Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

NRXN1 : complex neurodevelopmental disorder

HGNC:8008 | MONDO_0100038
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
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
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
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) 0
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 3 4.5 4
Laarakker MC et al. 2012 Feb 13 (PMID:22348092); Grayton HM et al. 2013 Jun 28 (PMID:23840597); Rabaneda LG et al. 2014 Jul 24 (PMID:25017069);
Cell culture model 1 0 - 2 2 0
Zeng L et al. 2013 Mar 25 (PMID:23536886); Pak C et al. 2015 Sep 3 (PMID:26279266);
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) 4



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 0 4 4 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Due to the size of the deletions observed (>10kb), unable to enter variants on Gene Curation Interface (preventing ability to score). See Evidence Summary for a complete description of scoring for all cases, which brings the total score into the Definitive range (15.6 points).
Variants in NRXN1 have been associated with a variety of different neurodevelopmental conditions, including intellectual disability, epilepsy, and autism spectrum disorder. At least 118 pathogenic or likely pathogenic variants have been reported in ClinVar (most being deletions, SNVs, or duplications), with the first reported NRXN1 deletion observed by The Autism Genome Project Consortium in 2007 (PMID: 17322880). Here, we report several cases that have led to a definitive classification between the curated disease entity, complex neurodevelopmental disorder (MONDO:0100038), and NRXN1. Zahir et al., 2008 (PMID: 18057082) report a 12yo male proband with ID, autistic features, and severe language and motor impairments; this individual had a heterozygous de novo deletion of ~320kb in NRXN1 (chr2:50,799,281-51,120,644 (hg18)), and was given 2 points. Another case report from Zehra et al., 2008 (PMID: 26438105) presented a 28yo female proband with ID, developmental delay, language delay, and impaired social interactions (heterozygous de novo deletion of ~455 kb (chr2:51,020,477-51,476,031 (hg19)) – this individual was given 1.5 points, as the effect of this variant on protein function was not clear. A family study by Wisniowiecka-Kowalnik et al., 2010 (PMID: 20162629) outlined three families (only two scored). Family 1 received a score of 1.5 points for an ~380 kb deletion in NRXN1 that was observed in all five affected members (chr2:50,034,351-50,413,346 (hg18)). Family 2 also received a score of 1.5 points for an inherited tandem duplication, found in all three affected individuals (chr2:50,011,487-50,195,746 (hg18)). Two final studies were assessed, both of which presented a number of unrelated individuals. In a paper from Gregor et al., 2011 (PMID: 21827697), four probands were scored (N1, N2, N5, and N6). All four were given defaults scores of 0.5 points for their NRXN1 deletions (chr2:50,806,393-51,208,000 (hg18); chr2:50,270,203-51,357,206 (hg17); chr2:50,861,527-51,090,563 (hg17); chr2:51,033,865-51,496,143 (hg17)). Finally, Ching et al., 2010 (PMID: 20468056) present twelve individuals, eight of which were scored. Patient 2 received a full score of 2 points for a 3923kb de novo deletion (chr2:50,128,256-54,050,713 (hg18)). Patient 3 received a downgraded score of 0.1 point for a 315kb deletion chr2:50,897,002-51,212,385 (hg18)) in light of a very mild neurodevelopmental disorder phenotype. Patients 4, 5, 6, 7, and 9 all received scores of 0.5. Patients 4, 6, 7, and 9 all had inherited deletions (chr2:50,936,914-51,167,934; chr2:51,059,410-51,316,396; chr2: 51,090,504-51,212,385; chr2:50,689,280-50,853,329 (hg18)), while patient 5 had a de novo deletion (chr2:50,920,082-51,059,469 (hg18)), but was downgraded due to a mild phenotype. The variant observed in patient 10 (chr2:50,714,927-50,853,329 (hg18)) only impacted intronic regions and was given a score of zero since at this time, only exonic NRXN1 variants are known to be pathogenic.. In total, 13.1 points were awarded for genetic evidence (note that more evidence is available, but not assessed given that this is above the 12 point cut-off), and 4 points for experimental evidence (max allowed for non-human model organisms), bringing the NRXN1-complex NDD classification into the definitive range (replicated over time) – 16 points.