EXTL3

protein-coding

exostosin like glycosyltransferase 3, the group of Exostosin glycosyltransferase family

Gene summary

This gene encodes a single-pass membrane protein which functions as a glycosyltransferase. The encoded protein catalyzes the transfer of N-acetylglucosamine to glycosaminoglycan chains. This reaction is important in heparin and heparan sulfate synthesis. Alternative splicing results in the multiple transcript variants. [provided by RefSeq, Nov 2012]

MANE transcript

NM_001440.4

Inheritance

ClinVar variants

P:2U:283B:271

Top phenotype

Immunoskeletal dysplasia with neurodevelopmental abnormalities

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr8:28,600,469-28,756,561

External References & Databases

Ensembl (ENSG00000012232)

Transcript & Mutation Effects

hg38 • Region Span ~156.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunoskeletal dysplasia with neurodevelopmental abnormalitiesMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044312

Submitter: ClinGen

EXTL3 was first reported in relation to autosomal recessive immunoskeletal dysplasia with neurodevelopmental abnormalities in 2017 (Oud et al., PMID: 28132690). This condition is characterized by variable expression of T cell lymphopenia, skeletal abnormalities, neurodevelopmental delays, and in some cases, liver and kidney cysts. Heterozygous carriers are reported to be unaffected. 11 missense variants that have been reported in 14 probands in 9 publications (PMIDs: 28132690, 28148688, 28331220, 38010033, 39215781, 35114981, 35080095, 38010729, 34089299) are included in this curation. Variants in this gene segregated with disease in five additional family members. EXTL3 deficiency causes defective thymopoiesis and specifically defective differentiation of thymic epithelial progenitors. The mechanism of pathogenicity is suspected to be loss of function. This gene-disease relationship is also supported by zebrafish model systems and rescue studies, functional alteration studies in patient cells, and expression studies in T cell and B cell lymphocytes (PMIDs: 28148688, 28132690). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date February 19, 2026 (SOP Version 12).

immunoskeletal dysplasia with neurodevelopmental abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044312

Submitter: PanelApp Australia

immunoskeletal dysplasia with neurodevelopmental abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044312

Submitter: Labcorp Genetics (formerly Invitae)

immunoskeletal dysplasia with neurodevelopmental abnormalitiesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044312

Submitter: G2P

Clinical Genomic Database (CGD)

Immunoskeletal dysplasia with neurodevelopmental abnormalitiesAR

Manifestation: Allergy/Immunology/Infectious; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: The condition can include severe combined immunodeficiency, and awareness may allow preventive measures and early and aggressive treatment of infections

Refs: 28148688; 28132690

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EXTL3 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 525

Inborn genetic diseasesTotal: 114

not specifiedTotal: 55

Immunoskeletal dysplasia with neurodevelopmental abnormalitiesTotal: 12

EXTL3-related disorderTotal: 11

Familial meningiomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001440.4. 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				260 clinvar	2 clinvar	262
missense		1 clinvar	267 clinvar	9 clinvar		277
nonsense		1 clinvar	6 clinvar			7
start loss			1 clinvar			1
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	2	283	269	2	556

Highest pathogenic variant AF is 0.000008673328

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001440.4	RefSeq	NP_001431.1	5	MANE Select
ENST00000220562.9	Ensembl	ENSP00000220562.4	5	MANE Select
NM_001437797.1	RefSeq	NP_001424726.1	5	Standard
NM_001438399.1	RefSeq	NP_001425328.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
extl3	Danio rerio	Structure: retinal ganglion cell Quality: organization quality abnormal

Gene / Model

Organism

Observed Phenotype

extl3

Danio rerio

Structure: retinal ganglion cell

Quality: organization quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosaminoglycan biosynthesis - heparan sulfate / heparin - Homo sapiens (human)
XBP1(S) activates chaperone genes
heparan sulfate biosynthesis (late stages)
heparan sulfate biosynthesis

Biological Process

protein glycosylation
heparan sulfate proteoglycan biosynthetic process
positive regulation of cell growth
IRE1-mediated unfolded protein response

Molecular Function

glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity
transferase activity, transferring glycosyl groups
metal ion binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
Golgi apparatus
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000220562
Coding exons: 5
Length: 155131
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.48	458	556	0.824	0.0000394	6005
Missense (PolyPhen)		91	176.92	0.51436		1866
Synonymous	-1.29	259	234	1.11	0.0000165	1919
Loss of Function	2.94	13	30.5	0.426	0.00000172	346

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Glycosyltransferase which regulates the biosynthesis of heparan sulfate (HS). Important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs) (PubMed:28132690, PubMed:28148688). Required for the function of REG3A in regulating keratinocyte proliferation and differentiation (PubMed:22727489). {ECO:0000269|PubMed:22727489, ECO:0000269|PubMed:28132690, ECO:0000269|PubMed:28148688}.;

Recessive Scores

pRec: 0.177

Intolerance Scores

LoFtool: 0.0851
RVIS EVS: -1.79
RVIS percentile EVS: 2.24

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.700

Gene Damage Prediction

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