Lissencephaly 9 with complex brainstem malformation

Summary

Lissencephaly 9 with complex brainstem malformation (MONDO:0032677) is a disease caused by MACF1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MACF1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 174
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	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:0001302	Pachygyria	Very frequent (80-99%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Very frequent (80-99%)
HP:0008936	Axial hypotonia	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0025100	Abnormal hippocampus morphology	Very frequent (80-99%)
HP:0030301	Abnormality of the anterior commissure	Very frequent (80-99%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0033725	Thin corpus callosum	Frequent (30-79%)
HP:0000011	Neurogenic bladder	Occasional (5-29%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0000609	Optic nerve hypoplasia	Occasional (5-29%)
HP:0000733	Abnormal repetitive mannerisms	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0032794	Myoclonic seizure	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lissencephaly 9 with complex brainstem malformation
Mondo ID	MONDO:0032677
OMIM	618325
Orphanet	572013
DOID	DOID:0112228
UMLS	C5193029
MedGen	1681109
GARD	0018007
Is cancer (heuristic)	no

Also known as: LIS9

Data availability: 174 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › lissencephaly spectrum disorders › lissencephaly spectrum disorder with complex brainstem malformation › lissencephaly 9 with complex brainstem malformation

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

174 retrieved; paginated sample, class counts are floors:

92 uncertain significance, 21 benign/likely benign, 19 benign, 15 conflicting classifications of pathogenicity, 10 likely pathogenic, 8 likely benign, 5 pathogenic/likely pathogenic, 3 pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1685933	NM_001394062.1(MACF1):c.12265C>T (p.Gln4089Ter)	MACF1	Pathogenic	criteria provided, single submitter
3767317	NM_001394062.1(MACF1):c.8892del (p.Gln2964fs)	MACF1	Pathogenic	criteria provided, single submitter
586948	NM_001394062.1(MACF1):c.21707G>T (p.Cys7236Phe)	MACF1	Pathogenic	criteria provided, single submitter
586949	NM_001394062.1(MACF1):c.21877G>T (p.Asp7293Tyr)	MACF1	Pathogenic/Likely pathogenic	no assertion criteria provided
586950	NM_001394062.1(MACF1):c.21883T>G (p.Cys7295Gly)	MACF1	Pathogenic/Likely pathogenic	no assertion criteria provided
586951	NM_001394062.1(MACF1):c.21884G>T (p.Cys7295Phe)	MACF1	Pathogenic/Likely pathogenic	no assertion criteria provided
586952	NM_012090.5(MACF1):c.10617+444_15577-288del	MACF1	Pathogenic/Likely pathogenic	no assertion criteria provided
586953	NM_001394062.1(MACF1):c.20293G>C (p.Gly6765Arg)	MACF1	Pathogenic/Likely pathogenic	no assertion criteria provided
1676542	NM_001394062.1(MACF1):c.1957C>T (p.Leu653Phe)	MACF1	Likely pathogenic	criteria provided, single submitter
1694447	NM_001394062.1(MACF1):c.21717G>T (p.Arg7239Ser)	MACF1	Likely pathogenic	criteria provided, single submitter
1699453	NM_001394062.1(MACF1):c.21803G>A (p.Arg7268His)	MACF1	Likely pathogenic	criteria provided, single submitter
2431958	NM_001394062.1(MACF1):c.7129dup (p.Arg2377fs)	MACF1	Likely pathogenic	criteria provided, single submitter
2441775	NM_001394062.1(MACF1):c.21820G>A (p.Val7274Met)	MACF1	Likely pathogenic	criteria provided, single submitter
2499569	NM_001394062.1(MACF1):c.21752G>C (p.Arg7251Pro)	MACF1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3024134	NM_001394062.1(MACF1):c.21679-2A>G	MACF1	Likely pathogenic	criteria provided, single submitter
3065758	NM_001394062.1(MACF1):c.16804-2A>G	MACF1	Likely pathogenic	criteria provided, single submitter
4291812	NM_001394062.1(MACF1):c.16149+1G>T	MACF1	Likely pathogenic	criteria provided, single submitter
4813443	NM_001394062.1(MACF1):c.20288T>G (p.Phe6763Cys)	MACF1	Likely pathogenic	criteria provided, single submitter
1012522	NM_001394062.1(MACF1):c.12904G>T (p.Asp4302Tyr)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031174	NM_001394062.1(MACF1):c.4099C>T (p.Arg1367Cys)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1314745	NM_012090.5(MACF1):c.35G>A (p.Arg12Gln)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1325546	NM_001394062.1(MACF1):c.744G>T (p.Glu248Asp)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2039439	NM_001394062.1(MACF1):c.14471C>T (p.Ala4824Val)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2047035	NM_001394062.1(MACF1):c.20455G>A (p.Val6819Ile)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2067606	NM_001394062.1(MACF1):c.14369C>T (p.Ala4790Val)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2433587	NM_001394062.1(MACF1):c.3698G>A (p.Arg1233Gln)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3121892	NM_001394062.1(MACF1):c.14296C>T (p.Arg4766Cys)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3699898	NM_001394062.1(MACF1):c.13484C>T (p.Thr4495Ile)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
718959	NM_001394062.1(MACF1):c.4103G>A (p.Arg1368His)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
806109	NM_001394062.1(MACF1):c.12857C>T (p.Ala4286Val)	MACF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
MACF1	Strong	Autosomal dominant	lissencephaly 9 with complex brainstem malformation	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MACF1	Orphanet:572013	Posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MACF1	HGNC:13664	ENSG00000127603	O94854	Microtubule-actin cross-linking factor 1, isoforms 6/7	gencc,clinvar

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MACF1	Scaffold/PPI	no		Spectrin_repeat, EF_hand_dom, GAR_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MACF1	303	ubiquitous	marker	inferior olivary complex, dorsal motor nucleus of vagus nerve, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MACF1	75

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MACF1	O94854	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of epithelial cell migration	1	2808.7×	0.002	MACF1
regulation of neuron projection arborization	1	2808.7×	0.002	MACF1
regulation of microtubule-based process	1	1872.4×	0.002	MACF1
intermediate filament cytoskeleton organization	1	936.2×	0.003	MACF1
regulation of focal adhesion assembly	1	601.9×	0.003	MACF1
Golgi to plasma membrane protein transport	1	526.6×	0.003	MACF1
positive regulation of axon extension	1	510.7×	0.003	MACF1
positive regulation of Wnt signaling pathway	1	383.0×	0.004	MACF1
wound healing	1	227.7×	0.005	MACF1
regulation of cell migration	1	157.5×	0.007	MACF1
Wnt signaling pathway	1	99.7×	0.010	MACF1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MACF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	MACF1

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)
MACF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.