Gene Validity Curation

POGZ - intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome

Gene: POGZ (HGNC:18801)
Classification - 03/09/2020
Disease: intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome (MONDO_0014606)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism
Evidence Summary: Variants in POGZ were first reported in association with White-Sutton syndrome (intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome) in 2016, at which time White et al. (PMID: 26739615) described five individuals with similar phenotypes, all of which had predicted LOF variants in POGZ. All individuals had a broad spectrum of intellectual disability/developmental delay with or without autism, and characteristic facial features. At this time, 59 pathogenic/likely pathogenic variants have been reported in humans, with all but one less than 51bp. Variants in this gene have been reported in a number of individual probands since 2016. Most are predicted LOF, as duplications, deletions, or frameshift variants lead to a premature stop codon. All are de novo, or assumed de novo (where DNA from one parent may not be available). With the expanding phenotypic spectrum (for example, as explored in Batzir et al., PMID: 31782611), it is highly likely that more cases of White-Sutton syndrome, caused by pathogenic variants in POGZ, will be reported, maintaining the definitive status of this gene-disease association. Non-human model organisms have been used to investigate the effect of POGZ LOF on brain function, and behaviours related to White-Sutton syndrome. In this curation, two such examples are presented: first, a Drosophila model from Stessman et al. (PMID: 26942287), and second, a KO mouse model from Suliman et al. (2018). Both supported an important role for POGZ in neuronal functioning, with an adverse behavioural phenotype presenting with POGZ LOF. Note that there was no PMID that could be found associated with the Suliman et al. paper (doi: https://doi.org/10.1101/437442). Based on the evidence presented in this paper, the default points for a non-human model organism (2 points) were awarded. In summary, at present there is an abundance of evidence to support a definitive classification for this gene-disease relationship. Future recurations will likely continue to support this recently described syndromic condition.
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 8
16
12
White J et al. 2016 Jan 6 (PMID:26739615); Stessman HAF et al. 2016 Mar 3 (PMID:26942287); Du X et al. 2018 Nov 30 (PMID:30555518); Ferretti A et al. 2019 Aug (PMID:31136090);
Proband with predicted or proven null variant 1.5 0-2 10 2 3 3
White J et al. 2016 Jan 6 (PMID:26739615); Loviglio MN et al. 2016 Nov 1 (PMID:27799067);
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
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1 1
Stessman HAF et al. 2016 Mar 3 (PMID:26942287);
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
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 1

 


 

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 1 13 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
03/10/2020
EXPERT CURATION (DATE)
Definitive
03/09/2020
EVIDENCE SUMMARY
Variants in POGZ were first reported in association with White-Sutton syndrome (intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome) in 2016, at which time White et al. (PMID: 26739615) described five individuals with similar phenotypes, all of which had predicted LOF variants in POGZ. All individuals had a broad spectrum of intellectual disability/developmental delay with or without autism, and characteristic facial features. At this time, 59 pathogenic/likely pathogenic variants have been reported in humans, with all but one less than 51bp. Variants in this gene have been reported in a number of individual probands since 2016. Most are predicted LOF, as duplications, deletions, or frameshift variants lead to a premature stop codon. All are de novo, or assumed de novo (where DNA from one parent may not be available). With the expanding phenotypic spectrum (for example, as explored in Batzir et al., PMID: 31782611), it is highly likely that more cases of White-Sutton syndrome, caused by pathogenic variants in POGZ, will be reported, maintaining the definitive status of this gene-disease association. Non-human model organisms have been used to investigate the effect of POGZ LOF on brain function, and behaviours related to White-Sutton syndrome. In this curation, two such examples are presented: first, a Drosophila model from Stessman et al. (PMID: 26942287), and second, a KO mouse model from Suliman et al. (2018). Both supported an important role for POGZ in neuronal functioning, with an adverse behavioural phenotype presenting with POGZ LOF. Note that there was no PMID that could be found associated with the Suliman et al. paper (doi: https://doi.org/10.1101/437442). Based on the evidence presented in this paper, the default points for a non-human model organism (2 points) were awarded. In summary, at present there is an abundance of evidence to support a definitive classification for this gene-disease relationship. Future recurations will likely continue to support this recently described syndromic condition.