Isolated unilateral hemispheric cerebellar hypoplasia

Summary

Isolated unilateral hemispheric cerebellar hypoplasia (MONDO:0017112) is a disease with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 3
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated unilateral hemispheric cerebellar hypoplasia
Mondo ID	MONDO:0017112
Orphanet	269218
ICD-11	1960392411
SNOMED CT	766934006
UMLS	C4707885
MedGen	1638819
GARD	0020995
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › isolated unilateral hemispheric cerebellar hypoplasia

Related subtypes (53): craniosynostosis-Dandy-Walker malformation-hydrocephalus syndrome, Aase-Smith syndrome, arachnoid cyst, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, Dandy-Walker malformation-postaxial polydactyly syndrome, cervical hypertrichosis-peripheral neuropathy syndrome, Joubert syndrome with oculorenal defect, NPHP3-related Meckel-like syndrome, orofaciodigital syndrome type 6, X-linked intellectual disability-cerebellar hypoplasia syndrome, syndromic X-linked intellectual disability Najm type, X-linked cerebral-cerebellar-coloboma syndrome syndrome, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, aprosencephaly cerebellar dysgenesis, Gomez-Lopez-Hernandez syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, pontine tegmental cap dysplasia, ataxia - intellectual disability - oculomotor apraxia - cerebellar cysts syndrome, cerebellar-facial-dental syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal recessive spinocerebellar ataxia 20, SLC39A8-CDG, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, isolated cerebellar vermis hypoplasia, cerebral gigantism-jaw cysts syndrome, holoprosencephaly-caudal dysgenesis syndrome, Joubert syndrome with ocular defect, macrocephaly-short stature-paraplegia syndrome, glioependymal/ependymal cyst, isolated cerebellar vermis agenesis, isolated bilateral hemispheric cerebellar hypoplasia, Hoyeraal-Hreidarsson syndrome, neural tube defect, partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, tubulinopathy-associated dysgyria, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, rhombencephalosynapsis, Lhermitte-Duclos disease, Ritscher-Schinzel syndrome, spinal muscular atrophy-Dandy-Walker malformation-cataracts syndrome, cystic malformation of the posterior fossa, pontocerebellar hypoplasia, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, hereditary cerebral malformation, isolated arhinencephaly

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

3 retrieved; paginated sample, class counts are floors:

3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
632584	NM_001387994.1(BAG6):c.3415C>T (p.Arg1139Ter)	BAG6	Uncertain significance	no assertion criteria provided
632589	NM_001394062.1(MACF1):c.22313G>A (p.Arg7438Gln)	MACF1	Uncertain significance	no assertion criteria provided
632590	NM_032108.4(SEMA6B):c.1834G>A (p.Val612Met)	SEMA6B	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEMA6B	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
MACF1	Orphanet:572013	Posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects syndrome

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
SEMA6B	HGNC:10739	ENSG00000167680	Q9H3T3	Semaphorin-6B	clinvar
MACF1	HGNC:13664	ENSG00000127603	O94854	Microtubule-actin cross-linking factor 1, isoforms 6/7	clinvar
BAG6	HGNC:13919	ENSG00000204463	P46379	Large proline-rich protein BAG6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SEMA6B	Semaphorin-6B	Functions as a cell surface repellent for mossy fibers of developing neurons in the hippocampus where it plays a role in axon guidance.
BAG6	Large proline-rich protein BAG6	ATP-independent molecular chaperone preventing the aggregation of misfolded and hydrophobic patches-containing proteins.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 1 · 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
Scaffold/PPI	2	11.5×	0.019
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SEMA6B	Scaffold/PPI	no		Semap_dom, Plexin_repeat, WD40/YVTN_repeat-like_dom_sf
MACF1	Scaffold/PPI	no		Spectrin_repeat, EF_hand_dom, GAR_dom
BAG6	Other/Unknown	no		Ubiquitin-like_dom, Ubiquitin_CS, BAG6

Expression context

Cohort genes with no expression data: 0.

3 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
anterior cingulate cortex	1
cingulate cortex	1
right frontal lobe	1
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
right lung	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SEMA6B	177	ubiquitous	marker	right frontal lobe, anterior cingulate cortex, cingulate cortex
MACF1	303	ubiquitous	marker	inferior olivary complex, dorsal motor nucleus of vagus nerve, right lung
BAG6	144	ubiquitous	marker	right testis, left testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BAG6	2,326
SEMA6B	722
MACF1	75

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BAG6	P46379	10
MACF1	O94854	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SEMA6B	Q9H3T3	74.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Insertion of tail-anchored proteins into the endoplasmic reticulum membrane	1	475.8×	0.004	BAG6
Protein localization	1	190.3×	0.005	BAG6

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
endoplasmic reticulum stress-induced pre-emptive quality control	1	2808.7×	0.007	BAG6
immune response-activating cell surface receptor signaling pathway	1	1872.4×	0.007	BAG6
obsolete maintenance of unfolded protein	1	1404.3×	0.007	BAG6
internal peptidyl-lysine acetylation	1	1123.5×	0.007	BAG6
regulation of epithelial cell migration	1	936.2×	0.007	MACF1
NK T cell activation	1	936.2×	0.007	BAG6
regulation of neuron projection arborization	1	936.2×	0.007	MACF1
regulation of microtubule-based process	1	624.1×	0.009	MACF1
post-translational protein targeting to endoplasmic reticulum membrane	1	468.1×	0.011	BAG6
intermediate filament cytoskeleton organization	1	312.1×	0.013	MACF1
tail-anchored membrane protein insertion into ER membrane	1	312.1×	0.013	BAG6
positive regulation of ERAD pathway	1	295.6×	0.013	BAG6
proteasomal protein catabolic process	1	255.3×	0.014	BAG6
negative regulation of proteolysis	1	224.7×	0.014	BAG6
synaptonemal complex assembly	1	216.1×	0.014	BAG6
regulation of focal adhesion assembly	1	200.6×	0.014	MACF1
natural killer cell activation	1	193.7×	0.014	BAG6
Golgi to plasma membrane protein transport	1	175.5×	0.014	MACF1
positive regulation of axon extension	1	170.2×	0.014	MACF1
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	1	165.2×	0.014	BAG6
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	160.5×	0.014	BAG6
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	133.8×	0.015	BAG6
semaphorin-plexin signaling pathway	1	133.8×	0.015	SEMA6B
positive regulation of Wnt signaling pathway	1	127.7×	0.015	MACF1
neural crest cell migration	1	112.3×	0.016	SEMA6B
regulation of embryonic development	1	110.1×	0.016	BAG6
hippocampus development	1	77.0×	0.022	SEMA6B
wound healing	1	75.9×	0.022	MACF1
lung development	1	66.1×	0.024	BAG6
ERAD pathway	1	60.4×	0.025	BAG6

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SEMA6B	0	0
MACF1	0	0
BAG6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
BAG6	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SEMA6B, MACF1, BAG6

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)
SEMA6B	0	—
MACF1	0	—
BAG6	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.