Mosaic variegated aneuploidy syndrome 1

Summary

Mosaic variegated aneuploidy syndrome 1 (MONDO:0009759) is a disease caused by BUB1B (GenCC Definitive), with 5 cohort genes. The dominant Reactome pathway is Mitotic Prometaphase (3 cohort genes).

At a glance

• Causal gene: BUB1B (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 1,019

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mosaic variegated aneuploidy syndrome 1
Mondo ID	MONDO:0009759
OMIM	257300
DOID	DOID:0080141
NCIT	C128192
UMLS	C1850343
MedGen	338026
GARD	0024694
Is cancer (heuristic)	no

Also known as: BUB1B mosaic variegated aneuploidy syndrome · mosaic variegated aneuploidy syndrome 1 · mosaic variegated aneuploidy syndrome caused by mutation in BUB1B · Mosaic variegated aneuploidy syndrome type 1 · mosaic variegated aneuploidy syndrome type 1 · MVA1

Data availability: 1,019 ClinVar variants · 5 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › mosaic variegated aneuploidy syndrome › mosaic variegated aneuploidy syndrome 1

Related subtypes (6): mosaic variegated aneuploidy syndrome 2, mosaic variegated aneuploidy syndrome 3, mosaic variegated aneuploidy syndrome 4, mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition, Atelis syndrome 1, Atelis syndrome 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

307 uncertain significance, 215 likely benign, 32 pathogenic, 19 benign, 18 conflicting classifications of pathogenicity, 6 likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070955	NM_001211.6(BUB1B):c.799C>T (p.Gln267Ter)	BUB1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1073991	NM_001211.6(BUB1B):c.422dup (p.Tyr141Ter)	BUB1B	Pathogenic	criteria provided, single submitter
1074988	NM_001211.6(BUB1B):c.693_694insTT (p.Ser232fs)	BUB1B	Pathogenic	criteria provided, single submitter
1299567	NM_001211.6(BUB1B):c.2636dup (p.His880fs)	BUB1B	Pathogenic	criteria provided, single submitter
1320272	NM_001211.6(BUB1B):c.1045del (p.Arg349fs)	BUB1B	Pathogenic	criteria provided, single submitter
1367214	NM_001211.6(BUB1B):c.2876T>G (p.Leu959Ter)	BUB1B	Pathogenic	criteria provided, single submitter
1386253	NM_001211.6(BUB1B):c.169C>T (p.Gln57Ter)	BUB1B	Pathogenic	criteria provided, single submitter
1392551	NM_001211.6(BUB1B):c.2334C>G (p.Tyr778Ter)	BUB1B	Pathogenic	criteria provided, single submitter
1398305	NM_001211.6(BUB1B):c.1298T>A (p.Leu433Ter)	BUB1B	Pathogenic	criteria provided, single submitter
1405980	NM_001211.6(BUB1B):c.1466_1470dup (p.Gly491fs)	BUB1B	Pathogenic	criteria provided, single submitter
1408436	NM_001211.6(BUB1B):c.1441C>T (p.Gln481Ter)	BUB1B	Pathogenic	criteria provided, single submitter
1443723	NM_001211.6(BUB1B):c.1906del (p.Glu636fs)	BUB1B	Pathogenic	criteria provided, single submitter
1450254	NM_001211.6(BUB1B):c.199C>T (p.Arg67Ter)	BUB1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1452898	NM_001211.6(BUB1B):c.877C>T (p.Gln293Ter)	BUB1B	Pathogenic	criteria provided, single submitter
1453887	NM_001211.6(BUB1B):c.2210del (p.Glu736_Leu737insTer)	BUB1B	Pathogenic	criteria provided, single submitter
1946449	NM_001211.6(BUB1B):c.310del (p.Arg104fs)	BUB1B	Pathogenic	criteria provided, single submitter
1980347	NM_001211.6(BUB1B):c.2848C>T (p.Gln950Ter)	BUB1B	Pathogenic	criteria provided, single submitter
2034835	NM_001211.6(BUB1B):c.1141del (p.Arg381fs)	BUB1B	Pathogenic	criteria provided, single submitter
2141736	NM_001211.6(BUB1B):c.1663C>T (p.Arg555Ter)	BUB1B	Pathogenic	criteria provided, single submitter
2152812	NM_001211.6(BUB1B):c.871del (p.Thr291fs)	BUB1B	Pathogenic	criteria provided, single submitter
2187691	NM_001211.6(BUB1B):c.1378C>T (p.Gln460Ter)	BUB1B	Pathogenic	criteria provided, single submitter
2196645	NM_001211.6(BUB1B):c.1743del (p.Phe581fs)	BUB1B	Pathogenic	criteria provided, single submitter
2202424	NM_001211.6(BUB1B):c.2153del (p.Thr718fs)	BUB1B	Pathogenic	criteria provided, single submitter
2423976	NC_000015.9:g.(?40453422)(40457417_?)del	BUB1B	Pathogenic	criteria provided, single submitter
2697026	NM_001211.6(BUB1B):c.94_95insGCTCTCCCTCTCCCTCTCCCGCTCCCGGGGGGGGGGGGGGGCGGGGGGGGGGGGGGGGGGGGGGGGGGGGGCGGGGGGGGGGGCGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAGAAAATGTACAACCTT (p.Leu32fs)	BUB1B	Pathogenic	criteria provided, single submitter
2729407	NM_001211.6(BUB1B):c.1313_1317del (p.Lys438fs)	BUB1B	Pathogenic	criteria provided, single submitter
2750610	NM_001211.6(BUB1B):c.2298C>G (p.Tyr766Ter)	BUB1B	Pathogenic	criteria provided, single submitter
2756659	NM_001211.6(BUB1B):c.897dup (p.Met300fs)	BUB1B	Pathogenic	criteria provided, single submitter
2820924	NM_001211.6(BUB1B):c.2896A>T (p.Lys966Ter)	BUB1B	Pathogenic	criteria provided, single submitter
2913819	NM_001211.6(BUB1B):c.897del (p.Met300fs)	BUB1B	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BUB1B	Definitive	Autosomal recessive	mosaic variegated aneuploidy syndrome 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BUB1B	Orphanet:1052	Mosaic variegated aneuploidy syndrome
CEP57	Orphanet:1052	Mosaic variegated aneuploidy syndrome

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BUB1B	HGNC:1149	ENSG00000156970	O60566	Mitotic checkpoint serine/threonine-protein kinase BUB1 beta	gencc,clinvar
CEP57	HGNC:30794	ENSG00000166037	Q86XR8	Centrosomal protein of 57 kDa	clinvar
ANKRD63	HGNC:40027	ENSG00000230778	C9JTQ0	Ankyrin repeat domain-containing protein 63	clinvar
BUB1B-PAK6	HGNC:52276	ENSG00000259288		BUB1B-PAK6 readthrough	clinvar
MAD1L1	HGNC:6762	ENSG00000002822	Q9Y6D9	Mitotic spindle assembly checkpoint protein MAD1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BUB1B	Mitotic checkpoint serine/threonine-protein kinase BUB1 beta	Essential component of the mitotic checkpoint.
CEP57	Centrosomal protein of 57 kDa	Centrosomal protein which may be required for microtubule attachment to centrosomes.
MAD1L1	Mitotic spindle assembly checkpoint protein MAD1	Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	5.5×	0.386
Scaffold/PPI	1	3.5×	0.386
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BUB1B	Kinase	yes	2.7.11.1	Kinase-like_dom_sf, Mad3/Bub1_I, Bub1/Mad3
CEP57	Other/Unknown	no		Cep57_MT-bd_dom, Cep57_CLD, Centrosomal_MT-associated
ANKRD63	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, Dendritic_Spine_Reg/Scaffold
BUB1B-PAK6	Other/Unknown	no
MAD1L1	Other/Unknown	no		Mad1

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
secondary oocyte	1
ventricular zone	1
calcaneal tendon	1
sperm	1
caudate nucleus	1
nucleus accumbens	1
putamen	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
left testis	1
right testis	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BUB1B	210	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
CEP57	292	ubiquitous	marker	oocyte, sperm, calcaneal tendon
ANKRD63	35	tissue_specific	yes	nucleus accumbens, putamen, caudate nucleus
BUB1B-PAK6	64		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa
MAD1L1	137	ubiquitous	marker	sural nerve, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BUB1B	4,042
MAD1L1	2,947
CEP57	1,345
ANKRD63	699
BUB1B-PAK6	0

Intra-cohort edges

A	B	Sources
BUB1B	CEP57	string_interaction
BUB1B	MAD1L1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BUB1B	O60566	9
MAD1L1	Q9Y6D9	5
CEP57	Q86XR8	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD63	C9JTQ0	61.92

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 5 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitotic Prometaphase	3	69.2×	7e-05	BUB1B, CEP57, MAD1L1
M Phase	3	66.0×	7e-05	BUB1B, CEP57, MAD1L1
Cell Cycle, Mitotic	3	48.2×	1e-04	BUB1B, CEP57, MAD1L1
Cell Cycle	3	36.0×	2e-04	BUB1B, CEP57, MAD1L1
Amplification of signal from the kinetochores	2	131.3×	6e-04	BUB1B, MAD1L1
Mitotic Spindle Checkpoint	2	105.7×	8e-04	BUB1B, MAD1L1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	2	77.7×	0.001	BUB1B, MAD1L1
Mitotic Metaphase and Anaphase	2	64.5×	0.001	BUB1B, MAD1L1
Mitotic Anaphase	2	64.5×	0.001	BUB1B, MAD1L1
EML4 and NUDC in mitotic spindle formation	2	61.9×	0.001	BUB1B, MAD1L1
Cell Cycle Checkpoints	2	59.0×	0.001	BUB1B, MAD1L1
Resolution of Sister Chromatid Cohesion	2	57.7×	0.001	BUB1B, MAD1L1
RHO GTPases Activate Formins	2	51.8×	0.002	BUB1B, MAD1L1
RHO GTPase Effectors	2	45.3×	0.002	BUB1B, MAD1L1
Separation of Sister Chromatids	2	40.5×	0.002	BUB1B, MAD1L1
Signaling by Rho GTPases	2	22.8×	0.006	BUB1B, MAD1L1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	2	22.3×	0.006	BUB1B, MAD1L1
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	1	211.5×	0.010	BUB1B
Inactivation of APC/C via direct inhibition of the APC/C complex	1	173.0×	0.012	BUB1B
APC-Cdc20 mediated degradation of Nek2A	1	141.0×	0.013	BUB1B
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	1	141.0×	0.013	BUB1B
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	1	135.9×	0.013	BUB1B
APC/C:Cdc20 mediated degradation of mitotic proteins	1	119.0×	0.014	BUB1B
APC/C-mediated degradation of cell cycle proteins	1	112.0×	0.014	BUB1B
Regulation of mitotic cell cycle	1	112.0×	0.014	BUB1B
Regulation of APC/C activators between G1/S and early anaphase	1	102.9×	0.015	BUB1B
Centrosome maturation	1	84.6×	0.017	CEP57
Cdc20:Phospho-APC/C mediated degradation of Cyclin A	1	57.7×	0.025	BUB1B
Loss of Nlp from mitotic centrosomes	1	52.9×	0.025	CEP57
Loss of proteins required for interphase microtubule organization from the centrosome	1	52.9×	0.025	CEP57

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitotic spindle assembly checkpoint signaling	2	374.5×	1e-04	BUB1B, MAD1L1
deactivation of mitotic spindle assembly checkpoint	1	1872.4×	0.003	MAD1L1
meiotic sister chromatid cohesion, centromeric	1	1123.5×	0.003	BUB1B
regulation of metaphase plate congression	1	1123.5×	0.003	MAD1L1
metaphase/anaphase transition of mitotic cell cycle	1	702.2×	0.003	BUB1B
protein localization to chromosome, centromeric region	1	702.2×	0.003	BUB1B
cell division	2	30.8×	0.003	BUB1B, MAD1L1
positive regulation of mitotic cell cycle spindle assembly checkpoint	1	510.7×	0.004	MAD1L1
attachment of mitotic spindle microtubules to kinetochore	1	351.1×	0.005	MAD1L1
thymus development	1	112.3×	0.012	MAD1L1
negative regulation of T cell proliferation	1	110.1×	0.012	MAD1L1
fibroblast growth factor receptor signaling pathway	1	95.2×	0.013	CEP57
spermatid development	1	48.4×	0.024	CEP57
protein homooligomerization	1	40.7×	0.026	CEP57
apoptotic process	1	9.6×	0.101	BUB1B

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 4

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
BUB1B	CERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BUB1B	1	4
CEP57	0	0
ANKRD63	0	0
BUB1B-PAK6	0	0
MAD1L1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERITINIB	4	BUB1B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
BUB1B	12	Binding:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BUB1B	2.7.11.1	non-specific serine/threonine protein kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CERITINIB	4	BUB1B

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BUB1B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	CEP57, ANKRD63, BUB1B-PAK6, MAD1L1

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CEP57	0	BUB1B
MAD1L1	0	BUB1B
ANKRD63	0	—
BUB1B-PAK6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.