Gene Validity Curation

DIS3L2 - Perlman syndrome

Gene: DIS3L2 (HGNC:28648)
Classification - 11/21/2019
Disease: Perlman syndrome (MONDO_0009965)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: There is abundant evidence published associating the DIS3L2 gene with Perlman syndrome, since the gene-disease relationship was first proposed by Astuti D, et al., 2012. Multiple case level studies (8 families) have been performed with Perlman syndrome patients that have variants in the DIS3L2 gene. The maximum points for genetic evidence has been reached (12 points). Abnormal expression of transcripts have been detected in cells from patients. Mutant DIS3L2 proteins lacking either exon 6 or exon 9 did not show substantial ribonuclease activity and results in aneuploidy and mitotic errors. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. Phenotypes consistent with Perlman syndrome have been reported in three mouse models and one zebrafish model. All of these types of evidence are consistent with a definitive relationship between the DIS3L2 gene and Perlman syndrome.
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
12.5
12
Astuti D et al. 2012 Feb 5 (PMID:22306653); Higashimoto K et al. 2013 Nov (PMID:23486540); Soma N et al. 2017 Apr (PMID:28328139);
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Astuti D et al. 2012 Feb 5 (PMID:22306653); Higashimoto K et al. 2013 Nov (PMID:23486540);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 1 1
Astuti D et al. 2012 Feb 5 (PMID:22306653);
Models Non-human model organism 2 0 - 4 4 2 3 4
Astuti D et al. 2012 Feb 5 (PMID:22306653); Hunter RW et al. 2018 July 1 (PMID:29950491);
Cell culture model 1 0 - 2 1 1
Astuti D et al. 2012 Feb 5 (PMID:22306653);
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
09/27/2019
EXPERT CURATION (DATE)
Definitive
11/21/2019
EVIDENCE SUMMARY
There is abundant evidence published associating the DIS3L2 gene with Perlman syndrome, since the gene-disease relationship was first proposed by Astuti D, et al., 2012. Multiple case level studies (8 families) have been performed with Perlman syndrome patients that have variants in the DIS3L2 gene. The maximum points for genetic evidence has been reached (12 points). Abnormal expression of transcripts have been detected in cells from patients. Mutant DIS3L2 proteins lacking either exon 6 or exon 9 did not show substantial ribonuclease activity and results in aneuploidy and mitotic errors. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. Phenotypes consistent with Perlman syndrome have been reported in three mouse models and one zebrafish model. All of these types of evidence are consistent with a definitive relationship between the DIS3L2 gene and Perlman syndrome.