Lissencephaly 6 with microcephaly

Summary

Lissencephaly 6 with microcephaly (MONDO:0014534) is a disease caused by KATNB1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: KATNB1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	lissencephaly 6 with microcephaly
Mondo ID	MONDO:0014534
OMIM	616212
DOID	DOID:0112236
UMLS	C4015525
MedGen	863962
GARD	0024999
Is cancer (heuristic)	no

Also known as: KATNB1 Microlissencephaly · KATNB1 microlissencephaly · LIS6 · lissencephaly 6 with microcephaly · lissencephaly 6, with microcephaly · Microlissencephaly caused by mutation in KATNB1 · microlissencephaly caused by mutation in KATNB1

Data availability: 22 ClinVar variants · 5 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 › microlissencephaly › lissencephaly 6 with microcephaly

Related subtypes (2): Norman-Roberts syndrome, lissencephaly 4

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

22 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 7 pathogenic, 2 conflicting classifications of pathogenicity, 2 benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
180636	NM_005886.3(KATNB1):c.1604C>T (p.Ser535Leu)	KATNB1	Pathogenic	no assertion criteria provided
180637	NM_005886.3(KATNB1):c.1619T>G (p.Leu540Arg)	KATNB1	Pathogenic	no assertion criteria provided
180638	NM_005886.3(KATNB1):c.447del (p.Val150fs)	KATNB1	Pathogenic	no assertion criteria provided
180639	NM_005886.3(KATNB1):c.1A>G (p.Met1Val)	KATNB1	Pathogenic	no assertion criteria provided
180640	NM_005886.3(KATNB1):c.97G>T (p.Gly33Trp)	KATNB1	Pathogenic	criteria provided, single submitter
180641	NM_005886.3(KATNB1):c.432+1G>A	KATNB1	Pathogenic	no assertion criteria provided
4818946	NM_005886.3(KATNB1):c.970C>T (p.Gln324Ter)	KATNB1	Pathogenic	criteria provided, single submitter
1324607	NM_005886.3(KATNB1):c.1416+1G>A	KATNB1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3731466	NM_005886.3(KATNB1):c.1061C>G (p.Ser354Ter)	KATNB1	Likely pathogenic	criteria provided, single submitter
1033039	NM_005886.3(KATNB1):c.1047-3C>T	KATNB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2070092	NM_005886.3(KATNB1):c.1558G>A (p.Asp520Asn)	KATNB1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1328151	NM_005886.3(KATNB1):c.131G>A (p.Arg44His)	KATNB1	Uncertain significance	criteria provided, single submitter
2163116	NM_005886.3(KATNB1):c.1357_1358delinsTT (p.Ala453Phe)	KATNB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432978	NM_005886.3(KATNB1):c.100C>T (p.Arg34Trp)	KATNB1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432979	NM_005886.3(KATNB1):c.1208T>A (p.Phe403Tyr)	KATNB1	Uncertain significance	criteria provided, single submitter
2432980	NM_005886.3(KATNB1):c.904C>A (p.Leu302Met)	KATNB1	Uncertain significance	criteria provided, single submitter
2689281	NM_005886.3(KATNB1):c.62G>A (p.Ser21Asn)	KATNB1	Uncertain significance	criteria provided, single submitter
3236076	NM_005886.3(KATNB1):c.134T>C (p.Val45Ala)	KATNB1	Uncertain significance	criteria provided, single submitter
3236752	NM_005886.3(KATNB1):c.1567-3C>G	KATNB1	Uncertain significance	criteria provided, single submitter
4277863	NM_005886.3(KATNB1):c.451C>T (p.Arg151Trp)	KATNB1	Uncertain significance	criteria provided, single submitter
1220936	NM_005886.3(KATNB1):c.726C>T (p.Asp242=)	KATNB1	Benign	criteria provided, multiple submitters, no conflicts
1236671	NM_005886.3(KATNB1):c.704+4C>T	KATNB1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
KATNB1	Definitive	Autosomal recessive	lissencephaly 6 with microcephaly	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KATNB1	Orphanet:89844	Lissencephaly syndrome, Norman-Roberts type

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
KATNB1	HGNC:6217	ENSG00000140854	Q9BVA0	Katanin p80 WD40 repeat-containing subunit B1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KATNB1	Katanin p80 WD40 repeat-containing subunit B1	Participates in a complex which severs microtubules in an ATP-dependent manner.

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)
KATNB1	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS

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
middle temporal gyrus	1
right frontal lobe	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KATNB1	280	ubiquitous	marker	middle temporal gyrus, right frontal lobe, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KATNB1	1,325

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KATNB1	Q9BVA0	79.58

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
mitotic chromosome movement towards spindle pole	1	3370.4×	0.001	KATNB1
positive regulation of microtubule depolymerization	1	3370.4×	0.001	KATNB1
microtubule severing	1	1296.3×	0.002	KATNB1
microtubule depolymerization	1	1053.2×	0.002	KATNB1
negative regulation of microtubule depolymerization	1	495.6×	0.004	KATNB1
protein targeting	1	366.4×	0.004	KATNB1
cytoplasmic microtubule organization	1	343.9×	0.004	KATNB1
positive regulation of neuron projection development	1	137.0×	0.009	KATNB1
positive regulation of apoptotic process	1	56.7×	0.020	KATNB1
cell division	1	46.2×	0.022	KATNB1

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
KATNB1	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
KATNB1	2	Binding:2

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	KATNB1

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)
KATNB1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.