RELN

Chr 7ADAR

reelin

Also known as: ETL7, LIS2, PRO1598, RL

NCBI Gene: 5649 ENSG00000189056 UniProt: P78509 OMIM: 600514

The protein is a large secreted extracellular matrix protein that controls cell positioning and neuronal migration during brain development. Mutations cause autosomal recessive lissencephaly type 2 (Norman-Roberts type) with cerebellar hypoplasia and autosomal dominant familial temporal lobe epilepsy type 7. The pathogenic mechanism involves loss of function, disrupting normal neuronal migration patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a large secreted extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development. This protein may be involved in schizophrenia, autism, bipolar disorder, major depression and in migration defects associated with temporal lobe epilepsy. Mutations of this gene are associated with autosomal recessive lissencephaly with cerebellar hypoplasia. Two transcript variants encoding distinct isoforms have been identified for this gene. Other transcript variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.182 OMIM phenotypes

Clinical Summary— RELN

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Gene-Disease Validity (ClinGen)

lissencephaly with cerebellar hypoplasia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 1.000

Z-score 11.05

OE 0.12 (0.09–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.25Z-score

OE missense 0.85 (0.82–0.89)

1577 obs / 1849.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.12 (0.09–0.18)

0≤0.351.4

Missense OE?0.85 (0.82–0.89)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 23 / 185.3Missense obs/exp: 1577 / 1849.2Syn Z: -1.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRELN-related lissencephalyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.3296th %ile

GOF

0.3887th %ile

LOF

0.71top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNPreviously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References