disease-associated mosaic variants were noted at a frequency of ∼1%-1.5% (Yang et al. 2013;Retterer et al. 2016;Cao et al. 2019). The frequency of mosaicism increases when examining for specific phenotypes. For example, in epilepsy-related neurodevelopmental disorders, 3% of the pathogenic variants identified by either an MPS epilepsy panel or ES were mosaic (Stosser et al. 2018). In certain disorders (e.g., McCune-Albright and PROS), mosaic variants are the primary mechanism of disease (Aldred and Trembath 2000;Keppler-Noreuil et al. 2015;Hucthagowder et al. 2016). > We evaluated two years of clinical ES data from our laboratory within a pediatric tertiary care center to determine the characteristics of disease-associated variants within our cohort, as well as to compare the diagnostic yield reported by the laboratory versus the ordering clinical provider's interpretation of laboratory reported variant causality. We sought to evaluate the concordance of the molecular ES diagnostic rate generated by the laboratory with clinical provider-confirmed diagnoses recorded in the electronic medical record (EMR) to test if the laboratory workflow, including selection of genes relevant to the proband phenotype and subsequent variant assessment, resulted in meaningful results being reported back to the ordering provider. We further summarized the characteristics of these provider-confirmed causal variants and evaluated the contribution of mosaic variants to genetic disease within the context of these diagnoses.

[13] Somatic NLRP3 mosaicism in patients with “mutation-negative” CAPS: insights from a single centre UK cohort

  • Authors: S. Melo Gomes, J. I. Arostegui, Ana Mensa-Vilaro, E. Omoyinmi, Ying Hong et al.
  • Year: 2025
  • Venue: Frontiers in Pediatrics
  • URL: https://www.semanticscholar.org/paper/82a19d6e3f0a753dcfea31f9d4a2933ba1eff5bf
  • DOI: 10.3389/fped.2025.1598748
  • PMID: 40538939
  • PMCID: 12176735
  • Citations: 1
  • Summary: Somatic NLRP3 mosaicism was present in 40% of this paediatric cohort, confirming the key role of this phenomenon in disease pathogenesis and in genetic confirmation of CAPS diagnosis, and warrants caution regarding lower detection limits of the sequencing techniques utilized.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > Advances in ADS technology could increase the success rate of genetic diagnosis for mutation-negative CAPS from 60 to 80%, which would greatly benefit the care of these patients by increasing diagnostic yield and help prevent potentially irreversible complications by allowing earlier targeted treatment with IL-1 blockade (8). > Although the phenotype of patients with somatic NLRP3 mosaicism is very typical of the disease, a few studies tried to ascertain if there were any differences in relation to CAPS patients with germline mutations (3,9). Thus, patients with CINCA/NOMID and NLRP3 mosaicism were found to have a lower incidence of intellectual disability, and milder neurological symptoms overall following genotype matched comparison. One possibility to explain this could be the level of mosaicism in central nervous system cells or glial cells (3). Regarding Muckle-Wells Syndrome (MWS), the differences between patients with germline and mosaic mutations were slightly broader. MWS patients with mosaicism seemed to have a reduced incidence of AA-type amyloidosis when compared to patients with germline mutations, an increased incidence of recurrent arthritis, as well as older ages at the onset of the disease and that of sensorineural deafness. Moreover, absence of family history is a requisite in patients with mosaicism, whilst patients with germline mutations may have affected first-degree relatives. However, one of the most important and impactful differences was the significant delay in obtaining access to treatment with anti-IL1 drugs in patients with mosaicism, which was only achieved once the molecular diagnosis of mosaicism was secured (9). > The differences in clinical severity between mosaic and germline CAPS patients can be due to several factors, including the type of amino acid exchange, its location in the cryopyrin protein, the functional consequence of the mutation, as well as the level (percentage of cells) and tissue distribution of the mosaicism (7,9).

[14] Mosaic results after preimplantation genetic testing for aneuploidy may be accompanied by changes in global gene expression

  • Authors: A. Martin, A. Mercader, F. Domínguez, A. Quiñonero, M. Perez et al.
  • Year: 2023
  • Venue: Frontiers in Molecular Biosciences
  • URL: https://www.semanticscholar.org/paper/649844fa594d4995c150ce769b856e81fd086dab
  • DOI: 10.3389/fmolb.2023.1180689
  • PMID: 37122560
  • PMCID: 10140421
  • Citations: 14
  • Influential citations: 2
  • Summary: Comparisons of transcriptome profiles of inner cell mass and trophectoderm samples from blastocysts with different levels of chromosomal mosaicism suggest that embryos with mosaic results may have a genuine molecular identity that is compatible with their reproductive potential.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > While this might be the most common scenario, the reproductive potential of these embryos may also be explained by the complex interplay of molecular mechanisms which become deregulated in the presence of aneuploid cells. Our findings also suggest that within mosaic embryos, those with low-level mosaicism may exhibit transcriptome profiles more closely resembling those of euploid embryos, while high-level mosaic embryos represent a distinct biological category characterized by molecular features indicative of a greater extent and burden of the cellular stress arising from aneuploidy. These findings align well with current perspectives on the reproductive potential of mosaic embryos, and contribute to the growing body of evidence suggesting that low and high levels of mosaicism after PGT-A deserve distinct clinical management. > Some limitations of our study should be acknowledged. First, given the difficulty of obtaining embryos with the highest morphological quality for research purposes, our analysis was restricted to embryos graded B or C. In addition, global gene expression may exhibit high heterogeneity even among highquality embryos at the same developmental stage (Shaw et al., 2013;Ntostis et al., 2019). This means that our results may not be generalizable to other embryo populations, especially those with higher morphological scores. Furthermore, beyond the potential effect of chromosome-specific gene expression, the impact of mosaic aneuploidies on global transcriptome profiles may be confounded by specific adaptive mechanisms, particularly considering the extraordinary plasticity of early human development (Coticchio et al., 2021). Finally, while transcriptomics can serve as a sensitive indicator of cellular stress, it provides little to no information on protein activity. Therefore, our results should be interpreted with caution, and further studies focusing on protein are necessary to confirm these findings. > In conclusion, our study demonstrates that mosaic results following PGT-A may be accompanied by significant alterations in gene expression across blastocyst compartments as well as by significant delays in cell cycle timings during the first mitotic divisions. The level of mosaicism was associated with the extent of transcriptome deregulation, and pathways involving apoptosis, mitosis, protein degradation, metabolism, and mitochondrial energy production were among the most deregulated within mosaic embryos.

[15] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

  • Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
  • Year: 2021
  • Venue: Molecular Genetics & Genomic Medicine
  • URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
  • DOI: 10.1002/mgg3.1809
  • PMID: 34519438
  • PMCID: 8580094
  • Citations: 12
  • Influential citations: 2
  • Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

[16] Animal models of intellectual disability: towards a translational approach

  • Authors: C. Scorza, E. Cavalheiro
  • Year: 2011
  • Venue: Clinics
  • URL: https://www.semanticscholar.org/paper/cdb05f879079d91e136441e780b0bbb6a819a080
  • DOI: 10.1590/S1807-59322011001300007
  • PMID: 21779723
  • PMCID: 3118438
  • Citations: 16
  • Influential citations: 1
  • Summary: Several animal models of potential intellectual disability risk factors are described and a comparative approach is needed to benefit the most from what each animal model can tell us.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > The understanding of the pathogenicity of the extra genomic material in trisomy 21 has accelerated in recent years because of the recent advances in genome sequencing, comparative genome analysis, functional genome exploration and the use of animal models. 30 Aneuploidy, defined as an abnormal number of copies of a genomic region, is recognized as a common mechanism of human genetic disease, often leading to abnormal gene expression patterns with overor underexpression of specific genes. 31 Surprisingly, a significant number of human brain cells (both neurons and non-neuronal cells) can be aneuploidy, and the resulting genetic mosaicism is a normal feature of the human central nervous system. 32 But, what could be the mechanisms by which the anatomical, chemical and neurophysiological brain abnormalities underlying ID arise from deregulation of gene expression? Major questions are still unanswered. Genetically modified mouse models have been helping to investigate the contributions of specific gene alterations and gene-environment interactions to the phenotype of several forms of ID. > Fragile X syndrome X-linked disorders may explain why males show a 25-35% higher incidence of mental disabilities than females. It is imperative to gain knowledge of the mechanisms specific to the X-chromosome (e.g., X-inactivation, gene regulation) that may be relevant to understanding some forms of Xlinked mental retardation. Fragile X syndrome (FXS) is the leading cause of heritable intelligence disability, affecting about 1 in 1400 males and 1 in 2500 females. FXS is caused by a trinucleotide expansion in the fragile X mental retardation 1 gene (fmr1) that prevents the expression of the encoded protein, called fragile X mental retardation protein (FMRP). 33 The genetic defect is an unstable region of DNA on the X chromosome that becomes highly expanded when transmitted through the maternal lineage. FXS is a common form of mental retardation associated with attention deficit, autistic behavior, hyperactivity and epileptic seizures. 34 The phenotype of FXS is reproduced in fmr1 knockout (KO) mice that, among others, have regionspecific altered expression of some gamma-aminobutyric acid (GABA) receptor subunits. 35,36

[17] In silico molecular cytogenetics: a bioinformatic approach to prioritization of candidate genes and copy number variations for basic and clinical genome research

  • Authors: I. Iourov, S. Vorsanova, Y. Yurov
  • Year: 2014
  • Venue: Molecular Cytogenetics
  • URL: https://www.semanticscholar.org/paper/a16e86a729a48ff5d168bf0e4b8a94e633fb86ca
  • DOI: 10.1186/s13039-014-0098-z
  • PMID: 25525469
  • PMCID: 4269961
  • Citations: 46
  • Summary: A bioinformatic approach combining filtering and ranking prioritization strategies, which includes analyzing metabolome and interactome data on proteins encoded by candidate genes, is proposed and is able to become useful for increasing the yield of molecular cytogenetic techniques.
  • Evidence snippets:
  • Snippet 1 (score: 0.366) > Therefore, such types of GIN/CIN are rarely evaluated by an in silico analysis, even though knowledge of their effects on cellular/ clinical phenotypes is able to shed light on new genetic mechanisms of biodiversity and disease [38]. Alternatively, it has been shown that either SGV or non-mosaic genomic variations can dysregulate chromosome segregation and genomic maintenance producing CIN or GIN [12]. These observations were used for suggesting that bioinformatic approaches might be useful for studying mechanisms and consequences of somatic mosaicism. Finally, the present approach based on prioritizing genetic variants using evaluation of epigenetic variation between tissues and cell types can be utilized in studies of tissue-specific mosaicism. > Until recently, somatic mosaicism has not been a major focus of genome research [33,39]. With the increase of interest in addressing SGV, several studies have posed questions about the relevance of SGV to genetic diversity and morbidity [39][40][41]. It is repeatedly noted that SGV are underrecognized sources of genomic, chromosomal and complex disorders [18,33,39,41]. Additionally, SGV affecting specific tissues often lead not only to cancer, but also to tissue-specific pathology. For instance, numerous brain diseases are associated with SGV (CIN/GIN) manifested as aneuploidy or structural genome variations [14,18,37,[42][43][44][45][46][47][48]. These data have served as a basis for speculations about diagnostic applications of SGV analysis in brain disease and regeneration therapy [49]. Still, the idea remains undeveloped and further theoretical input is needed. It can be expected that molecular cytogenetic studies of SGV would benefit from in silico evaluations of their mechanisms and consequences.

[18] Double homozygosity in CEP57 and DYNC2H1 genes detected by WES: Composite or expanded phenotype?

  • Authors: L. Pezzani, L. Pezzoli, Alessandra Pansa, B. Facchinetti, D. Marchetti et al.
  • Year: 2020
  • Venue: Molecular Genetics & Genomic Medicine
  • URL: https://www.semanticscholar.org/paper/3aec92f37c87b59c0db11d3f9606950caffb1088
  • DOI: 10.1002/mgg3.1064
  • PMID: 31943948
  • PMCID: 7057129
  • Citations: 10
  • Summary: Three‐whole exome sequencing (WES) analysis has demonstrated its potential in obtaining genetic diagnoses even in nonspecific clinical pictures and in atypical presentations of known diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.365) > Mosaic variegated aneuploidy is a genetically heterogeneous autosomal recessive disease caused by mutations of three different genes: BUB1B (MVA1, OMIM # 257,300) (Hanks et al., 2004), CEP57 (MVA2, OMIM # 614,114) (Snape et al., 2011), and TRIP13 (MVA3, OMIM # 617,598) (Yost et al., 2017). The presence of constitutional mosaic aneuploidies due to gain or loss of multiple different chromosomes is the hallmark of MVA syndromes, while the related clinical phenotype can vary according to the involved causal gene. Cancer predisposition is one of the most important associations of MVA due to BUB1B and TRIP13 variants, with substantial increased risk of childhood malignancies, particularly Wilms tumor, rhabdomyosarcoma, and leukemia (Hanks et al., 2004;Jacquemont, Bocéno, Rival, Méchinaud, & David, 2002;Yost et al., 2017). On the contrary none of the seven patients with CEP57 mutation reported to date in the literature developed cancer (Brightman, Ejaz, & Dauber, 2018;De la Torre-García et al., 2019;Pinson et al., 2014) even if a recent work proved that MVA2 syndrome or haploinsufficiency in CEP57 are associated with impaired tumor suppression (Aziz et al., 2018). Cancer proneness in MVA2 thus deserves further investigation since our patient died at 6 months of life and none of the reported MVA2 patients have reached adulthood yet. So, the careful description of additional cases, and the follow-up of the already reported patients will be important to better delineate this important aspect.

[19] A Massively Parallel Pipeline to Clone DNA Variants and Examine Molecular Phenotypes of Human Disease Mutations

  • Authors: Xiaomu Wei, Jishnu Das, Robert Fragoza, Jin Liang, F. M. Bastos de Oliveira et al.
  • Year: 2014
  • Venue: PLoS Genetics
  • URL: https://www.semanticscholar.org/paper/830329784c911d37c86ddcd3fc4af6d8b3a0ac53
  • DOI: 10.1371/journal.pgen.1004819
  • PMID: 25502805
  • PMCID: 4263371
  • Citations: 52
  • Summary: This work describes a massively-parallel site-directed mutagenesis approach, “Clone-seq”, leveraging next-generation sequencing to rapidly and cost-effectively generate a large number of mutant alleles, and develops a comparative interactome-scanning pipeline integrating high-throughput GFP, yeast two-hybrid, and mass spectrometry assays to systematically evaluate the functional impact of mutations on protein stability and interactions.
  • Evidence snippets:
  • Snippet 1 (score: 0.364) > We then analyzed whether the molecular phenotypes measured by our high-throughput GFP and Y2H assays are correlated with corresponding disease phenotypes. We first examined how mutation pairs on the same gene affect protein stability and its relationship to their corresponding diseases. We find that pairs of mutations that are either both stable or both unstable cause the same disease in 68% and 70% of cases, respectively. However, pairs comprising one stable and one unstable mutation cause the same disease in only 30% of cases (P = 6610 29 and 8610 210 , respectively, Fig. 5a). For example, we find that the mutations R727C and L844F on the spindle checkpoint kinase Bub1b both cause the protein to become unstable and lose all its interactors. These mutations are both associated with the same disease, mosaic variegated aneuploidy, an autosomal recessive disorder that causes predominantly trisomies and monosomies of different chromosomes [22,23]. Since our GFP assay shows that these two mutations cause loss of protein product, our results are consistent with Matusuura et al.'s finding that a more than 50% decrease in Bub1b activity leads to abnormal mitotic spindle checkpoint function and mosaic variegated aneuploidy [24]. > We then examined whether mutation pairs on the same gene disrupt the same set or different sets of interactions (i.e., their interaction disruption profiles) and investigated whether their disruption profiles correlates with disease phenotypes. We found that mutation pairs with the exact same disruption profile are significantly more likely to cause the same disease than those with different profiles (70% and 61% respectively, P = 3610 25 , Fig. 5b). For example, we found that two mutations on Smad4, R361C and Y353S, disrupt its interactions with Smad3 and Smad9 while leaving the interactions with Lmo4 and Rassf5 unaltered (Fig. 5c). These two mutations both cause juvenile polyposis coli [25,26], a disease is known to be caused by disruption of the core Smad/Bmp signaling pathways [27].

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.