Severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome

Summary

Severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome (MONDO:0010334) is a disease caused by BCAP31 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BCAP31 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 19
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001954	Recurrent fever	Frequent (30-79%)
HP:0002445	Tetraplegia	Frequent (30-79%)
HP:0006808	Cerebral hypomyelination	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0003429	CNS hypomyelination	Occasional (5-29%)
HP:0007371	Corpus callosum atrophy	Occasional (5-29%)
HP:0012444	Brain atrophy	Occasional (5-29%)
HP:0012762	Cerebral white matter atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome
Mondo ID	MONDO:0010334
MeSH	C564508
OMIM	300475
Orphanet	369939
DOID	DOID:0112123
UMLS	C3806634
MedGen	812964
GARD	0017592
Is cancer (heuristic)	no

Also known as: DDCH · deafness, dystonia, and cerebral hypomyelination · deafness, dystonia, and cerebral hypomyelination, X-linked recessive

Data availability: 19 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › chromosomal disorder › syndrome caused by partial chromosomal deletion › severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome

Related subtypes (26): Smith-Magenis syndrome, partial chromosome Y deletion, partial deletion of chromosome 1, partial deletion of chromosome 2, partial deletion of chromosome 3, partial deletion of chromosome 4, partial deletion of chromosome 5, partial deletion of chromosome 6, partial deletion of chromosome 7, partial deletion of chromosome 8, partial deletion of chromosome 9, partial deletion of chromosome 10, partial deletion of chromosome 11, partial deletion of chromosome 16, partial deletion of chromosome 17, partial deletion of chromosome 18, partial deletion of chromosome 19, partial deletion of chromosome 20, partial deletion of the long arm of chromosome 13, partial deletion of the long arm of chromosome 14, partial deletion of the long arm of chromosome 15, partial deletion of the long arm of chromosome 21, partial deletion of chromosome X, partial deletion of chromosome 12, 3q27.3 microdeletion syndrome, chromosome 22q deletion

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

19 retrieved; paginated sample, class counts are floors:

9 pathogenic, 5 uncertain significance, 5 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500712	NC_000023.11:g.153714363_153781647del	ABCD1	Pathogenic	criteria provided, single submitter
374401	NM_001256447.2(BCAP31):c.-44-270C>A	BCAP31	Pathogenic	no assertion criteria provided
419708	NM_001256447.2(BCAP31):c.341+2T>G	BCAP31	Pathogenic	criteria provided, single submitter
488474	NM_001256447.2(BCAP31):c.365_366del (p.Leu122fs)	BCAP31	Pathogenic	criteria provided, multiple submitters, no conflicts
68444	NM_001256447.2(BCAP31):c.194-2A>G	BCAP31	Pathogenic	no assertion criteria provided
68445	NC_000023.11:g.153696346_153701690del	BCAP31	Pathogenic	no assertion criteria provided
68446	NM_001256447.2(BCAP31):c.97C>T (p.Gln33Ter)	BCAP31	Pathogenic	no assertion criteria provided
804102	NM_001256447.2(BCAP31):c.415C>T (p.Gln139Ter)	BCAP31	Pathogenic	criteria provided, single submitter
625802	GRCh37/hg19 Xq28(chrX:152980470-153032459)	PLXNB3	Pathogenic	criteria provided, single submitter
988783	NC_000023.10:g.(152886255_152976269)del		Likely pathogenic	no assertion criteria provided
988784	NC_000023.10:g.(152982350_153041544)del		Likely pathogenic	no assertion criteria provided
988785	NC_000023.10:g.(152882907_152991027)del		Likely pathogenic	no assertion criteria provided
3338048	NM_001256447.2(BCAP31):c.247C>T (p.Gln83Ter)	BCAP31	Likely pathogenic	criteria provided, single submitter
4796011	NM_001256447.2(BCAP31):c.466C>T (p.Gln156Ter)	BCAP31	Likely pathogenic	criteria provided, single submitter
1029148	NM_001256447.2(BCAP31):c.492C>G (p.Asp164Glu)	BCAP31	Uncertain significance	criteria provided, single submitter
1347813	NM_001256447.2(BCAP31):c.716G>A (p.Gly239Asp)	BCAP31	Uncertain significance	criteria provided, multiple submitters, no conflicts
2439483	NM_001256447.2(BCAP31):c.477+8del	BCAP31	Uncertain significance	criteria provided, single submitter
2439484	NM_001256447.2(BCAP31):c.709G>C (p.Val237Leu)	BCAP31	Uncertain significance	criteria provided, single submitter
976022	NM_001256447.2(BCAP31):c.317C>T (p.Ala106Val)	BCAP31	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
BCAP31	Definitive	X-linked	severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BCAP31	Orphanet:369939	Severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome
BCAP31	Orphanet:369942	CADDS
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BCAP31	HGNC:16695	ENSG00000185825	P51572	B-cell receptor-associated protein 31	gencc,clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar
PLXNB3	HGNC:9105	ENSG00000198753	Q9ULL4	Plexin-B3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCAP31	B-cell receptor-associated protein 31	Functions as a chaperone protein.
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.
PLXNB3	Plexin-B3	Receptor for SEMA5A that plays a role in axon guidance, invasive growth and cell migration.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	25.9×	0.114
Antibody/Immunoglobulin	1	9.7×	0.149
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCAP31	Other/Unknown	no		BAP29/BAP31, BAP29/BAP31_N, Bap31/Bap29_C
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
PLXNB3	Antibody/Immunoglobulin	yes		Semap_dom, Plexin_repeat, IPT_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	2
right adrenal gland	1
right adrenal gland cortex	1
ileal mucosa	1
left adrenal gland cortex	1
C1 segment of cervical spinal cord	1
right hemisphere of cerebellum	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCAP31	292	ubiquitous	marker	left adrenal gland, right adrenal gland, right adrenal gland cortex
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
PLXNB3	133	ubiquitous	yes	C1 segment of cervical spinal cord, tibial nerve, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCAP31	3,085
ABCD1	1,181
PLXNB3	1,117

Intra-cohort edges

A	B	Sources
ABCD1	BCAP31	string_interaction
ABCD1	PLXNB3	string_interaction
BCAP31	PLXNB3	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCD1	P33897	14
BCAP31	P51572	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLXNB3	Q9ULL4	81.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 3 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
Defective ABCD1 causes ALD	1	1903.3×	0.018	ABCD1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	634.4×	0.020	ABCD1
Linoleic acid (LA) metabolism	1	380.7×	0.020	ABCD1
Beta-oxidation of very long chain fatty acids	1	292.8×	0.020	ABCD1
alpha-linolenic acid (ALA) metabolism	1	237.9×	0.020	ABCD1
Peroxisomal lipid metabolism	1	223.9×	0.020	ABCD1
ABC transporters in lipid homeostasis	1	200.3×	0.020	ABCD1
Other semaphorin interactions	1	200.3×	0.020	PLXNB3
Class I peroxisomal membrane protein import	1	173.0×	0.020	ABCD1
Apoptotic cleavage of cellular proteins	1	158.6×	0.020	BCAP31
Apoptotic execution phase	1	158.6×	0.020	BCAP31
ABC transporter disorders	1	146.4×	0.020	ABCD1
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	131.3×	0.020	BCAP31
Respiratory Syncytial Virus Infection Pathway	1	65.6×	0.036	BCAP31
Protein localization	1	63.4×	0.036	ABCD1
Disease	2	8.7×	0.036	BCAP31, ABCD1
Apoptosis	1	56.0×	0.037	BCAP31
RSV-host interactions	1	52.1×	0.037	BCAP31
Programmed Cell Death	1	48.8×	0.037	BCAP31
Disorders of transmembrane transporters	1	46.4×	0.037	ABCD1
Fatty acid metabolism	1	43.8×	0.038	ABCD1
ABC-family protein mediated transport	1	40.5×	0.039	ABCD1
RHOA GTPase cycle	1	24.9×	0.060	BCAP31
Class I MHC mediated antigen processing & presentation	1	23.4×	0.062	BCAP31
RHO GTPase cycle	1	20.0×	0.069	BCAP31
Signaling by Rho GTPases	1	11.4×	0.113	BCAP31
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	11.2×	0.113	BCAP31
Metabolism of lipids	1	10.5×	0.113	ABCD1
Viral Infection Pathways	1	10.3×	0.113	BCAP31
Adaptive Immune System	1	9.9×	0.113	BCAP31

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peroxisomal membrane transport	1	2808.7×	0.005	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	2808.7×	0.005	ABCD1
positive regulation of retrograde protein transport, ER to cytosol	1	1872.4×	0.005	BCAP31
positive regulation of unsaturated fatty acid biosynthetic process	1	1872.4×	0.005	ABCD1
sterol homeostasis	1	1404.3×	0.005	ABCD1
negative regulation of lamellipodium assembly	1	1123.5×	0.005	PLXNB3
long-chain fatty acid import into peroxisome	1	1123.5×	0.005	ABCD1
regulation of fatty acid beta-oxidation	1	936.2×	0.005	ABCD1
long-chain fatty acid catabolic process	1	936.2×	0.005	ABCD1
myelin maintenance	1	936.2×	0.005	ABCD1
regulation of mitochondrial depolarization	1	936.2×	0.005	ABCD1
fatty acid elongation	1	802.5×	0.005	ABCD1
very long-chain fatty acid catabolic process	1	802.5×	0.005	ABCD1
protein localization to endoplasmic reticulum exit site	1	702.2×	0.005	BCAP31
positive regulation of fatty acid beta-oxidation	1	510.7×	0.006	ABCD1
fatty acid derivative biosynthetic process	1	510.7×	0.006	ABCD1
regulation of cellular response to oxidative stress	1	432.1×	0.007	ABCD1
regulation of oxidative phosphorylation	1	401.2×	0.007	ABCD1
neuron projection maintenance	1	374.5×	0.007	ABCD1
negative regulation of GTPase activity	1	351.1×	0.007	PLXNB3
negative regulation of reactive oxygen species biosynthetic process	1	330.4×	0.007	ABCD1
fatty acid homeostasis	1	312.1×	0.007	ABCD1
alpha-linolenic acid metabolic process	1	295.6×	0.007	ABCD1
positive regulation of ERAD pathway	1	295.6×	0.007	BCAP31
peroxisome organization	1	267.5×	0.007	ABCD1
positive chemotaxis	1	267.5×	0.007	PLXNB3
very long-chain fatty acid metabolic process	1	255.3×	0.007	ABCD1
linoleic acid metabolic process	1	234.1×	0.008	ABCD1
unsaturated fatty acid biosynthetic process	1	216.1×	0.008	ABCD1
obsolete protein targeting to mitochondrion	1	193.7×	0.008	BCAP31

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BCAP31	0	0
ABCD1	0	0
PLXNB3	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
BCAP31	8	Binding:8

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: 3; 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	1	ABCD1
D	Druggable family + AlphaFold only, no drug	1	PLXNB3
E	Difficult family or no structure, no drug	1	BCAP31

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)
BCAP31	8	—
ABCD1	0	—
PLXNB3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.