Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures

Summary

Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures (MONDO:0014121) is a disease caused by BICD2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BICD2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 802
• Phenotypes (HPO): 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

17 HPO clinical features (Orphanet curated; top 17 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002515	Waddling gait	Frequent (30-79%)
HP:0003391	Gowers sign	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0005853	Congenital foot contraction deformities	Frequent (30-79%)
HP:0008944	Distal lower limb amyotrophy	Frequent (30-79%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001385	Hip dysplasia	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0003307	Hyperlordosis	Occasional (5-29%)
HP:0005109	Abnormality of the Achilles tendon	Occasional (5-29%)
HP:0003547	Shoulder girdle muscle weakness	Very rare (<1-4%)
HP:0030237	Hand muscle weakness	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures
Mondo ID	MONDO:0014121
OMIM	615290
Orphanet	363454
DOID	DOID:0070349
UMLS	C4747715
MedGen	1669929
GARD	0013222
Is cancer (heuristic)	no

Also known as: autosomal dominant spinal muscular atrophy, lower extremity-predominant 2 · Lower extremity-predominant autosomal dominant proximal spinal muscular atrophy with contractures · SMALED2 · spinal muscular atrophy, lower extremity-predominant 2, autosomal dominant · spinal muscular atrophy, LOWER extremity-predominant, 2, autosomal dominant · spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant

Data availability: 802 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › spinal muscular atrophy › proximal spinal muscular atrophy › autosomal dominant childhood-onset proximal spinal muscular atrophy › autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures

Related subtypes (2): autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, spinal muscular atrophy, lower extremity-predominant, 2b, prenatal onset, autosomal dominant

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

600 retrieved; paginated sample, class counts are floors:

262 likely benign, 258 uncertain significance, 37 conflicting classifications of pathogenicity, 22 benign/likely benign, 12 benign, 7 likely pathogenic, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
210526	NM_001003800.2(BICD2):c.2080C>T (p.Arg694Cys)	BICD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2865170	NM_001003800.2(BICD2):c.1922T>A (p.Leu641Gln)	BICD2	Pathogenic	criteria provided, single submitter
1018827	NM_001003800.2(BICD2):c.2058G>T (p.Lys686Asn)	BICD2	Likely pathogenic	criteria provided, single submitter
1375587	NM_001003800.2(BICD2):c.567C>G (p.Ile189Met)	BICD2	Likely pathogenic	criteria provided, single submitter
2431200	NM_001003800.2(BICD2):c.2200A>G (p.Lys734Glu)	BICD2	Likely pathogenic	criteria provided, single submitter
2442262	NM_001003800.2(BICD2):c.1922T>G (p.Leu641Arg)	BICD2	Likely pathogenic	no assertion criteria provided
2444193	NM_001003800.2(BICD2):c.629A>C (p.His210Pro)	BICD2	Likely pathogenic	criteria provided, single submitter
3064531	NM_001003800.2(BICD2):c.535C>T (p.Gln179Ter)	BICD2	Likely pathogenic	criteria provided, single submitter
3773706	NM_001003800.2(BICD2):c.570C>A (p.Ser190Arg)	BICD2	Likely pathogenic	criteria provided, single submitter
1037444	NM_001003800.2(BICD2):c.1417C>T (p.Arg473Cys)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1187715	NM_001003800.2(BICD2):c.386G>A (p.Arg129His)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1232519	NM_001003800.2(BICD2):c.1697G>T (p.Arg566Leu)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1312806	NM_001003800.2(BICD2):c.162G>C (p.Lys54Asn)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1381411	NM_001003800.2(BICD2):c.1211A>G (p.Lys404Arg)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1400970	NM_001003800.2(BICD2):c.79A>G (p.Lys27Glu)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1441759	NM_001003800.2(BICD2):c.803A>G (p.Asn268Ser)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1497963	NM_001003800.2(BICD2):c.1388G>A (p.Arg463His)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1508668	NM_001003800.2(BICD2):c.1693G>A (p.Gly565Ser)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1512331	NM_001003800.2(BICD2):c.991A>G (p.Ser331Gly)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
155729	NM_001003800.2(BICD2):c.1993G>T (p.Val665Leu)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1791371	NM_001003800.2(BICD2):c.2444C>T (p.Pro815Leu)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2030246	NM_001003800.2(BICD2):c.2240G>T (p.Arg747Leu)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2037914	NM_001003800.2(BICD2):c.1120G>A (p.Glu374Lys)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2164311	NM_001003800.2(BICD2):c.1428T>G (p.Ala476=)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2165739	NM_001003800.2(BICD2):c.812_814del (p.Phe271del)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235235	NM_001003800.2(BICD2):c.269A>G (p.Lys90Arg)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2659306	NM_001003800.2(BICD2):c.2368C>T (p.Leu790=)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2723434	NM_001003800.2(BICD2):c.1375A>G (p.Thr459Ala)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
383686	NM_001003800.2(BICD2):c.2142G>C (p.Lys714Asn)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
388509	NM_001003800.2(BICD2):c.1421A>G (p.Tyr474Cys)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 1 · 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
BICD2	Definitive	Autosomal dominant	autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BICD2	Orphanet:363454	BICD2-related autosomal dominant childhood-onset proximal spinal muscular atrophy

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
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	gencc,clinvar
ASPN	HGNC:14872	ENSG00000106819	Q9BXN1	Asporin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BICD2	Protein bicaudal D homolog 2	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.
ASPN	Asporin	Negatively regulates periodontal ligament (PDL) differentiation and mineralization to ensure that the PDL is not ossified and to maintain homeostasis of the tooth-supporting system.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BICD2	Other/Unknown	no		BICD
ASPN	Other/Unknown	no		LRRNT, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp

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
gingiva	1
gingival epithelium	1
hair follicle	1
periodontal ligament	1
synovial joint	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BICD2	290	ubiquitous	marker	gingival epithelium, gingiva, hair follicle
ASPN	243	broad	marker	tendon of biceps brachii, synovial joint, periodontal ligament

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BICD2	2,275
ASPN	2,075

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BICD2	Q8TD16	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ASPN	Q9BXN1	85.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.033	BICD2
ECM proteoglycans	1	75.1×	0.033	ASPN
Golgi-to-ER retrograde transport	1	66.4×	0.033	BICD2
Intra-Golgi and retrograde Golgi-to-ER traffic	1	52.4×	0.033	BICD2
Extracellular matrix organization	1	31.6×	0.044	ASPN
Membrane Trafficking	1	18.5×	0.057	BICD2
Vesicle-mediated transport	1	17.4×	0.057	BICD2

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
negative regulation of tooth mineralization	1	4213.0×	0.002	ASPN
microtubule anchoring at microtubule organizing center	1	4213.0×	0.002	BICD2
response to fluoride	1	2808.7×	0.002	ASPN
minus-end-directed organelle transport along microtubule	1	2106.5×	0.002	BICD2
centrosome localization	1	443.5×	0.005	BICD2
protein localization to Golgi apparatus	1	401.2×	0.005	BICD2
regulation of microtubule cytoskeleton organization	1	271.8×	0.007	BICD2
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	168.5×	0.009	BICD2
microtubule-based movement	1	147.8×	0.009	BICD2
bone mineralization	1	135.9×	0.009	ASPN
mRNA transport	1	131.7×	0.009	BICD2
negative regulation of transforming growth factor beta receptor signaling pathway	1	86.9×	0.012	ASPN
protein transport	1	21.9×	0.045	BICD2

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
BICD2	0	0
ASPN	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	0
E	Difficult family or no structure, no drug	2	BICD2, ASPN

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)
BICD2	0	—
ASPN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.