ZDHHC9

protein-coding

zinc finger DHHC-type palmitoyltransferase 9, the group of Zinc fingers DHHC-type

Gene summary

This gene encodes an integral membrane protein that is a member of the zinc finger DHHC domain-containing protein family. The encoded protein forms a complex with golgin subfamily A member 7 and functions as a palmitoyltransferase. This protein specifically palmitoylates HRAS and NRAS. Mutations in this gene are associated with X-linked cognitive disability. Alternate splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, May 2010]

Previous symbols:

ZDHHC10
CXorf11

MANE transcript

NM_016032.4

Inheritance

ClinVar variants

P:24U:184B:87

Top phenotype

Intellectual developmental disorder, X-linked syndromic, Raymond type

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chrX:129,803,288-129,843,909

External References & Databases

Ensembl (ENSG00000188706)

Transcript & Mutation Effects

hg38 • Region Span ~40.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked, syndromic, Raymond typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010427

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked, syndromic, Raymond typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010427

Submitter: G2P

intellectual developmental disorder, X-linked, syndromic, Lujan-Fryns typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010655

Submitter: Orphanet

intellectual developmental disorder, X-linked, syndromic, Raymond typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010427

Submitter: ClinGen

Variants in the ZDHHC9 gene were first reported in relation to syndromic X-linked Intellectual disability in 2016 (Raymond et al., PMID: 17436253). Raymond et al. reported one frameshift, one splice site, and two missense variants in highly conserved residues of the gene. At least seven unique variants have been reported in humans, and X linked syndromic ID is characterized by mildly to severely impaired intellectual development including difficulties with speech and language . Individuals showed variable clinical features such as marfanoid habitus, facial dysmorphism, and hypotonia. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Case level data: ZDHHC9 variants have been reported in at least seven probands in six publications (PMIDs: 17436253, 19377476, 24357419, 29681091, 28687527, 20848651). Publications reported putative LOF (i.e. duplications, deletions, nonsense) variants and some missense variants. Additionally, variants segregated with syndromic X-linked ID in 11 additional family members. Experimental data: The relationship between ZDHHC9 and syndromic X-linked ID is supported by animal models and in vitro functional assays. Kouskou et al. 2018 (PMID: 29944857) showed that Zdhhc9 knockout mice exhibit altered behavior that is consistent with reduced anxiety levels. Knockout mice also scored lower on the Morris water maze test indicating deficits in hippocampal-dependent spatial learning and memory. MRI analyses revealed a 36% reduction in corpus callosum volume. Shimell et al. 2019 (PMID: 31747610) investigated Zdhcc9 function in hippocampal cultures. Loss of Zdhhc9 function resulted in shorter dendritic arbors and fewer inhibitory synapses, suggesting an important role for Zdhhc9 in neuronal development. In summary, ZDHCC9 is definitively associated wtih syndromic X-linked intellectual disability, and there is an abundance of evidence to support this association. This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on 05/19/2020 (SOP version 7).

intellectual developmental disorder, X-linked, syndromic, Raymond typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010427

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked syndromic, Raymond typeXL

Manifestation: 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: 17436253; 19377476

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZDHHC9 variants in ClinVar

11 Conditions Cataloged

Syndromic X-linked intellectual disability Raymond typeTotal: 230

not providedTotal: 67

Inborn genetic diseasesTotal: 31

not specifiedTotal: 30

ZDHHC9-related disorderTotal: 5

Intellectual disabilityTotal: 3

Neurodevelopmental disorderTotal: 1

History of neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016032.4. 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			19 clinvar	64 clinvar	6 clinvar	89
missense	2 clinvar	6 clinvar	141 clinvar	14 clinvar	2 clinvar	165
nonsense	1 clinvar	4 clinvar	6 clinvar	1 clinvar		12
start loss						0
frameshift	4 clinvar	2 clinvar	1 clinvar			7
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	17 clinvar			22
Total	8	16	184	79	8	295

Highest pathogenic variant AF is 9.120767e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016032.4	RefSeq	NP_057116.2	9	MANE Select
ENST00000357166.11	Ensembl	ENSP00000349689.6	9	MANE Select
NM_001008222.3	RefSeq	NP_001008223.1	9	Standard
ENST00000371064.7	Ensembl	ENSP00000360103.3	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

protein targeting to membrane
peptidyl-L-cysteine S-palmitoylation
protein palmitoylation

Molecular Function

protein binding
palmitoyltransferase activity
protein-cysteine S-palmitoyltransferase activity
Ras palmitoyltransferase activity

Cellular Component

palmitoyltransferase complex
endoplasmic reticulum
endoplasmic reticulum membrane
Golgi apparatus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357166
Coding exons: 9
Length: 40622
Individuals with no LoFs: 125742
Homozygous LoFs: 1
Heterozygous LoFs: 3
Defined: 125746
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.55	66	156	0.424	0.0000127	2396
Missense (PolyPhen)		20	72.664	0.27524		1041
Synonymous	-1.17	68	56.8	1.20	0.00000459	718
Loss of Function	2.85	2	13.1	0.152	0.00000111	201

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000063	0.000046	rare
European (Non-Finnish)	0.000024	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The ZDHHC9-GOLGA7 complex is a palmitoyltransferase specific for HRAS and NRAS. {ECO:0000269|PubMed:16000296}.;
Disease: DISEASE: Mental retardation, X-linked, syndromic, ZDHHC9-related (MRXSZ) [MIM:300799]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Some MRXSZ patients have marfanoid habitus as an additional feature. {ECO:0000269|PubMed:17436253, ECO:0000269|PubMed:19377476}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0958

Intolerance Scores

LoFtool: 0.377
RVIS EVS: -0.12
RVIS percentile EVS: 44.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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