Gene Validity Classification Summary

Gene/Disease Pair:

DHCR7 : Smith-Lemli-Opitz syndrome

HGNC:2860 | MONDO_0010035
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Autism and Intellectual Disability EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max 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
12
12
Witsch-Baumgartner M et al. 2000 Feb (PMID:10677299); Witsch-Baumgartner M et al. 2005 Apr (PMID:15776424); Jong Hee Chae et al. 2007 Nov (PMID:18006960); Quélin C et al. 2012 Feb (PMID:22226660); Lanthaler B et al. 2015 Aug (PMID:25040602);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
 
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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 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
1
1
Waterham HR et al. 2000 May (PMID:10905895);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4 4
Wassif CA et al. 2001 Mar 15 (PMID:11230174); Fitzky BU et al. 2001 Sep (PMID:11560960);
Cell culture model 1 0 - 2 1
Fitzky BU et al. 1998 Jul 7 (PMID:9653161);
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
2
Yu H et al. 2005 Apr 21 (PMID:15862627);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2 1
Wassif CA et al. 1998 Jul (PMID:9634533);
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 12 5 17 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
09/09/2018
EXPERT CURATION (DATE)
Definitive
09/11/2018
EVIDENCE SUMMARY
The association between the DHCR7 gene and Smith-Lemli-Opitz syndrome (SLOS) is well-characterized, with over 150 unique variants described in HGMD, including nonsense, missense, splice, and deletion variants reported in dozens of publications. Experimental evidence includes three mouse models of disease, rescue experiments showing normalized 7-DCH levels in patient-derived fibroblasts transfected with WT DHCR7, and additional studies demonstrating null or hypomorphic mRNA or protein expression in genes harboring pathogenic variants. Almost all SLOS patients demonstrate intellectual disability (Cunniff et al., 1997; Ryan et al., 1998) and about half meet the DSM-IV criteria for autism diagnosis (Tierney et al., 2000).