Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NLGN4X : complex neurodevelopmental disorder

HGNC:14287 | MONDO_0100038
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Intellectual Disability and Autism
SOP: Gene Clinical Validity Standard Operating Procedures (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 1
Talebizadeh Z et al. 2006 May (PMID:16648374);
Proband with predicted or proven null variant 1.5 0-2 10 6 9 9
Grozeva D et al. 2015 Dec (PMID:26350204); Laumonnier F et al. 2004 Mar (PMID:14963808); Jamain S et al. 2003 May (PMID:12669065); Yu TW et al. 2013 Jan 23 (PMID:23352163); C Yuen RK et al. 2017 Apr (PMID:28263302);
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 1 1  
Candidate gene sequencing 3.3 1
Laumonnier F et al. 2004 Mar (PMID:14963808);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.3    
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) 11
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 2 1.5
Jamain S et al. 2003 May (PMID:12669065); Hoon M et al. 2011 Feb 15 (PMID:21282647);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0.5
Delattre V et al. 2013 Oct 9 (PMID:24104404);
Models Non-human model organism 2 0 - 4 4 2 3 4
El-Kordi A et al. 2013 Aug 15 (PMID:23183221); Unichenko P et al. 2018 Aug 1 (PMID:29106499);
Cell culture model 1 0 - 2 1 1
Kim JE et al. 2011 Feb 15 (PMID:21278334);
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
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 11 6 17 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between the NLGN4X gene and X-linked complex neurodevelopmental disorder was assessed using the ClinGen Clinical Validity Framework on 7/26/2018. The observed phenotypes for patients with variants in this gene include autism spectrum disorders, intellectual disability, attention deficit hyperactivity disorder (ADHD), and/or cerebral palsy. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern. Therefore, all of the disease entities have been lumped into one disease entity, complex neurodevelopmental disorder. Supporting evidence includes both case-level data and experimental data. Variants in NLGN4X in individuals with complex neurodevelopmental disorders were reported as early as 2003 (Jamain et al. PMID:12669065). Since that time, multiple variants (e.g. missense, nonsense, frameshift, large deletions)have been reported, including the 7 variants documented here (26350204, 14963808, 12669065, 23352163, 28263302,16648374). Of note, our curation also includes the exonic deletion reported by Lawson-Yuen et al. (PMID:18231125) (at 1.5 points); this evidence was not formally documented in the same manner as the smaller single nucleotide variants due to limitations registering larger variants in the ClinGen Allele Registry. Variants in this gene have been reported to segregate with disease in at least one large family comprised of 13 affected family members (PMID:14963808). More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is loss of function, as many of the cases in the publications cited above have null variants in hemizygous males. This gene-disease association is supported by mouse models displaying neurodevelopmental phenotypes consistent with autism, as well as expression and functional alteration studies (12669065, 21282647, 24104404, 23183221, 29106499, 21278334). In summary, NLGN4X is definitively associated with X-linked complex neurodevelopmental disorder. 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 ID/Autism GCEP on 8/1/2018.