XK-related neurodegenerative disease

Summary

XK-related neurodegenerative disease (MONDO:0018945) is a disease caused by XK (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: XK (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	XK-related neurodegenerative disease
Mondo ID	MONDO:0018945
MeSH	C564038
OMIM	300842
Orphanet	59306
DOID	DOID:0112107
ICD-11	1749275115
SNOMED CT	234411007
UMLS	C0398568
MedGen	140765
GARD	0010731
Is cancer (heuristic)	no

Also known as: MCLDS · McLeod neuroacanthocytosis syndrome · McLeod syndrome · MLS · X-linked McLeod syndrome · XK disease

Data availability: 27 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › neuroacanthocytosis › XK-related neurodegenerative disease

Related subtypes (1): VPS13A-related neurodegenerative disease

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

27 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 10 pathogenic, 2 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3235121	Single allele	CFAP47	Pathogenic	no assertion criteria provided
1299565	NM_021083.4(XK):c.664C>T (p.Arg222Ter)	XK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4077101	NM_021083.4(XK):c.719dup (p.Ile241fs)	XK	Pathogenic	criteria provided, single submitter
9764	NM_021083.4(XK):c.508+1G>A	XK	Pathogenic	no assertion criteria provided
9765	NM_021083.4(XK):c.509-1G>A	XK	Pathogenic	no assertion criteria provided
9766	XK, 1-BP DEL	XK	Pathogenic	no assertion criteria provided
9767	NM_021083.4(XK):c.1013del (p.Phe338fs)	XK	Pathogenic	no assertion criteria provided
9768	NM_021083.4(XK):c.880T>C (p.Cys294Arg)	XK	Pathogenic	no assertion criteria provided
9769	NM_021083.4(XK):c.938_951del (p.Asn313fs)	XK	Pathogenic	no assertion criteria provided
9770	NM_021083.4(XK):c.941G>A (p.Trp314Ter)	XK	Pathogenic	no assertion criteria provided
9771	NM_021083.4(XK):c.895C>T (p.Gln299Ter)	XK	Pathogenic	no assertion criteria provided
1057784	NM_021083.4(XK):c.554T>C (p.Leu185Ser)	XK	Uncertain significance	criteria provided, multiple submitters, no conflicts
1300237	NM_021083.4(XK):c.664C>G (p.Arg222Gly)	XK	Uncertain significance	criteria provided, single submitter
2159928	NM_021083.4(XK):c.71T>A (p.Leu24Gln)	XK	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438618	NM_021083.4(XK):c.100C>G (p.Arg34Gly)	XK	Uncertain significance	criteria provided, single submitter
2438619	NM_021083.4(XK):c.85C>G (p.Arg29Gly)	XK	Uncertain significance	criteria provided, single submitter
2438620	NM_021083.4(XK):c.200C>T (p.Pro67Leu)	XK	Uncertain significance	criteria provided, single submitter
2438621	NM_021083.4(XK):c.335A>G (p.Asn112Ser)	XK	Uncertain significance	criteria provided, single submitter
2438622	NM_021083.4(XK):c.794A>G (p.Glu265Gly)	XK	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438623	NM_021083.4(XK):c.404C>T (p.Ala135Val)	XK	Uncertain significance	criteria provided, single submitter
2438624	NM_021083.4(XK):c.1220C>T (p.Pro407Leu)	XK	Uncertain significance	criteria provided, single submitter
4076331	NM_021083.4(XK):c.1168A>G (p.Arg390Gly)	XK	Uncertain significance	criteria provided, single submitter
4081017	NM_021083.4(XK):c.264C>T (p.Cys88=)	XK	Uncertain significance	criteria provided, single submitter
4081018	NM_021083.4(XK):c.694G>A (p.Val232Ile)	XK	Uncertain significance	criteria provided, single submitter
4081019	NM_021083.4(XK):c.818G>T (p.Arg273Ile)	XK	Uncertain significance	criteria provided, single submitter
1300236	NM_021083.4(XK):c.508+5G>A	XK	not provided	no classification provided
1300238	NM_021083.4(XK):c.979G>A (p.Glu327Lys)	XK	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 2 · 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
XK	Strong	X-linked	XK-related neurodegenerative disease	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
XK	Orphanet:59306	McLeod neuroacanthocytosis syndrome
CFAP47	Orphanet:137893	Male infertility due to large-headed multiflagellar polyploid spermatozoa

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
XK	HGNC:12811	ENSG00000047597	P51811	Endoplasmic reticulum membrane adapter protein XK	gencc,clinvar
CFAP47	HGNC:26708	ENSG00000165164	Q6ZTR5	Cilia- and flagella-associated protein 47	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
XK	Endoplasmic reticulum membrane adapter protein XK	Recruits the lipid transfer protein VPS13A from lipid droplets to the endoplasmic reticulum (ER) membrane.
CFAP47	Cilia- and flagella-associated protein 47	Plays a role in flagellar formation and sperm motility.

Protein-family classification

Druggable: 1 · Difficult: 0 · 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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
XK	Other/Unknown	no		XK-rel, XK-related_adapter
CFAP47	Antibody/Immunoglobulin	yes		CH_dom, Ig-like_fold, CH_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic mucosa	1
jejunal mucosa	1
trabecular bone tissue	1
bronchial epithelial cell	1
bronchus	1
oviduct epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
XK	221	broad	marker	trabecular bone tissue, jejunal mucosa, colonic mucosa
CFAP47	95	tissue_specific	marker	bronchial epithelial cell, bronchus, oviduct epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFAP47	1,256
XK	697

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
XK	P51811	81.89
CFAP47	Q6ZTR5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Peptide ligand-binding receptors	1	74.2×	0.013	XK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of axon diameter	1	1685.2×	0.003	XK
intracellular magnesium ion homeostasis	1	1404.3×	0.003	XK
regulation of cell size	1	383.0×	0.008	XK
skeletal muscle fiber development	1	271.8×	0.008	XK
sperm axoneme assembly	1	234.1×	0.008	CFAP47
amino acid transport	1	156.0×	0.010	XK
myelination	1	125.8×	0.010	XK
intracellular calcium ion homeostasis	1	72.6×	0.015	XK
cilium assembly	1	36.8×	0.027	CFAP47

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
XK	0	0
CFAP47	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
D	Druggable family + AlphaFold only, no drug	1	CFAP47
E	Difficult family or no structure, no drug	1	XK

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
XK	0	—
CFAP47	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.