Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

RELN : complex neurodevelopmental disorder

HGNC:9957 | 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 9
0
0
Neale BM et al. 2012 Apr 4 (PMID:22495311); Iossifov I et al. 2014 Nov 13 (PMID:25363768); De Rubeis S et al. 2014 Nov 13 (PMID:25363760); Stessman HA et al. 2017 Apr (PMID:28191889); Yuen RK et al. 2015 Feb (PMID:25621899);
Proband with predicted or proven null variant 1.5 0-2 10 2 0 0
De Rubeis S et al. 2014 Nov 13 (PMID:25363760);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 15
0
0
Dazzo E et al. 2015 Jun 4 (PMID:26046367); Alvarez-Mora MI et al. 2016 Feb-Mar (PMID:26845707); Groen JL et al. 2015 Mar (PMID:25648840); Hayashi S et al. 2017 Aug 7 (PMID:28783747); Matsunami N et al. 2014 Jan 27 (PMID:24467814); Koshimizu E et al. 2013 Sep 16 (PMID:24066114);
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 10
0
0
Devlin B et al. 2004 Apr 1 (PMID:15048647); He Y et al. 2011 May 30 (PMID:20554015); Krebs MO et al. 2002 (PMID:12192627); Li J et al. 2004 Apr 1 (PMID:15048648); Fu X et al. 2013 Dec (PMID:24385848); Holt R et al. 2010 Sep (PMID:20442744); Skaar DA et al. 2005 Jun (PMID:15558079); Wang Z et al. 2014 Mar (PMID:24453138);
Aggregate Variant Analysis 0-6 3
0
Bonora E et al. 2003 Oct (PMID:14515139); Stessman HA et al. 2017 Apr (PMID:28191889); Persico AM et al. 2001 Mar (PMID:11317216);
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 3
0
2
Groc L et al. 2007 Sep 19 (PMID:17881522); Kupferman JV et al. 2014 Sep 11 (PMID:25201528); Pla R et al. 2006 Jun 28 (PMID:16807322);
Protein Interaction 0.5 0 - 2 2 0
Telese F et al. 2015 May 6 (PMID:25892301); Zhubi A et al. 2014 Jan 21 (PMID:24448211);
Expression 0.5 0 - 2 4 2
Dazzo E et al. 2015 Jun 4 (PMID:26046367); Fatemi SH et al. 2005 Apr 1 (PMID:15820235); Balthazart J et al. 2008 Jun 2 (PMID:18448255); Senzaki K et al. 1999 Dec 10 (PMID:10612399);
Functional Alteration Patient cells 1 0 - 2 2 2
0
0
Arioka Y et al. 2018 July 19 (PMID:30022058); Lintas C et al. 2016 Apr 29 (PMID:27134686);
Non-patient cells 0.5 0 - 1 2 0
Lammert DB et al. 2017 July (PMID:28419454); Arioka Y et al. 2018 July 19 (PMID:30022058);
Models Non-human model organism 2 0 - 4 4 14 2 2
Costa E et al. 2002 Feb (PMID:11786309); Podhorna J et al. 2004 Aug 12 (PMID:15219705); Krueger DD et al. 2006 Nov (PMID:16977475); Larson J et al. 2003 May 2 (PMID:12691835); Shehabeldin R et al. 2018 July 12 (PMID:30001399); Barr AM et al. 2008 May (PMID:18547243); Howell KR et al. 2016 July (PMID:26059812); Kutiyanawalla A et al. 2012 Sep (PMID:21777509); Laviola G et al. 2009 Apr (PMID:18845182); Romano E et al. 2014 Apr (PMID:24337025); Qiu S et al. 2006 May (PMID:16376115); Iafrati J et al. 2014 Apr (PMID:23752244); Bouamrane L et al. 2017 Jan 12 (PMID:28127276); Whittaker DE et al. 2017 Mar 1 (PMID:28165338);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
0
Rogers JT et al. 2013 Apr (PMID:23104248);
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
(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 0 4 4 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)
Limited
05/03/2019
MODIFY CALCULATED CLASSIFICATION
YES
MODIFIED CLASSIFICATION (DATE)
Disputed
05/03/2019
REASON(S) FOR CHANGE
https://www.biorxiv.org/content/10.1101/115964v1 This new paper on bioarchive brought into question the statistical analysis of the Stessman et al. 2017 paper resulting in edits by the Stessman et al. 2017 group. After further revision they reported that RELN was not significantly associated with autism. Overall, there is no genetic evidence that can be scored because all the case-control analyses either do not have significant results or are not adequately designed to provide supporting evidence for RELN's association with this complex neurodevelopmental disorder.
EXPERT CURATION (DATE)
Disputed
05/01/2019
EVIDENCE SUMMARY
The gene RELN (protein name: reelin) was first reported in relation to autosomal dominant complex neurodevelopmental disorder (which may include autism, intellectual disability, and/or epilepsy) in 2012 (Neale et al., PMID 22495311), albeit the first report of RELN variation in relation to autosomal dominant autism was in 2001 (Persico et al., PMID: 11317216). Since 2001, autosomal dominant variation in RELN has been asserted in the literature in relation to multiple different disease entities including autism, intellectual disability, adult onset epilepsy, myoclonus dystonia, and pontine and cerebellar hypoplasia with accompanying microcephaly and intellectual disability ( PMIDs: 28191889, 26046367, 25648840, 28783747). Variants in RELN (missense, nonsense, and triplet repeats) have been reported in at least 25 probands with complex neurodevelopmental disorder (including intellectual disability, autism, seizures, etc) in at least 10 publications, however the molecular mechanism for autosomal dominant RELN variation in complex neurodevelopmental disorder is unclear. Many of the RELN variants have been reported as part of large sequencing projects of patients with autism and/or intellectual disability and assert de novo inheritance (PMIDs: 26845707, 24467814, 25363760, 22495311, 25363768, 25621899, 28191889). Furthermore, several publications have repeatedly used these large sequencing cohorts in their analysis, thus in order not to conflate the gene-disease classification we scored one study that combined all the large sequencing cohort data in a case-control study (Stessman et al., 2017 PMID 28191889). In Stessman et al., 2017, the cases were compared to ExAC participants and unaffected siblings for private mutations, and the authors note they found an FDR-corrected private burden of 1.22E-1 for likely gene deleterious (LGD) and 3.04E-1 for missense with a CADD score above 30 (MIS30) and did not indicate these as being significant (Supplemental Table 15, linked to Table 2). The significance that the Stessman paper indicates for RELN variation is a significant increase in de novo variation in autism vs. intellectual disability, which is a case vs. case comparison and is not scored per our current Gene Validity Matrix (version 6). Moreover, contradictory evidence to the statistical analysis performed for the autism vs. intellectual disability analysis in the Stessman paper was brought to light by Barrett et al., 2017 (BioRxiv: https://www.biorxiv.org/content/10.1101/115964v1 ; https://www.biorxiv.org/content/10.1101/115964v3 ; DOI: https://doi.org/10.1101/115964), which prompted reanalysis by Stessman et al., (https://disq.us/url?url=https%3A%2F%2Feichlerlab.gs.washington.edu%2Fdata%2FStessman_CorrectedTables.xlsx%3AMSR7DuYiWDGGTxpMOvbv-22-2c0&cuid=2634513). The reanalysis indicates no significant increase in de novo RELN variation in autism vs intellectual disability, and no significance in de novo RELN variation between cases (autism and intellectual disability) vs. ExAC control cohorts. In addition, the majority of the control cohort, which was made up from ExAC, was not age-matched, sex-matched, or ethnically-matched and thus represents an inadequate control comparison, thus given the overall data this evidence was scored as zero. It is also important to note that there were other cases not included in this case-control study in which RELN variation was asserted (PMIDs 6845707, 24467814, 25363760, 24453138, 22495311, 25363768, 25621899, 24385848, 20442744, 20466114, 25201528, 15558079, ). These cases were not scored due to lack of sequencing validation and/or evidence for pathogenicity. Despite the large number of individuals with asserted de novo RELN variants, the mechanism for disease is unknown, the phenotype is relatively non-specific and is associated with high genetic heterogeneity, and there are many instances of RELN variants in reportedly unaffected controls (ExAC and gnoMAD data). Furthermore, several lines of contradictory data have been reported indicating the GGC trinucleotide repeat immediately upstream of the RELN 5’-UTR (first reported in Persico et al., 2001 PMID: 11317216) is not significantly increased in cases vs controls, as well as finding no increases in other RELN variants in cases vs controls (PMIDs: 12192627, 20554015, 15048648, 15048647, 14515139). This trinucleotide repeat is also present in control cohorts represented in gnomAD at frequency above 1% which also support lack of pathogenicity for this variation. Multiple lines of experimental evidence have been reported including animal models, expression studies, and in vitro functional assays, however it is important to note that many of the heterozygous reelin mouse models have failed to replicate significant behavioral findings from previous papers (PMIDs 18448255, 10612399, 26046367, 15820235, 28419454, 30022058, 27134686, 11786309, 15219705, 16977475, 12691835, 30001399, 18547243, 26059812, 21777509, 18845182, 24337025, 16807322, 16376115, 1992965, 23752244, 28127276, 23104248, 25892301, 28165338, 24448211). Furthermore, the phenotypes outlined in these studies indicate deficits in neuronal migration, which corresponds more closely with the role of RELN in lissencephaly (see below), and thus was not scored as part of this curation. According to nosological sites (OMIM and Orphanet), RELN has been asserted in association with autosomal dominant familial temporal lobe epilepsy (MIM:616436; ORPHA:101046 ) and autosomal recessive lissencephaly 2 (MIM:257320; ORPHA:89844). Per the ClinGen Lumping and Splitting Working Group criteria we find that the RELN-lissencephaly 2 gene-disease relationship follows a different inheritance pattern and has a different phenotypic spectrum, and therefore this relationship will be assessed as a separate, independent curation by the ClinGen Brain Malformations Gene Curation Working Group. Similarly, the relationship of RELN with autosomal dominant familial temporal epilepsy indicates a different phenotype and inheritance pattern, and thus represents a separate, independent curation than the RELN-complex neurodevelopmental disorder curation outlined above. In summary, there is convincing evidence disputing the relationship between RELN and autosomal dominant complex neurodevelopmental disorders; particularly this gene's relationship with autism. More evidence is needed to either support or refute the role of RELN in complex neurodevelopmental disorder .This classification was approved by the ClinGen ID/Autism Gene Curation Expert Panel on 4/29/2019 (SOP Version 6)