Gene Validity Curation

CEP57 - mosaic variegated aneuploidy syndrome 2

Gene: CEP57 (HGNC:30794)
Classification - 11/22/2019
Disease: mosaic variegated aneuploidy syndrome 2 (MONDO_0013582)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: Centrosomal protein 57kDa, also known as Translokin or TLk, encoded by CEP57 gene functions in microtubular stabilization and mediates its nuclear translocation and mitogenic activity. Mutations in this gene have been found to cause mosaic variegated aneuploidy (MVA) syndrome type 2. Snape K et al., (2011) using exome sequencing identified biallelic LoF CEP57 mutation as a cause of constitutional mosaic aneuploidies. In this article, two Mexican siblings with MVA carry the same compound heterozygous CEP57 mutations, a 2-bp deletion (520delGA) in exon 5, and an 11-bp duplication in exon 9 (915_925dup11); Another 2 individuals with biallelic CEP57 mutations, homozygous for c.341C>T;p.R81X, and c.915_925dup11, from a cohort of 13 BUB1B negative families with MVA were also identified. De La Torre-Garcia et al., (2018) identified a Mexico boy with MVA homozygous for CEP57 c.915_925dup11. Pinson L et al., (2014) found a Morocan girl from a consanguineous family homozygous for CEP57 c.915_925dup11. Brightman DS et al.(2018) found a Pakistani girl with MVA of a consanguineous family homozygous for CEP57 c.697delA, p.Lys235Argfs*31). Experimental evidences showed CEP57 protein is localized to kinetochore contributing spindle microtubule organization, CEP57 depletion leads to missegregation of chromosome. siRNA resistant Cep57 wt with mutated siRNA targeted region in HeLa cells rescued the phenotypes. Research on CEP57 gene function in microtubule stability has been upheld over time. In summary, there have been sufficient evidences supporting the association of CEP57 with autosomal recessive inherited Mosaic Variegated Aneuploidy (MVA) type 2.
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 6
12
12
Snape K et al. 2011 Jun (PMID:21552266); Pinson L et al. 2014 Jan (PMID:24259107); Brightman DS et al. 2018 Aug (PMID:30147898); De la Torre-García O et al. 2018 Jul 17. (PMID:30010053);
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 3
1.5
2
Emanuele MJ et al. 2007 Sep 7 (PMID:17803911); He R et al. 2013 May 17 (PMID:23569207); Wu Q et al. 2012 Sep (PMID:22508265);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Andersen JS et al. 2003 Dec 4 (PMID:14654843);
Functional Alteration Patient cells 1 0 - 2 2 1
1
1.5
De la Torre-García O et al. 2018 Jul 17. (PMID:30010053);
Non-patient cells 0.5 0 - 1 1 0.5
Zhou H et al. 2016 Jan 8 (PMID:26743940);
Models Non-human model organism 2 0 - 4 4 1 2 3
Aziz K et al. 2018 Aug 1 (PMID:30035751);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2 1 1
Zhou H et al. 2016 Jan 8 (PMID:26743940);
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
10/11/2019
EXPERT CURATION (DATE)
Definitive
11/22/2019
EVIDENCE SUMMARY
Centrosomal protein 57kDa, also known as Translokin or TLk, encoded by CEP57 gene functions in microtubular stabilization and mediates its nuclear translocation and mitogenic activity. Mutations in this gene have been found to cause mosaic variegated aneuploidy (MVA) syndrome type 2. Snape K et al., (2011) using exome sequencing identified biallelic LoF CEP57 mutation as a cause of constitutional mosaic aneuploidies. In this article, two Mexican siblings with MVA carry the same compound heterozygous CEP57 mutations, a 2-bp deletion (520delGA) in exon 5, and an 11-bp duplication in exon 9 (915_925dup11); Another 2 individuals with biallelic CEP57 mutations, homozygous for c.341C>T;p.R81X, and c.915_925dup11, from a cohort of 13 BUB1B negative families with MVA were also identified. De La Torre-Garcia et al., (2018) identified a Mexico boy with MVA homozygous for CEP57 c.915_925dup11. Pinson L et al., (2014) found a Morocan girl from a consanguineous family homozygous for CEP57 c.915_925dup11. Brightman DS et al.(2018) found a Pakistani girl with MVA of a consanguineous family homozygous for CEP57 c.697delA, p.Lys235Argfs*31). Experimental evidences showed CEP57 protein is localized to kinetochore contributing spindle microtubule organization, CEP57 depletion leads to missegregation of chromosome. siRNA resistant Cep57 wt with mutated siRNA targeted region in HeLa cells rescued the phenotypes. Research on CEP57 gene function in microtubule stability has been upheld over time. In summary, there have been sufficient evidences supporting the association of CEP57 with autosomal recessive inherited Mosaic Variegated Aneuploidy (MVA) type 2.