syndromic X-linked intellectual disability Raymond type

Summary

syndromic X-linked intellectual disability Raymond type (MONDO:0010427) is a disease caused by ZDHHC9 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: ZDHHC9 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 235

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic X-linked intellectual disability Raymond type
Mondo ID	MONDO:0010427
OMIM	300799
DOID	DOID:0060824
UMLS	C3275406
MedGen	477037
GARD	0015264
Is cancer (heuristic)	no

Also known as: intellectual disability, X-linked syndromic, Raymond type · intellectual disability, X-linked, syndromic, Raymond type · mental retardation, X-linked, syndromic, Raymond type · MRXSR · syndromic X-linked intellectual disability Raymond type

Data availability: 235 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › syndromic X-linked intellectual disability Raymond type

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, MEHMO syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, Allan-Herndon-Dudley syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 14, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked, syndromic, Bain type, Borjeson-Forssman-Lehmann syndrome, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, Prieto syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, ATR-X-related syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

235 retrieved; paginated sample, class counts are floors:

96 likely benign, 82 uncertain significance, 27 benign, 9 conflicting classifications of pathogenicity, 7 likely pathogenic, 6 pathogenic, 4 pathogenic/likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3245284	NC_000023.10:g.(?128674417)(128975921_?)del	APLN	Pathogenic	criteria provided, single submitter
10709	NM_016032.4(ZDHHC9):c.172_175del (p.Arg58fs)	ZDHHC9	Pathogenic	no assertion criteria provided
10710	NM_016032.4(ZDHHC9):c.167+5G>C	ZDHHC9	Pathogenic	no assertion criteria provided
10711	NM_016032.4(ZDHHC9):c.442C>T (p.Arg148Trp)	ZDHHC9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10712	NM_016032.4(ZDHHC9):c.448C>T (p.Pro150Ser)	ZDHHC9	Pathogenic	no assertion criteria provided
1705029	NM_016032.4(ZDHHC9):c.267del (p.Ser89fs)	ZDHHC9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2126777	NM_016032.4(ZDHHC9):c.361C>T (p.Arg121Ter)	ZDHHC9	Pathogenic	criteria provided, multiple submitters, no conflicts
2228665	NM_016032.4(ZDHHC9):c.892C>T (p.Arg298Ter)	ZDHHC9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
429192	NM_016032.4(ZDHHC9):c.286C>T (p.Arg96Trp)	ZDHHC9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
873026	NC_000023.10:g.(?128946967)(128948896_?)del	ZDHHC9	Pathogenic	no assertion criteria provided
3363161	NM_001130438.3(SPTAN1):c.6043del (p.Ser2015fs)	SPTAN1	Likely pathogenic	criteria provided, single submitter
3062259	NM_016032.4(ZDHHC9):c.167+1G>A	ZDHHC9	Likely pathogenic	criteria provided, single submitter
3640685	NM_016032.4(ZDHHC9):c.488-2A>G	ZDHHC9	Likely pathogenic	criteria provided, single submitter
3724442	NM_016032.4(ZDHHC9):c.777+1G>A	ZDHHC9	Likely pathogenic	criteria provided, single submitter
4795936	NM_016032.4(ZDHHC9):c.811C>T (p.Gln271Ter)	ZDHHC9	Likely pathogenic	criteria provided, single submitter
619977	NM_016032.4(ZDHHC9):c.268G>A (p.Asp90Asn)	ZDHHC9	Likely pathogenic	criteria provided, single submitter
931980	NM_016032.4(ZDHHC9):c.852dup (p.Glu285Ter)	ZDHHC9	Likely pathogenic	criteria provided, single submitter
2426260	NC_000023.10:g.(?128674417)(129299630_?)del	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1004950	NM_016032.4(ZDHHC9):c.718G>C (p.Val240Leu)	ZDHHC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1187285	NM_016032.4(ZDHHC9):c.1045C>T (p.Pro349Ser)	ZDHHC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1308638	NM_016032.4(ZDHHC9):c.496G>A (p.Asp166Asn)	ZDHHC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1501034	NM_016032.4(ZDHHC9):c.544C>T (p.Arg182Cys)	ZDHHC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2607811	NM_016032.4(ZDHHC9):c.1034A>C (p.Glu345Ala)	ZDHHC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
537741	NM_016032.4(ZDHHC9):c.881+3G>A	ZDHHC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
833652	NM_016032.4(ZDHHC9):c.808G>A (p.Val270Ile)	ZDHHC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
998899	NM_016032.4(ZDHHC9):c.764C>A (p.Thr255Lys)	ZDHHC9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
831120	NC_000023.10:g.(?128674397)(128975941_?)dup	APLN	Uncertain significance	criteria provided, single submitter
1029571	NM_016032.4(ZDHHC9):c.421T>C (p.Cys141Arg)	ZDHHC9	Uncertain significance	criteria provided, single submitter
1043073	NM_016032.4(ZDHHC9):c.20G>C (p.Arg7Thr)	ZDHHC9	Uncertain significance	criteria provided, single submitter
1044283	NM_016032.4(ZDHHC9):c.331G>T (p.Ala111Ser)	ZDHHC9	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ZDHHC9	Definitive	X-linked	syndromic X-linked intellectual disability Raymond type	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZDHHC9	Orphanet:776	Lujan-Fryns syndrome
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome
AIFM1	Orphanet:101078	X-linked Charcot-Marie-Tooth disease type 4
AIFM1	Orphanet:139583	X-linked hereditary sensory and autonomic neuropathy with deafness
AIFM1	Orphanet:238329	Severe X-linked mitochondrial encephalomyopathy
AIFM1	Orphanet:83629	Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZDHHC9	HGNC:18475	ENSG00000188706	Q9Y397	Palmitoyltransferase ZDHHC9	gencc,clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
APLN	HGNC:16665	ENSG00000171388	Q9ULZ1	Apelin	clinvar
AIFM1	HGNC:8768	ENSG00000156709	O95831	Apoptosis-inducing factor 1, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZDHHC9	Palmitoyltransferase ZDHHC9	Palmitoyltransferase that catalyzes the addition of palmitate onto various protein substrates, such as ADRB2, GSDMD, HRAS, NRAS and CGAS.
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
APLN	Apelin	Peptide hormone that functions as endogenous ligand for the G-protein-coupled apelin receptor (APLNR/APJ), that plays a role in cadiovascular homeostasis.
AIFM1	Apoptosis-inducing factor 1, mitochondrial	Functions both as NADH oxidoreductase and as regulator of apoptosis.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	6.0×	0.112
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZDHHC9	Enzyme (other)	yes	2.3.1.225	Palmitoyltrfase_DHHC, PFA4/ZDH16/20/ERF2-like
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
APLN	Other/Unknown	no		Apelin
AIFM1	Enzyme (other)	yes	7.1.1.2	FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, AIF_C

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus callosum	1
inferior vagus X ganglion	1
kidney epithelium	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
C1 segment of cervical spinal cord	1
left ventricle myocardium	1
spinal cord	1
adult mammalian kidney	1
apex of heart	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZDHHC9	238	ubiquitous	marker	corpus callosum, inferior vagus X ganglion, kidney epithelium
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
APLN	177	broad	yes	C1 segment of cervical spinal cord, spinal cord, left ventricle myocardium
AIFM1	273	ubiquitous	marker	apex of heart, adult mammalian kidney, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AIFM1	4,780
SPTAN1	3,083
APLN	1,213
ZDHHC9	1,045

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIFM1	O95831	26
SPTAN1	Q13813	7
APLN	Q9ULZ1	5
ZDHHC9	Q9Y397	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Caspase-mediated cleavage of cytoskeletal proteins	1	317.2×	0.046	SPTAN1
Apoptotic cleavage of cellular proteins	1	158.6×	0.046	SPTAN1
Nephrin family interactions	1	158.6×	0.046	SPTAN1
Apoptotic execution phase	1	158.6×	0.046	SPTAN1
RAS processing	1	158.6×	0.046	ZDHHC9
Interaction between L1 and Ankyrins	1	122.8×	0.046	SPTAN1
Sensory processing of sound	1	102.9×	0.046	SPTAN1
RHOV GTPase cycle	1	95.2×	0.046	SPTAN1
RHOU GTPase cycle	1	92.8×	0.046	SPTAN1
NCAM signaling for neurite out-growth	1	90.6×	0.046	SPTAN1
Maturation of spike protein	1	88.5×	0.046	ZDHHC9
Sensory processing of sound by outer hair cells of the cochlea	1	68.0×	0.055	SPTAN1
Apoptosis	1	56.0×	0.057	SPTAN1
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.057	SPTAN1
Programmed Cell Death	1	48.8×	0.057	SPTAN1
Cell-Cell communication	1	45.9×	0.057	SPTAN1
ER to Golgi Anterograde Transport	1	44.3×	0.057	SPTAN1
MAPK1/MAPK3 signaling	1	43.8×	0.057	SPTAN1
L1CAM interactions	1	40.1×	0.057	SPTAN1
COPI-mediated anterograde transport	1	36.6×	0.057	SPTAN1
MAPK family signaling cascades	1	34.3×	0.057	SPTAN1
Transport to the Golgi and subsequent modification	1	34.3×	0.057	SPTAN1
Signal Transduction	2	6.8×	0.057	SPTAN1, APLN
Sensory Perception	1	31.7×	0.058	SPTAN1
Class A/1 (Rhodopsin-like receptors)	1	24.7×	0.069	APLN
Peptide ligand-binding receptors	1	24.7×	0.069	APLN
GPCR ligand binding	1	21.4×	0.074	APLN
RAF/MAP kinase cascade	1	20.4×	0.074	SPTAN1
Asparagine N-linked glycosylation	1	20.0×	0.074	SPTAN1
RHO GTPase cycle	1	20.0×	0.074	SPTAN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of corticotropin-releasing hormone secretion	1	2106.5×	0.007	APLN
protein import into mitochondrial intermembrane space	1	1404.3×	0.007	AIFM1
apelin receptor signaling pathway	1	1404.3×	0.007	APLN
protein import into the intermembrane space via the disulfide relay system	1	1404.3×	0.007	AIFM1
positive regulation of G protein-coupled receptor internalization	1	1404.3×	0.007	APLN
positive regulation of heat generation	1	842.6×	0.007	APLN
positive regulation of corticotropin secretion	1	842.6×	0.007	APLN
mitochondrial respiratory chain complex assembly	1	702.2×	0.007	AIFM1
positive regulation of necroptotic process	1	702.2×	0.007	AIFM1
non-canonical inflammasome complex assembly	1	702.2×	0.007	ZDHHC9
positive regulation of pyroptotic inflammatory response	1	601.9×	0.007	ZDHHC9
cellular response to aldosterone	1	601.9×	0.007	AIFM1
positive regulation of heart contraction	1	526.6×	0.007	APLN
positive regulation of cGAS/STING signaling pathway	1	526.6×	0.007	ZDHHC9
negative regulation of vasoconstriction	1	421.3×	0.008	APLN
response to L-glutamate	1	421.3×	0.008	AIFM1
actin filament capping	1	383.0×	0.008	SPTAN1
host-mediated activation of viral process	1	351.1×	0.008	ZDHHC9
peptidyl-L-cysteine S-palmitoylation	1	300.9×	0.009	ZDHHC9
negative regulation of systemic arterial blood pressure	1	263.3×	0.009	APLN
negative regulation of fibroblast growth factor receptor signaling pathway	1	263.3×	0.009	APLN
regulation of the force of heart contraction	1	247.8×	0.009	APLN
drinking behavior	1	247.8×	0.009	APLN
cellular response to nitric oxide	1	234.1×	0.009	AIFM1
positive regulation of phosphorylation	1	210.7×	0.009	APLN
positive regulation of vascular endothelial cell proliferation	1	210.7×	0.009	APLN
gastrulation	1	175.5×	0.011	APLN
positive regulation of heart rate	1	175.5×	0.011	APLN
negative regulation of vascular associated smooth muscle cell proliferation	1	168.5×	0.011	APLN
negative regulation of blood pressure	1	162.0×	0.011	APLN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SPTAN1	1	2
ZDHHC9	0	0
APLN	0	0
AIFM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SPTAN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SPTAN1	7	Binding:7
AIFM1	2	Binding:2
ZDHHC9	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ZDHHC9	2.3.1.225	protein S-acyltransferase
AIFM1	7.1.1.2	NADH:ubiquinone reductase (H+-translocating)

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	SPTAN1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	SPTAN1
C	Druggable family + PDB, no drug	2	ZDHHC9, AIFM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	APLN

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ZDHHC9	1	—
APLN	0	—
AIFM1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.