Gene Validity Classification Summary

Gene/Disease Pair:

NLGN3 : complex neurodevelopmental disorder

HGNC:14289 | MONDO_0100038
Mode of Inheritance: X-linked inheritance (HP:0001417)
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
1
1
Iossifov I et al. 2014 Nov 13 (PMID:25363768);
Proband with predicted or proven null variant 1.5 0-2 10 4 4
C Yuen RK et al. 2017 Apr (PMID:28263302); Deciphering Developmental Disorders Study et al. 2015 Mar 12 (PMID:25533962); Kenny EM et al. 2014 Aug (PMID:24126926);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.6
0.6
Jamain S et al. 2003 May (PMID:12669065); 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 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) 5.6
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
1.5
Protein Interaction 0.5 0 - 2 1
Ichtchenko K et al. 1996 Feb 2 (PMID:8576240); Meyer G et al. 2004 Oct (PMID:15458844);
Expression 0.5 0 - 2 0.5
Shen EH et al. 2012 Dec (PMID:23041053);
Functional Alteration Patient cells 1 0 - 2 2
1.5
Non-patient cells 0.5 0 - 1 1.5
Chih B et al. 2004 Jul 15 (PMID:15150161); De Jaco A et al. 2010 Sep 10 (PMID:20615874);
Models Non-human model organism 2 0 - 4 4 7 4
Chadman KK et al. 2008 Jun (PMID:19360662); Etherton M et al. 2011 Aug 16 (PMID:21808020); Hamilton SM et al. 2014 Apr (PMID:24773431); Radyushkin K et al. 2009 Jun (PMID:19243448);
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) 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 5.6 6 11.6 NO
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)
Strong
09/14/2018
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Moderate
09/14/2018
REASON(S) FOR CHANGE
The current scoring system is not overly strict, thus the group feels more comfortable to not round up the points.
EXPERT CURATION (DATE)
Moderate
09/19/2018
EVIDENCE SUMMARY
Variants in NLGN3 have been identified in individuals with autism, intellectual disability, and/or schizophrenia. In vitro studies underscore a critical role of NLGN3 in synaptic transmission. Mouse models with R451C mutation or KO of NLGN3 show somewhat differential behavioral abnormalities, raising the question of LOF vs. GOF mechanism.