ZBTB20

protein-coding

zinc finger and BTB domain containing 20, the group of Zinc fingers C2H2-type|MicroRNA protein coding host genes|BTB domain containing

Gene summary

This gene, which was initially designated as dendritic cell-derived BTB/POZ zinc finger (DPZF), belongs to a family of transcription factors with an N-terminal BTB/POZ domain and a C-terminal DNA-bindng zinc finger domain. The BTB/POZ domain is a hydrophobic region of approximately 120 aa which mediates association with other BTB/POZ domain-containing proteins. This gene acts as a transcriptional repressor and plays a role in many processes including neurogenesis, glucose homeostasis, and postnatal growth. Mutations in this gene have been associated with Primrose syndrome as well as the 3q13.31 microdeletion syndrome. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

Previous symbols:

ZNF288

MANE transcript

NM_001348800.3

Inheritance

ClinVar variants

P:93U:195B:184

Top phenotype

Primrose syndrome

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr3:114,314,500-115,147,292

External References & Databases

Ensembl (ENSG00000181722)

Transcript & Mutation Effects

hg38 • Region Span ~832.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Primrose syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009798

Submitter: Labcorp Genetics (formerly Invitae)

Primrose syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009798

Submitter: PanelApp Australia

Primrose syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009798

Submitter: G2P

Primrose syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0009798

Submitter: Ambry Genetics

Primrose syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009798

Submitter: ClinGen

Variants in *ZBTB20* zinc finger regions were first reported in individuals with autosomal dominant Primrose syndrome in 2014 (Cordeddu et al., PMID: 25017102). Phenotypes commonly reported with *ZBTB20* variants include macrocephaly, hypotonia, developmental delay, intellectual disability with expressive speech delay, behavioral issues, facial dysmorphic features, calcification of the external ear cartilage, sparse body hair, skeletal anomalies, distal muscle wasting, contractures, decreased bone mineral density, hearing loss, ocular anomalies, cryptorchidism, findings on brain imaging and altered glucose metabolism (PMID: 33956417). Both missense and putative loss of function variants in *ZBTB20* have been reported in individuals with overlapping features; additionally, *ZBTB20* is the main candidate gene for the 3q13.31 microdeletion syndrome, which also shares clinical features with Primrose syndrome. Individuals with deletions and putative loss of function variants appear to have milder manifestations, while individuals with missense variants appear to be more severely affected. Evidence suggests that the more severe missense variants are acting via a dominant negative effect. Because the phenotypes of individuals with loss of function and dominant negative variants overlap and appear to be part of the same clinical spectrum, the ClinGen ID/Autism GCEP is curating all of this information together under the disease term Primrose syndrome. Seventeen variants (missense, in-frame deletion, frameshift), reported in seventeen probands in five publications (PMIDs: 25017102, 32266967, 30637921, 29737001, 32266967) are included in this curation. The variant p.Met625Val is recurrent and has been reported two times in the published literature (PMIDs: 31321892, 32266967). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by experimental evidence. In summary, there is definitive evidence to support the relationship between *ZBTB20* and Primrose syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 18th, 2023 (SOP Version 9).

Primrose syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009798

Submitter: Genomics England PanelApp

diabetes mellitusSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005015

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Primrose syndromeAD

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25062845; 25017102; 27061120; 30256248

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZBTB20 variants in ClinVar

17 Conditions Cataloged

not providedTotal: 360

Primrose syndromeTotal: 84

Inborn genetic diseasesTotal: 68

not specifiedTotal: 39

ZBTB20-related disorderTotal: 32

Intellectual disabilityTotal: 7

Neurodevelopmental disorderTotal: 3

Moderate global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001348800.3. 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	123 clinvar	3 clinvar	127
missense	29 clinvar	35 clinvar	183 clinvar	45 clinvar	12 clinvar	304
nonsense	3 clinvar	4 clinvar	5 clinvar	1 clinvar		13
start loss						0
frameshift	10 clinvar	9 clinvar	4 clinvar			23
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	2 clinvar			5
Total	43	50	195	169	15	472

Highest pathogenic variant AF is 0.000010533843

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 710 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001348800.3	RefSeq	NP_001335729.1	4	MANE Select
ENST00000675478.1	Ensembl	ENSP00000501561.1	4	MANE Select
NM_001164342.2	RefSeq	NP_001157814.1	4	Standard
NM_001164343.2	RefSeq	NP_001157815.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
positive regulation of interferon-beta production
positive regulation of interleukin-6 production
positive regulation of tumor necrosis factor production
positive regulation of glycolytic process

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
transcription regulatory region DNA binding
metal ion binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000474710
Coding exons: 4
Length: 809178
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125746
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.27	217	481	0.452	0.0000335	4859
Missense (PolyPhen)		67	241.18	0.27781		2262
Synonymous	1.12	201	222	0.904	0.0000183	1493
Loss of Function	4.02	3	24.4	0.123	0.00000115	268

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.0000095	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be a transcription factor that may be involved in hematopoiesis, oncogenesis, and immune responses (PubMed:11352661). Plays a role in postnatal myogenesis, may be involved in the regulation of satellite cells self-renewal (By similarity). {ECO:0000250|UniProtKB:Q8K0L9, ECO:0000269|PubMed:11352661}.;
Disease: DISEASE: Primrose syndrome (PRIMS) [MIM:259050]: A disease characterized by macrocephaly, intellectual disability, disturbed behavior, dysmorphic facial features, ectopic calcifications, large calcified ear auricles, and progressive muscle wasting. {ECO:0000269|PubMed:25017102}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.151

Intolerance Scores

RVIS EVS: 0.35
RVIS percentile EVS: 74.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

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