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

This gene encodes a member of the atrophin family of arginine-glutamic acid (RE) dipeptide repeat-containing proteins. The encoded protein co-localizes with a transcription factor in the nucleus, and its overexpression triggers apoptosis. A similar protein in mouse associates with histone deacetylase and is thought to function as a transcriptional co-repressor during embryonic development. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

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 OE?0.05 (0.02–0.12)

0≤0.351.4

Missense OE?0.81 (0.76–0.86)

0≤0.61.4

Synonymous OE?1.18

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

This gene — mechanism propensity

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 1p36.1

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

References