RELN

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0009760

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014639

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0019450

Submitter: ClinGen

RELN was first reported in relation to autosomal recessive lissencephaly with cerebellar hypoplasia in 2000 (Hong et al., PMID: 10973257). This condition is also described in the literature as lissencephaly-2 (Norman Roberts syndrome) (OMIM 257320). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism, inheritance pattern and phenotypic variability with other conditions reported to be associated with this gene. Therefore, the following disease entities are not included in this curation: autosomal dominant complex neurodevelopmental disorder, autosomal dominant familial temporal lobe epilepsy, autosomal dominant lissencephaly spectrum disorder; see PMID 35769015 for a discussion of the various phenotypes reported to be associated with this gene. Seven variants (2 missense, 1 nonsense, 2 splice-disrupting, 2 frameshifts) that have been reported in six probands in five publications (PMIDs: 10973257, 27000652, 26395554, 28454995, 35769015) are included in this curation. Five of these six probands were homozygous variant carriers in consanguineous families, many of which had more than one affected homozygote. At least four cases of structural chromosome abnormalities disrupting the RELN gene have also been reported (PMID 10973257, 16958033, 17431900, 35769015) for three of which an absence of Reelin protein has been demonstrated; these were not scored in this curation due to the absence of an accurate sequence level variant description, however they do provide additional support for this assertion. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by several spontaneous and experimentally generated reeler mouse mutants; the structural features of Relnrl/rl brain are consistent with the lissencephaly with cerebellar hypoplasia observed in the patients (PMID: 17185001). In summary, RELN is definitively associated with autosomal recessive AR lissencephaly with cerebellar hypoplasia. 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 Brain Malformations gene curation expert panel on 26.Sept.2023.

Inheritance Pattern: AR

Disease ID:MONDO:0009760

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0005306

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014639

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009760

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009760

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009760

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014639

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0010898

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009760

Submitter: Illumina