CHST14

protein-coding

carbohydrate sulfotransferase 14, the group of Sulfotransferases, membrane bound

Gene summary

This gene encodes a member of the HNK-1 family of sulfotransferases. The encoded protein transfers sulfate to the C-4 hydroxyl of N-acetylgalactosamine residues in dermatan sulfate. Mutations in this gene have been associated with adducted thumb-clubfoot syndrome.[provided by RefSeq, Mar 2010]

Previous symbols:

D4ST1

MANE transcript

NM_130468.4

Inheritance

ClinVar variants

P:45U:222B:180

Top phenotype

Ehlers-Danlos syndrome, musculocontractural type 1

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr15:40,470,984-40,473,158

External References & Databases

Ensembl (ENSG00000169105)

Transcript & Mutation Effects

hg38 • Region Span ~2.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Ehlers-Danlos syndrome, musculocontractural type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020681

Submitter: Ambry Genetics

Ehlers-Danlos syndrome, musculocontractural type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020681

Submitter: ClinGen

CHST14 (OMIM: 608429) was first reported in relation to autosomal recessive Ehlers-Danlos syndrome, musculocontractural type 1 (OMIM:601776) in 2009 (Dundar et al., PMID: 20004762). Evidence supporting this gene-disease relationship includes case-level data and experimental data. The CHST14 gene encodes the enzyme carbohydrate sulfotransferase 14 which is also known as Derman-4-O sulfotransferase. This enzyme actively transfers an active sulfate to position 4 of N-acetyl-D-galactosamine residues on dermatan sulfate. Pathogenic variants in the CHST14 gene result in a deficiency of dermatan sulfate, disrupting glycosaminoglycan constituents in fibroblasts impairing collagen fibril linkage. The disease mechanism is therefore loss-of –function. The major clinical features include distinctive craniofacial dysmorphism, congenital contractures including adducted thumbs and clenched fists, clubfeet, severe kyphoscoliosis, muscular hypotonia, hyperextensible thin skin that bruises easily and atrophic scarring, wrinkled palms, joint hypermobility, and ocular involvement (PMID: 34815299). Affected fetuses have been found to have the following ultrasound abnormalities: congenital contractures, adducted thumbs and hydronephrosis. At least 26 variants (missense, nonsense, in-frame deletion and frameshift) have been reported in humans. For the purposes of this curation, 15 variants in this gene were scored in the following 7 publications: PMIDs 20004762, 20533528, 21744491, 20842734, 25703627, 30249733, 35464846. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by biochemical and expression studies (20004762, 20533528, 25703627). In summary, there is definitive evidence to support the relationship between CHST14 and autosomal recessive Ehlers-Danlos syndrome, musculocontractural type 1. 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 Prenatal Expert Panel on the 10/01/2025 (SOP Version 11).

Ehlers-Danlos syndrome, musculocontractural typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011142

Submitter: Orphanet

Ehlers-Danlos syndrome, musculocontractural type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020681

Submitter: Labcorp Genetics (formerly Invitae)

Ehlers-Danlos syndrome, musculocontractural type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020681

Submitter: G2P

Ehlers-Danlos syndrome, musculocontractural type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020681

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Ehlers-Danlos syndrome, musculocontractural type 1AR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Hematologic; Musculoskeletal; Ophthalmologic

Intervention: Hematologic; Musculoskeletal; Ophthalmologic

Rationale: Clinical issues relate to connective tissue fragility may affect multiple organs, and may include severe bleeding episodes (eg, after minor trauma), such that recognition may allow precautions and preventive measures, as well as rapid treatment in the case of bleeding; Medical treatment (eg, with oral dermatan sulfate) may be beneficial; Due to risk of glaucoma, surveillance may allow early management

Refs: 9084938; 10766984; 11370633; 16158441; 20004762; 20503305; 20842734; 20533528; 21744491; 22581468; 22407744; 22987394; 23704329

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHST14 variants in ClinVar

7 Conditions Cataloged

Cardiovascular phenotypeTotal: 301

Ehlers-Danlos syndrome, musculocontractural typeTotal: 183

not providedTotal: 75

not specifiedTotal: 45

Ehlers-Danlos syndrome, musculocontractural type 1Total: 26

CHST14-related disorderTotal: 13

Ehlers-Danlos syndromeTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_130468.4. 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			6 clinvar	161 clinvar	2 clinvar	169
missense	3 clinvar	5 clinvar	212 clinvar	17 clinvar		237
nonsense	7 clinvar	2 clinvar	1 clinvar			10
start loss		1 clinvar				1
frameshift	15 clinvar	12 clinvar	3 clinvar			30
splice donor/acceptor (+/-2bp)						0
Total	25	20	222	178	2	447

Highest pathogenic variant AF is 0.000019206558

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_130468.4	RefSeq	NP_569735.1	1	MANE Select
ENST00000306243.7	Ensembl	ENSP00000307297.6	1	MANE Select
ENST00000559991.1	Ensembl	ENSP00000453882.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate - Homo sapiens (human)
Metapathway biotransformation Phase I and II
Metabolism of carbohydrates
Dermatan sulfate biosynthesis
Chondroitin sulfate/dermatan sulfate metabolism

Biological Process

carbohydrate biosynthetic process
dermatan sulfate biosynthetic process
dermatan sulfate proteoglycan metabolic process

Molecular Function

N-acetylgalactosamine 4-O-sulfotransferase activity
phosphate ion binding

Cellular Component

Golgi membrane
integral component of membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000306243
Coding exons: 1
Length: 2194
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.683	182	210	0.867	0.0000108	2370
Missense (PolyPhen)		57	66.339	0.85922		844
Synonymous	0.703	87	95.8	0.909	0.00000479	841
Loss of Function	2.31	2	9.83	0.203	5.21e-7	98

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	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the transfer of sulfate to position 4 of the N-acetylgalactosamine (GalNAc) residue of dermatan sulfate. Plays a pivotal role in the formation of 4-0-sulfated IdoA blocks in dermatan sulfate. Transfers sulfate to the C-4 hydroxyl of beta1,4-linked GalNAc that is substituted with an alpha-linked iduronic acid (IdoUA) at the C-3 hydroxyl. Transfers sulfate more efficiently to GalNAc residues in -IdoUA-GalNAc-IdoUA- than in -GlcUA-GalNAc-GlcUA-sequences. Has preference for partially desulfated dermatan sulfate. Addition of sulfate to GalNAc may occur immediately after epimerization of GlcUA to IdoUA. Appears to have an important role in the formation of the cerebellar neural network during postnatal brain development. {ECO:0000269|PubMed:19661164}.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.574
RVIS EVS: -0.14
RVIS percentile EVS: 43.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.123

Gene Damage Prediction

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