chromosome Xq28 duplication syndrome

Summary

chromosome Xq28 duplication syndrome (MONDO:0010436) is a disease with 8 cohort genes.

At a glance

• Cohort genes: 8
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	chromosome Xq28 duplication syndrome
Mondo ID	MONDO:0010436
MeSH	C567580
OMIM	300815
UMLS	C2749007
MedGen	411727
GARD	0015266
Is cancer (heuristic)	no

Also known as: chromosome Xq28 duplication syndrome

Data availability: 10 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › syndromic X-linked intellectual disability Lubs type › chromosome Xq28 duplication syndrome

Subtypes (1): distal Xq28 microduplication syndrome

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

10 retrieved; paginated sample, class counts are floors:

7 pathogenic, 2 not provided, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703536	GRCh37/hg19 Xq28(chrX:152372767-155233731)	ABCD1	Pathogenic	no assertion criteria provided
3066030	NC_000023.11:g.153670446_154329698dup	ARHGAP4	Pathogenic	no assertion criteria provided
3235933	GRCh38/hg38 Xq28(chrX:154895862-155336084)	CMC4	Pathogenic	criteria provided, single submitter
4081872	NC_000023.11:g.154398510_154619228dup	FAM223A	Pathogenic	no assertion criteria provided
1065195	GRCh38/hg38 Xq28(chrX:153858452-154332213)x2	LOC130068840	Pathogenic	no assertion criteria provided
4277373	Single allele	LOC130068843	Pathogenic	criteria provided, single submitter
2580330	GRCh37/hg19 Xq28(chrX:153247464-153522710)x3	OPN1LW	Pathogenic	criteria provided, single submitter
1162265	NC_000023.11:g.(?144988272)(145271978_?)dup	SPANXN1	Uncertain significance	no assertion criteria provided
1339850	GRCh37/hg19 Xq28(chrX:154124170-154528181)x3	BRCC3	not provided	no classification provided
2572018	GRCh37/hg19 Xq28(chrX:153566798-153748208)x4	EMD	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRCC3	Orphanet:280679	Moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome
EMD	Orphanet:98863	X-linked Emery-Dreifuss muscular dystrophy
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease
OPN1LW	Orphanet:16	Blue cone monochromatism
OPN1LW	Orphanet:1872	Cone rod dystrophy
OPN1LW	Orphanet:90001	X-linked cone dysfunction syndrome with myopia

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRCC3	HGNC:24185	ENSG00000185515	P46736	Lys-63-specific deubiquitinase BRCC36	clinvar
FAM223A	HGNC:30612	ENSG00000279245	Q8IWN6	Protein FAM223A	clinvar
SPANXN1	HGNC:33174	ENSG00000203923	Q5VSR9	Sperm protein associated with the nucleus on the X chromosome N1	clinvar
EMD	HGNC:3331	ENSG00000102119	P50402	Emerin	clinvar
CMC4	HGNC:35428	ENSG00000182712	P56277	Cx9C motif-containing protein 4	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar
ARHGAP4	HGNC:674	ENSG00000089820	P98171	Rho GTPase-activating protein 4	clinvar
OPN1LW	HGNC:9936	ENSG00000102076	P04000	Long-wave-sensitive opsin 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRCC3	Lys-63-specific deubiquitinase BRCC36	Metalloprotease that specifically cleaves ‘Lys-63’-linked polyubiquitin chains.
EMD	Emerin	Stabilizes and promotes the formation of a nuclear actin cortical network.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
ARHGAP4	Rho GTPase-activating protein 4	Inhibitory effect on stress fiber organization.
OPN1LW	Long-wave-sensitive opsin 1	Visual pigments are the light-absorbing molecules that mediate vision.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.38

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
Transporter	1	9.7×	0.474
Protease	1	4.6×	0.474
GPCR	1	3.0×	0.474
Scaffold/PPI	1	2.2×	0.474
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRCC3	Protease	yes		JAMM/MPN+_dom, MPN_BRCC36, MPN
FAM223A	Other/Unknown	no
SPANXN1	Other/Unknown	no		SPAN-X_fam
EMD	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM_emerin
CMC4	Other/Unknown	no		Cys_alpha_HP_mot_SF, CMC4
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
ARHGAP4	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain
OPN1LW	GPCR	yes		GPCR_Rhodpsn, Opsin_red/grn, Opsin

Expression context

Cohort genes with no expression data: 0.

5 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)	2
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
male germ line stem cell (sensu Vertebrata) in testis	2
buccal mucosa cell	1
oral cavity	1
parotid gland	1
mucosa of transverse colon	1
primordial germ cell in gonad	1
right testis	1
left ovary	1
left uterine tube	1
popliteal artery	1
apex of heart	1
heart left ventricle	1
right atrium auricular region	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1
monocyte	1
spleen	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRCC3	281	ubiquitous	marker	parotid gland, oral cavity, buccal mucosa cell
FAM223A	123		yes	male germ line stem cell (sensu Vertebrata) in testis, granulocyte, mucosa of transverse colon
SPANXN1	6	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis
EMD	284	ubiquitous	marker	left ovary, left uterine tube, popliteal artery
CMC4	134	ubiquitous	yes	right atrium auricular region, heart left ventricle, apex of heart
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
ARHGAP4	229	broad	marker	granulocyte, spleen, monocyte
OPN1LW	16	tissue_specific	marker	ganglionic eminence, sural nerve, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EMD	3,503
BRCC3	3,428
ABCD1	1,181
ARHGAP4	1,088
CMC4	925
OPN1LW	612
SPANXN1	450
FAM223A	2

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCD1	P33897	14
EMD	P50402	6
BRCC3	P46736	4
CMC4	P56277	3
ARHGAP4	P98171	1
OPN1LW	P04000	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SPANXN1	Q5VSR9	68.68
FAM223A	Q8IWN6	34.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 8 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective visual phototransduction due to OPN1LW loss of function	1	1903.3×	0.026	OPN1LW
Defective ABCD1 causes ALD	1	951.7×	0.026	ABCD1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	317.2×	0.037	ABCD1
The retinoid cycle in cones (daylight vision)	1	271.9×	0.037	OPN1LW
Opsins	1	211.5×	0.037	OPN1LW
Linoleic acid (LA) metabolism	1	190.3×	0.037	ABCD1
RAC1 GTPase cycle	2	20.4×	0.037	EMD, ARHGAP4
Beta-oxidation of very long chain fatty acids	1	146.4×	0.037	ABCD1
Depolymerization of the Nuclear Lamina	1	126.9×	0.037	EMD
alpha-linolenic acid (ALA) metabolism	1	119.0×	0.037	ABCD1
Peroxisomal lipid metabolism	1	112.0×	0.037	ABCD1
ABC transporters in lipid homeostasis	1	100.2×	0.037	ABCD1
Initiation of Nuclear Envelope (NE) Reformation	1	100.2×	0.037	EMD
Class I peroxisomal membrane protein import	1	86.5×	0.037	ABCD1
DNA Double Strand Break Response	1	79.3×	0.037	BRCC3
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	79.3×	0.037	EMD
Nuclear Envelope Breakdown	1	76.1×	0.037	EMD
ABC transporter disorders	1	73.2×	0.037	ABCD1
Homology Directed Repair	1	51.4×	0.046	BRCC3
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	51.4×	0.046	BRCC3
Metalloprotease DUBs	1	50.1×	0.046	BRCC3
DNA Double-Strand Break Repair	1	41.4×	0.053	BRCC3
RHOD GTPase cycle	1	34.0×	0.062	EMD
Protein localization	1	31.7×	0.064	ABCD1
Mitochondrial protein import	1	28.0×	0.066	CMC4
Nonhomologous End-Joining (NHEJ)	1	28.0×	0.066	BRCC3
RHOG GTPase cycle	1	24.7×	0.067	EMD
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	24.4×	0.067	BRCC3
Disorders of transmembrane transporters	1	23.2×	0.067	ABCD1
G2/M Checkpoints	1	22.4×	0.067	BRCC3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peroxisomal membrane transport	1	1685.2×	0.011	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	1685.2×	0.011	ABCD1
positive regulation of unsaturated fatty acid biosynthetic process	1	1123.5×	0.011	ABCD1
sterol homeostasis	1	842.6×	0.011	ABCD1
long-chain fatty acid import into peroxisome	1	674.1×	0.011	ABCD1
absorption of visible light	1	561.7×	0.011	OPN1LW
regulation of fatty acid beta-oxidation	1	561.7×	0.011	ABCD1
long-chain fatty acid catabolic process	1	561.7×	0.011	ABCD1
myelin maintenance	1	561.7×	0.011	ABCD1
regulation of mitochondrial depolarization	1	561.7×	0.011	ABCD1
fatty acid elongation	1	481.5×	0.011	ABCD1
very long-chain fatty acid catabolic process	1	481.5×	0.011	ABCD1
nuclear membrane organization	1	481.5×	0.011	EMD
negative regulation of fibroblast migration	1	306.4×	0.013	ARHGAP4
positive regulation of fatty acid beta-oxidation	1	306.4×	0.013	ABCD1
fatty acid derivative biosynthetic process	1	306.4×	0.013	ABCD1
regulation of cellular response to oxidative stress	1	259.3×	0.015	ABCD1
regulation of oxidative phosphorylation	1	240.7×	0.015	ABCD1
neuron projection maintenance	1	224.7×	0.015	ABCD1
regulation of DNA damage checkpoint	1	224.7×	0.015	BRCC3
cellular response to light stimulus	1	210.7×	0.015	OPN1LW
negative regulation of reactive oxygen species biosynthetic process	1	198.3×	0.015	ABCD1
fatty acid homeostasis	1	187.2×	0.015	ABCD1
response to X-ray	1	177.4×	0.015	BRCC3
alpha-linolenic acid metabolic process	1	177.4×	0.015	ABCD1
peroxisome organization	1	160.5×	0.015	ABCD1
mitotic G2/M transition checkpoint	1	160.5×	0.015	BRCC3
positive regulation of protein export from nucleus	1	160.5×	0.015	EMD
very long-chain fatty acid metabolic process	1	153.2×	0.015	ABCD1
negative regulation of axon extension	1	146.5×	0.015	ARHGAP4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 8

Druggability breadth: 3 of 8 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRCC3	0	0
FAM223A	0	0
SPANXN1	0	0
EMD	0	0
CMC4	0	0
ABCD1	0	0
ARHGAP4	0	0
OPN1LW	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
OPN1LW	4	Binding:4
BRCC3	1	Binding:1
EMD	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	3	BRCC3, ABCD1, OPN1LW
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	FAM223A, SPANXN1, EMD, CMC4, ARHGAP4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BRCC3	1	—
FAM223A	0	—
SPANXN1	0	—
EMD	1	—
CMC4	0	—
ABCD1	0	—
ARHGAP4	0	—
OPN1LW	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.