Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

Summary

Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (MONDO:0008026) is a disease caused by DYNC1H1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DYNC1H1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 118

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		37	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures
Mondo ID	MONDO:0008026
MeSH	C563560
OMIM	158600
Orphanet	209341
DOID	DOID:0070351
UMLS	C5780022
MedGen	1830501
GARD	0013519
Is cancer (heuristic)	no

Also known as: Lower extremity-predominant autosomal dominant proximal spinal muscular atrophy without contractures · SMALED1 · spinal muscular atrophy, lower extremity-predominant 1, AD · spinal muscular atrophy, LOWER extremity-predominant, 1, autosomal dominant

Data availability: 118 ClinVar variants · 3 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 without contractures

Related subtypes (2): autosomal dominant childhood-onset proximal spinal muscular atrophy with 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

118 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 32 conflicting classifications of pathogenicity, 13 benign/likely benign, 13 likely pathogenic, 10 benign, 4 pathogenic/likely pathogenic, 4 pathogenic, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075692	NM_001376.5(DYNC1H1):c.1739A>C (p.Glu580Ala)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
139652	NM_001376.5(DYNC1H1):c.1792C>T (p.Arg598Cys)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685755	NM_001376.5(DYNC1H1):c.3395G>A (p.Gly1132Glu)	DYNC1H1	Pathogenic	criteria provided, multiple submitters, no conflicts
245597	NM_001376.5(DYNC1H1):c.5884C>T (p.Arg1962Cys)	DYNC1H1	Pathogenic	criteria provided, multiple submitters, no conflicts
246081	NM_001376.5(DYNC1H1):c.1793G>T (p.Arg598Leu)	DYNC1H1	Pathogenic	criteria provided, multiple submitters, no conflicts
30029	NM_001376.5(DYNC1H1):c.917A>G (p.His306Arg)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372934	NM_001376.5(DYNC1H1):c.2327C>T (p.Pro776Leu)	DYNC1H1	Pathogenic	criteria provided, multiple submitters, no conflicts
472535	NM_001376.5(DYNC1H1):c.4532C>T (p.Pro1511Leu)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334533	NM_001376.5(DYNC1H1):c.9547dup (p.Tyr3183fs)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
1526100	NM_001376.5(DYNC1H1):c.1867T>C (p.Phe623Leu)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
1685305	NM_001376.5(DYNC1H1):c.791G>C (p.Arg264Pro)	DYNC1H1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685306	NM_001376.5(DYNC1H1):c.3157-2A>T	DYNC1H1	Likely pathogenic	criteria provided, single submitter
180211	NM_001376.5(DYNC1H1):c.3603G>T (p.Arg1201Ser)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
208862	NM_001376.5(DYNC1H1):c.1738G>A (p.Glu580Lys)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
2442259	NM_001376.5(DYNC1H1):c.596A>C (p.Asn199Thr)	DYNC1H1	Likely pathogenic	no assertion criteria provided
2506366	NM_001376.5(DYNC1H1):c.1793G>C (p.Arg598Pro)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
2582561	NM_001376.5(DYNC1H1):c.6148G>C (p.Ala2050Pro)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
30034	NM_001376.5(DYNC1H1):c.2909A>G (p.Tyr970Cys)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
373213	NM_001376.5(DYNC1H1):c.5885G>A (p.Arg1962His)	DYNC1H1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4819768	NM_001376.5(DYNC1H1):c.3162G>T (p.Trp1054Cys)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
637515	NM_001376.5(DYNC1H1):c.1195A>G (p.Arg399Gly)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
1057796	NM_001376.5(DYNC1H1):c.11543G>A (p.Gly3848Asp)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1395098	NM_001376.5(DYNC1H1):c.8390G>A (p.Arg2797His)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1435402	NM_001376.5(DYNC1H1):c.12687C>T (p.Gly4229=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1480475	NM_001376.5(DYNC1H1):c.4597C>G (p.Leu1533Val)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1708512	NM_001376.5(DYNC1H1):c.3624G>T (p.Trp1208Cys)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1709833	NM_001376.5(DYNC1H1):c.161_172del (p.50AALE[1])	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197195	NM_001376.5(DYNC1H1):c.752G>A (p.Arg251His)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210873	NM_001376.5(DYNC1H1):c.5985C>T (p.Ala1995=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210882	NM_001376.5(DYNC1H1):c.7918G>A (p.Glu2640Lys)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
DYNC1H1	Definitive	Autosomal dominant	autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O
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
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	gencc,clinvar
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
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.

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)
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
BICD2	Other/Unknown	no		BICD

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
cortical plate	1
ganglionic eminence	1
ventricular zone	1
gingiva	1
gingival epithelium	1
hair follicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
BICD2	290	ubiquitous	marker	gingival epithelium, gingiva, hair follicle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC1H1	4,215
BICD2	2,275

Intra-cohort edges

A	B	Sources
BICD2	DYNC1H1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
BICD2	Q8TD16	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 24. 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	2	207.6×	5e-04	DYNC1H1, BICD2
Aggrephagy	1	124.1×	0.032	DYNC1H1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	96.8×	0.032	DYNC1H1
Loss of Nlp from mitotic centrosomes	1	79.3×	0.032	DYNC1H1
Loss of proteins required for interphase microtubule organization from the centrosome	1	79.3×	0.032	DYNC1H1
AURKA Activation by TPX2	1	76.1×	0.032	DYNC1H1
Recruitment of mitotic centrosome proteins and complexes	1	68.0×	0.032	DYNC1H1
Golgi-to-ER retrograde transport	1	66.4×	0.032	BICD2
Regulation of PLK1 Activity at G2/M Transition	1	63.4×	0.032	DYNC1H1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.032	DYNC1H1
Recruitment of NuMA to mitotic centrosomes	1	58.3×	0.032	DYNC1H1
Anchoring of the basal body to the plasma membrane	1	56.5×	0.032	DYNC1H1
COPI-mediated anterograde transport	1	54.9×	0.032	DYNC1H1
Intra-Golgi and retrograde Golgi-to-ER traffic	1	52.4×	0.032	BICD2
EML4 and NUDC in mitotic spindle formation	1	46.4×	0.032	DYNC1H1
MHC class II antigen presentation	1	44.6×	0.032	DYNC1H1
Resolution of Sister Chromatid Cohesion	1	43.3×	0.032	DYNC1H1
HCMV Early Events	1	40.5×	0.032	DYNC1H1
RHO GTPases Activate Formins	1	38.8×	0.032	DYNC1H1
Mitotic Prometaphase	1	34.6×	0.034	DYNC1H1
Separation of Sister Chromatids	1	30.4×	0.037	DYNC1H1
Membrane Trafficking	1	18.5×	0.058	BICD2
Vesicle-mediated transport	1	17.4×	0.059	BICD2
Neutrophil degranulation	1	11.5×	0.085	DYNC1H1

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
microtubule anchoring at microtubule organizing center	1	4213.0×	0.004	BICD2
minus-end-directed organelle transport along microtubule	1	2106.5×	0.004	BICD2
regulation of metaphase plate congression	1	1685.2×	0.004	DYNC1H1
establishment of spindle localization	1	1404.3×	0.004	DYNC1H1
positive regulation of spindle assembly	1	1053.2×	0.004	DYNC1H1
positive regulation of intracellular transport	1	842.6×	0.004	DYNC1H1
retrograde axonal transport	1	766.0×	0.004	DYNC1H1
P-body assembly	1	526.6×	0.005	DYNC1H1
centrosome localization	1	443.5×	0.005	BICD2
regulation of mitotic spindle organization	1	421.3×	0.005	DYNC1H1
protein localization to Golgi apparatus	1	401.2×	0.005	BICD2
nuclear migration	1	366.4×	0.005	DYNC1H1
stress granule assembly	1	300.9×	0.006	DYNC1H1
regulation of microtubule cytoskeleton organization	1	271.8×	0.006	BICD2
cytoplasmic microtubule organization	1	172.0×	0.008	DYNC1H1
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	168.5×	0.008	BICD2
microtubule-based movement	1	147.8×	0.009	BICD2
mitotic spindle organization	1	135.9×	0.009	DYNC1H1
mRNA transport	1	131.7×	0.009	BICD2
positive regulation of cold-induced thermogenesis	1	81.8×	0.013	DYNC1H1
cell division	1	23.1×	0.045	DYNC1H1
protein transport	1	21.9×	0.045	BICD2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DYNC1H1	1	2
BICD2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DYNC1H1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DYNC1H1	7	Binding:7

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

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	DYNC1H1

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	DYNC1H1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BICD2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BICD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.