Gene Validity Curation

BUB1B - mosaic variegated aneuploidy syndrome 1

Gene: BUB1B (HGNC:1149)
Classification - 11/22/2019
Disease: mosaic variegated aneuploidy syndrome 1 (MONDO_0009759)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: BUBR1 protein encoded by BUB1B gene is an important protein in the spindle assembly checkpoint. Constitutional homozygotes of hypomorphic mutations or compound heterozygote of a null mutation and a missense/hypomorphic mutation in the BUB1B gene cause the rare human disorder mosaic variegated aneuploidy (MVA) syndrome type I (MIM 257300). Hanks S et al., (2004) identified 6 individuals from 5 unrelated families with typical phenotypes of MVA carry biallelic BUB1B mutations. Rio Frio T et al. (2010) identified a male of 34 yr-old from a consanguineous family with MVA phenotype and many types of cancers homozygous for BUB1B 2386-11A>G mutation. Ochiai H et al., (2004) found a Japanese infant with MVA homozygous for mutation ss802470619,NC_000015.10:g.40117088G>A (GRCh38), which is the second allele to the seven individuals who had one allele previously identified (Matsuura S, et al. (2006)). This mutation is a hypomorphic mutation that down regulate the expression of BUB1B gene. Using human HeLa cells Bohers et al. (2008) showed the levels of PCS (premature chromatid separation) and aneuploidy were correlated to the decrease of BUB1B expression. BubR1−/− embryos present mosaicism with a significant percentage of aneuploid cells and premature chromatic separation, growth retardation and marked developmental abnormalities. Progressive apoptosis and reduced cell proliferation finally lead to severe morphological malformation and embryonic death (Schmid M et al., 2014.). More evidence is available in literatures, but the maximum score from genetic evidence and experimental evidences has been reached. In summary, BUB1B gene is definitively associated with mosaic variegated aneuploidy syndrome 1. Variants in this gene have been independently and replicably identified in many individuals with MVA.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 8
16
12
Hanks S et al. 2004 Nov (PMID:15475955); Rio Frio T et al. 2010 Dec 30 (PMID:21190457); Ochiai H et al. 2014 Jan 28 (PMID:24344301); Matsuura S et al. 2006 Feb 15 (PMID:16411201);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
0.5
Ochiai H et al. 2014 Jan 28 (PMID:24344301);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 3
3
2
Rio Frio T et al. 2010 Dec 30 (PMID:21190457); Ochiai H et al. 2014 Jan 28 (PMID:24344301);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 4
Schmid M et al. 2014 Sep (PMID:24981203);
Cell culture model 1 0 - 2 2 2
Ochiai H et al. 2014 Jan 28 (PMID:24344301); Bohers E et al. 2008 Dec (PMID:18932004);
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
11/22/2019
EXPERT CURATION (DATE)
Definitive
11/22/2019
EVIDENCE SUMMARY
BUBR1 protein encoded by BUB1B gene is an important protein in the spindle assembly checkpoint. Constitutional homozygotes of hypomorphic mutations or compound heterozygote of a null mutation and a missense/hypomorphic mutation in the BUB1B gene cause the rare human disorder mosaic variegated aneuploidy (MVA) syndrome type I (MIM 257300). Hanks S et al., (2004) identified 6 individuals from 5 unrelated families with typical phenotypes of MVA carry biallelic BUB1B mutations. Rio Frio T et al. (2010) identified a male of 34 yr-old from a consanguineous family with MVA phenotype and many types of cancers homozygous for BUB1B 2386-11A>G mutation. Ochiai H et al., (2004) found a Japanese infant with MVA homozygous for mutation ss802470619,NC_000015.10:g.40117088G>A (GRCh38), which is the second allele to the seven individuals who had one allele previously identified (Matsuura S, et al. (2006)). This mutation is a hypomorphic mutation that down regulate the expression of BUB1B gene. Using human HeLa cells Bohers et al. (2008) showed the levels of PCS (premature chromatid separation) and aneuploidy were correlated to the decrease of BUB1B expression. BubR1−/− embryos present mosaicism with a significant percentage of aneuploid cells and premature chromatic separation, growth retardation and marked developmental abnormalities. Progressive apoptosis and reduced cell proliferation finally lead to severe morphological malformation and embryonic death (Schmid M et al., 2014.). More evidence is available in literatures, but the maximum score from genetic evidence and experimental evidences has been reached. In summary, BUB1B gene is definitively associated with mosaic variegated aneuploidy syndrome 1. Variants in this gene have been independently and replicably identified in many individuals with MVA.