RERE

protein-coding

arginine-glutamic acid dipeptide repeats, the group of Myb/SANT domain containing|Atrophins|GATA zinc finger domain containing

Gene summary

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]

Previous symbols:

ATN1L

MANE transcript

NM_001042681.2

Inheritance

ClinVar variants

P:78U:609B:365

Top phenotype

Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr1:8,352,397-8,848,921

External References & Databases

Ensembl (ENSG00000142599)

Transcript & Mutation Effects

hg38 • Region Span ~496.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with or without anomalies of the brain, eye, or heartSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014857

Submitter: PanelApp Australia

neurodevelopmental disorder with or without anomalies of the brain, eye, or heartDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014857

Submitter: G2P

neurodevelopmental disorder with or without anomalies of the brain, eye, or heartSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014857

Submitter: Ambry Genetics

neurodevelopmental disorder with or without anomalies of the brain, eye, or heartSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014857

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorder with or without congenital anomaliesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100465

Submitter: ClinGen

*RERE* was first reported in relation to autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies in 2016 (Fregeau et al., PMID: 27087320). *RERE*-related complex neurodevelopmental disorder with or without congenital anomalies most often presents with developmental delay, intellectual disability, and autism. Additional syndromic abnormalities, which are not always present, most commonly involve the eyes, heart, and genitourinary system (i.e. coloboma, optic atrophy/hypoplasia, ventricular septal defect, gastroesophageal reflux disease, and hypotonia). Nine variants (missense, nonsense, and frameshift) that have been reported in 9 probands in 3 publications (PMIDs: 27087320, 29330883, 31452935) are included in this curation. The mechanism of pathogenicity is believed to be loss of function. This gene-disease relationship is also supported by a mouse model recapitulating the human phenotype (postnatal growth deficiency, brain hypoplasia, decreased numbers of hippocampal neurons, hearing loss, cardiovascular malformations, ventriculomegaly, incomplete closure of the optic fissure, and renal agenesis) and biochemical function demonstrating *RERE*’s role in development through retinoic acid signaling (PMIDs: 20164929, 23451234). In summary, there is definitive evidence supporting the relationship between *RERE* and autosomal dominant complex neurodevelopmental disorder with or without congenital anomalies. 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 Intellectual Disability and Autism Gene Curation Expert Panel on March 21, 2023 (SOP Version 9).

neurodevelopmental disorder with or without anomalies of the brain, eye, or heartSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014857

Submitter: Orphanet

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with or without anomalies of the brain, eye, or heartAD

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 27087320

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RERE variants in ClinVar

15 Conditions Cataloged

not providedTotal: 782

Inborn genetic diseasesTotal: 302

Neurodevelopmental disorder with or without anomalies of the brain, eye, or heartTotal: 190

not specifiedTotal: 120

RERE-related disorderTotal: 83

See casesTotal: 7

CHARGE syndromeTotal: 1

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001042681.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	12 clinvar	196 clinvar	27 clinvar	236
missense	6 clinvar	18 clinvar	582 clinvar	130 clinvar	12 clinvar	748
nonsense	4 clinvar	10 clinvar	5 clinvar			19
start loss						0
frameshift	11 clinvar	21 clinvar	4 clinvar			36
splice donor/acceptor (+/-2bp)		7 clinvar	6 clinvar			13
Total	21	57	609	326	39	1052

Highest pathogenic variant AF is 0.000008754804

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001042681.2	RefSeq	NP_001036146.1	22	MANE Select
ENST00000400908.7	Ensembl	ENSP00000383700.2	22	MANE Select
NM_001042682.2	RefSeq	NP_001036147.1	9	Standard
NM_012102.4	RefSeq	NP_036234.3	22	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rerea	Danio rerio	Structure: hair cell Quality: quality abnormal

Gene / Model

Organism

Observed Phenotype

rerea

Danio rerio

Structure: hair cell

Quality: quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

chromatin remodeling
regulation of transcription by RNA polymerase II
NLS-bearing protein import into nucleus
cerebellar Purkinje cell layer maturation
cerebellar granule cell precursor proliferation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II transcription factor binding
DNA binding
chromatin binding
transcription coactivator activity

Cellular Component

histone deacetylase complex
nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000337907
Coding exons: 22
Length: 465246
Individuals with no LoFs: 125713
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125747
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.03	737	909	0.810	0.0000589	10049
Missense (PolyPhen)		187	316.28	0.59124		3317
Synonymous	-2.83	453	383	1.18	0.0000269	3205
Loss of Function	7.11	3	64.7	0.0463	0.00000377	718

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.000062	rare
Latino/Admixed American	0.00012	0.000058	rare
Ashkenazi Jewish	0.00021	0.00020	rare
East Asian	0.00011	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00038	0.00021	rare
South Asian	0.00025	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role as a transcriptional repressor during development. May play a role in the control of cell survival. Overexpression of RERE recruits BAX to the nucleus particularly to POD and triggers caspase-3 activation, leading to cell death. {ECO:0000269|PubMed:11331249}.;
Disease: DISEASE: Note=A chromosomal aberration involving RERE is found in the neuroblastoma cell line NGP. Translocation t(1;15)(p36.2;q24).; DISEASE: Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH) [MIM:616975]: An autosomal dominant syndrome characterized by developmental delay, intellectual disability, brain anomalies, and neurological abnormalities including seizures, hypotonia, and behavioral problems such as autism spectrum disorders. Brain anomalies include abnormalities and/or thinning of the corpus callosum, diminished white matter volume, abnormal cerebellar vermis, and ventriculomegaly. Congenital defects of the eye, heart and genitourinary system are present in half of the patients. {ECO:0000269|PubMed:27087320}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.139

Intolerance Scores

LoFtool: 0.0674
RVIS EVS: -2.63
RVIS percentile EVS: 0.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.717

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium