Gene Validity Curation

PHF8 - syndromic X-linked intellectual disability Siderius type

Gene: PHF8 (HGNC:20672)
Classification - 11/07/2018
Disease: syndromic X-linked intellectual disability Siderius type (MONDO_0010286)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism
Evidence Summary: The PHF8 gene has been associated with syndromic X-linked intellectual disability, Siderius type. Variants in PHF8 have been reported in humans as early as 1999 (10398231, 10470851). The affected males typically have mild to moderate intellectual disability. They often have delayed speech and motor development, and cleft lip/palate. Some of the them also manifest distinctive facial features, including a long face, a sloping forehead, a broad nasal bridge, a prominent bone in the lower forehead (supraorbital ridge), upslanting palpebral fissures, low-set ears, and large hands. This disease association was made using case-level data and experimental data. At least 7 variants (missense, nonsense, frameshift, and splice site variant) were curated from five publications (17594395, 29276005, 17661819, 16199551, 25167861). To date, 8 unique variants with PHF8 have been classified as Pathogenic in ClinVar. The gene-disease association is supported by mouse model, zebrafish model, cell culture model, and their respective rescue experiments. In summary, PHF8 is definitively associated with syndromic X-linked intellectual disability, Siderius type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/7/18 (SOP Version 6).
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 3
3.5
3.5
Abidi F et al. 2007 Jul (PMID:17594395); Faundes V et al. 2018 Jan 4 (PMID:29276005);
Proband with predicted or proven null variant 1.5 0-2 10 4 4 4
Laumonnier F et al. 2005 Oct (PMID:16199551); Retterer K et al. 2016 July (PMID:26633542); Faundes V et al. 2018 Jan 4 (PMID:29276005);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
0.6
0.6
Koivisto AM et al. 2007 Aug (PMID:17661819); Redin C et al. 2014 Nov (PMID:25167861);
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 0.5 0.5  
Candidate gene sequencing 2.78 1
Laumonnier F et al. 2005 Oct (PMID:16199551);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 2.78    
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) 8.6
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 1 1
Kleine-Kohlbrecher D et al. 2010 Apr 23 (PMID:20346720);
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 2 2 4
Chen X et al. 2018 Jan 9 (PMID:29317619); Qi HH et al. 2010 Jul 22 (PMID:20622853);
Cell culture model 1 0 - 2 1 0.5
Qiu J et al. 2010 Aug (PMID:20548336);
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 2
1.5
Chen X et al. 2018 Jan 9 (PMID:29317619); Qi HH et al. 2010 Jul 22 (PMID:20622853);
Rescue in cell culture model 1 0 - 2 1 0.5
Qiu J et al. 2010 Aug (PMID:20548336);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5

 


 

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 8.6 5 13.6 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
09/26/2019
EXPERT CURATION (DATE)
Definitive
11/07/2018
EVIDENCE SUMMARY
The PHF8 gene has been associated with syndromic X-linked intellectual disability, Siderius type. Variants in PHF8 have been reported in humans as early as 1999 (10398231, 10470851). The affected males typically have mild to moderate intellectual disability. They often have delayed speech and motor development, and cleft lip/palate. Some of the them also manifest distinctive facial features, including a long face, a sloping forehead, a broad nasal bridge, a prominent bone in the lower forehead (supraorbital ridge), upslanting palpebral fissures, low-set ears, and large hands. This disease association was made using case-level data and experimental data. At least 7 variants (missense, nonsense, frameshift, and splice site variant) were curated from five publications (17594395, 29276005, 17661819, 16199551, 25167861). To date, 8 unique variants with PHF8 have been classified as Pathogenic in ClinVar. The gene-disease association is supported by mouse model, zebrafish model, cell culture model, and their respective rescue experiments. In summary, PHF8 is definitively associated with syndromic X-linked intellectual disability, Siderius type. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/7/18 (SOP Version 6).