RELN

Gene Facts

• HGNC Symbol: RELN (HGNC:9957)
• HGNC Name: reelin
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: RL, PRO1598
• %HI: 1.1
• pLI: 1
• LOEUF: 0.28
• Cytoband: 7q22.1
• Genomic Coordinates:

  GRCh37/hg19:	chr7:103112236-103630105
  GRCh38/hg38:	chr7:103471789-103989658

• MANE Select Transcript: NM_005045.4 ENST00000428762.6
• Function: Extracellular matrix serine protease that plays a role in layering of neurons in the cerebral cortex and cerebellum. Regulates microtubule function in neurons and neuronal migration. Affects migration of sympathetic preganglionic neurons in the spinal cord, where it seems to act as a barrier to neuronal migration. Enzymatic activity is important for the modulation of cell adhesion. Binding to the extracellular domains of lipoprotein receptors VLDLR and LRP8/APOER2 induces tyrosine phosphorylatio... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-4467
• ClinGen Curation ID: CCID:007761
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Yes
• Last Evaluated: 12/14/2023

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency

HI Disease

• Complex neurodevelopmental disorder

• HI Evidence Comments: The RELN gene, encoding reelin, has been reported in relation with multiple neurodevelopmental disorders and inheritance patterns. Biallelic variants have be reported in individuals with lissencephaly with cerebellar hypoplasia; this relationship has been evaluated by the Brain Malformations GCEP as definitive: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_28da7e7d-fa9c-4f7a-8962-ece6f572adc7-2023-12-04T200000.000Z?page=1&size=25&search=. Monoallelic variants have also been reported in individuals with non-specific neurodevelopmental disorders (PMID: 35769015). The ID Autism GCEP has evaluated this relationship and determined it to be disputed: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_28da7e7d-fa9c-4f7a-8962-ece6f572adc7-2023-12-04T200000.000Z?page=1&size=25&search=. Newer literature has identified individuals with monoallelic variants and lissencephaly (PMID:35769015). Though evidence is 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 biallelic variants may be associated with lissencephaly due to a dosage-sensitive loss of function. The focus of this curation is on heterozygous loss of function variants that have been associated with complex neurodevelopmental disorder (PMIDs: 25363760, 25363768, 25621899, 28191889, 28867142, 31981491, 33057194). In general, these variants are either observed at high frequencies in the general population or inherited from reportedly unaffected parents; further the parents of individuals with biallelic lissencephaly, who are carriers with loss of function variants, are reportedly unaffected. There is limited evidence at this time to determine if heterozygous loss of function variants cause complex neurodevelopmental disorder. Therefore the haploinsufficiency score is 0.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity