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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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