Submission Details

The RELN gene, encoding reelin, has been reported in relation with multiple neurodevelopmental disorders and inheritance patterns. Biallelic RELN variants have been reported in individuals with lissencephaly and severe intellectual disability. Monoallelic variants have also been reported in individuals with lissencephaly but with variable developmental outcomes, as well as in individuals with nonspecific neurodevelopmental disorders (PMID: 35769015). The ClinGen Intellectual Disability and Autism Gene Curation Expert Panel has decided that the variants reported with lissencephaly (both monoallelic and biallelic) should be curated separately from the monoallelic variants reported in individuals with nonspecific complex neurodevelopmental disorder. Though evidence is still emerging, there has been some suggestion that the different presentations are due to different mechanisms of action. Some of the heterozygous, de novo, missense variants in probands with mild lissencephaly (pachygyria) demonstrated a dominant negative effect (https://www.biorxiv.org/content/10.1101/2021.05.25.445586v1); other work has suggested that the heterozygous variants reported in individuals with complex neurodevelopmental disorder may be due to a dosage-sensitive loss of function (PMID: 35769015). More information is needed to better understand the relationship between variation in RELN and this broad spectrum of neurodevelopmental presentations. The lissencephaly presentations will be assessed separately by the ClinGen Brain Malformations Gene Curation Expert Panel.

RELN was first reported in relation to autosomal dominant autism in 2001 (Persico et al., PMID: 11317216), when a GGC trinucleotide repeat immediately upstream of the RELN 5’-UTR was found to be more frequent in a small sample of cases compared to controls. However, subsequent studies showed no significant increase of this or other RELN variants in autism vs controls (PMIDs: 12192627, 14515139, 15048647, 15048648, 20554015). Since 2001, numerous heterozygous coding variants in RELN have been reported in individuals with complex neurodevelopmental disorders, including intellectual disability (ID) and autism, but their pathogenicity is unclear (PMIDs: 25363760, 25363768, 25621899, 28191889, 28867142, 31981491, 33057194). For this reason, these variants were not scored. Several heterozygous truncating variants have also been reported in autism or ID, including 5 de novo (PMIDs: 25363760, 28191889, 31981491, 33057194). However, some truncating variants are inherited (with no information about the parental phenotype; PMIDs: 25363760, 28191889), or occur in healthy controls (PMID: 31981491). Although RELN is highly constrained for truncating variants (pLI = 1, gnomAD v2.1.1), there are 33 instances of truncating variants in gnomAD. Of note, carrier parents of individuals with autosomal recessive lissencephaly with cerebellar hypoplasia due to biallelic loss-of-function RELN variants (truncating variants or chromosomal rearrangements) were not noted to have abnormal phenotypes, consistent with the lack of pathogenicity of heterozygous variants (PMIDs: 16958033, 17431900). Thus, truncating variants were also not scored, given the overall lack of convincing evidence that heterozygous loss-of-function variation causes disease.

Multiple lines of experimental evidence have been reported, including animal models, expression studies, and in vitro functional assays (PMIDs: 10612399, 11786309, 12691835, 16977475, 18547243, 18845182, 21777509, 23104248, 23752244, 27134686, 30022058); however, it should be noted that many of the heterozygous reelin mouse models have failed to replicate significant behavioral findings from previous papers. Furthermore, the phenotypes outlined in these studies indicate deficits in neuronal migration, which is more consistent with the role of RELN in autosomal recessive lissencephaly, and thus was not scored as part of this curation (PMID: 30022058).

In summary, there is no convincing genetic evidence to support the relationship between RELN and autosomal dominant complex neurodevelopmental disorders, including autism spectrum disorder, so this gene-disease relationship is disputed. This gene-disease pair was originally evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on April 29, 2019 with a final classification of Disputed. It was reevaluated both on March 17, 2021 and July 19, 2023. As a result of these reevaluations, the original classification of Disputed did not change. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 19, 2023 (SOP Version 9).