RERE

Chr 1AD

arginine-glutamic acid dipeptide repeats

Also known as: ARG, ARP, ATN1L, DNB1, NEDBEH

NCBI Gene: 473 ENSG00000142599 UniProt: Q9P2R6 OMIM: 605226

The protein functions as a transcriptional repressor during embryonic development and associates with histone deacetylase complexes in the nucleus. Mutations cause a neurodevelopmental disorder with variable features including intellectual disability and possible anomalies of the brain, eye, or heart, inherited in an autosomal dominant pattern. This gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.12), indicating that such variants are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.121 OMIM phenotype

Clinical Summary— RERE

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder with or without congenital anomalies · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

0.12LOEUF

pLI 1.000

Z-score 7.11

OE 0.05 (0.02–0.12)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

2.03Z-score

OE missense 0.81 (0.76–0.86)

737 obs / 909.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.05 (0.02–0.12)

0≤0.351.4

Missense OE0.81 (0.76–0.86)

0≤0.61.4

Synonymous OE1.18

0≤1.21.6

LoF obs/exp: 3 / 64.7Missense obs/exp: 737 / 909.5Syn Z: -2.83

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRERE-related phenocopy of proximal 1p36 deletionsLOFAD

0.16100th %ile

GOF

0.15100th %ile

LOF

0.91top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.12

Literature Evidence

LOFIt follows that haploinsufficiency of RERE may contribute-alone or in conjunction with other genetic, environmental, or stochastic factors-to the development of many of the phenotypes seen in individuals with terminal and interstitial deletions that include the proximal region of chromosome 1p36.PMID:23451234

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