Intellectual developmental disorder with severe speech and ambulation defects

Summary

Intellectual developmental disorder with severe speech and ambulation defects (MONDO:0032770) is a disease caused by ACTL6B (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ACTL6B (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder with severe speech and ambulation defects
Mondo ID	MONDO:0032770
OMIM	618470
UMLS	C5193115
MedGen	1682234
GARD	0018518
Is cancer (heuristic)	no

Also known as: ACTL6B-related BAFopathy · IDDSSAD

Data availability: 16 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › BAFopathy › intellectual developmental disorder with severe speech and ambulation defects

Related subtypes (14): Coffin-Siris syndrome 1, Baraitser-Winter syndrome 1, intellectual disability-sparse hair-brachydactyly syndrome, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, Coffin-Siris syndrome 5, Dias-Logan syndrome, Coffin-Siris syndrome 8, Coffin-Siris syndrome 6, intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities, ACTL6A-related BAFopathy, PBRM1-related BAFopathy, SMARCC1-associated developmental dysgenesis syndrome

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

16 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 6 likely pathogenic, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
430804	NM_016188.5(ACTL6B):c.1027G>A (p.Gly343Arg)	ACTL6B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702533	NM_016188.5(ACTL6B):c.554T>C (p.Leu185Pro)	ACTL6B	Likely pathogenic	criteria provided, single submitter
1705593	NM_016188.5(ACTL6B):c.1027G>T (p.Gly343Trp)	ACTL6B	Likely pathogenic	criteria provided, single submitter
1709092	NM_016188.5(ACTL6B):c.375C>A (p.Asn125Lys)	ACTL6B	Likely pathogenic	criteria provided, single submitter
3068401	NM_016188.5(ACTL6B):c.445del (p.Cys149fs)	ACTL6B	Likely pathogenic	criteria provided, single submitter
4532039	NM_016188.5(ACTL6B):c.990_993delinsAGCA (p.Gly331Ala)	ACTL6B	Likely pathogenic	criteria provided, single submitter
692137	NM_016188.5(ACTL6B):c.289C>T (p.Arg97Ter)	ACTL6B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710282	NM_016188.5(ACTL6B):c.155T>C (p.Leu52Pro)	ACTL6B	Uncertain significance	criteria provided, single submitter
2585503	NM_016188.5(ACTL6B):c.112C>G (p.Pro38Ala)	ACTL6B	Uncertain significance	criteria provided, single submitter
3239368	NM_016188.5(ACTL6B):c.1261G>A (p.Val421Met)	ACTL6B	Uncertain significance	criteria provided, multiple submitters, no conflicts
3376620	NM_016188.5(ACTL6B):c.1157G>A (p.Arg386His)	ACTL6B	Uncertain significance	criteria provided, single submitter
3376890	NM_016188.5(ACTL6B):c.922C>A (p.Pro308Thr)	ACTL6B	Uncertain significance	criteria provided, single submitter
3774894	NM_016188.5(ACTL6B):c.1088G>A (p.Arg363Gln)	ACTL6B	Uncertain significance	criteria provided, multiple submitters, no conflicts
4293039	NM_016188.5(ACTL6B):c.185G>A (p.Gly62Glu)	ACTL6B	Uncertain significance	criteria provided, single submitter
635107	NM_016188.5(ACTL6B):c.230A>G (p.Asp77Gly)	ACTL6B	Uncertain significance	criteria provided, single submitter
1188858	NM_016188.5(ACTL6B):c.*98T>A	ACTL6B	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
ACTL6B	Definitive	Autosomal recessive	developmental and epileptic encephalopathy, 76	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTL6B	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ACTL6B	Orphanet:528084	Non-specific syndromic intellectual disability

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
ACTL6B	HGNC:160	ENSG00000077080	O94805	Actin-like protein 6B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTL6B	Actin-like protein 6B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACTL6B	Other/Unknown	no		Actin, Actin_CS, ATPase_NBD

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
cerebellar hemisphere	1
cortical plate	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTL6B	164	broad	marker	cortical plate, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTL6B	4,543

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTL6B	O94805	91.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 1 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
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	456.8×	0.015	ACTL6B
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	1	300.5×	0.015	ACTL6B
RMTs methylate histone arginines	1	146.4×	0.015	ACTL6B
Transcriptional regulation by RUNX1	1	146.4×	0.015	ACTL6B
Chromatin organization	1	81.6×	0.021	ACTL6B
Chromatin modifying enzymes	1	72.3×	0.021	ACTL6B
RNA Polymerase II Transcription	1	22.5×	0.057	ACTL6B
Gene expression (Transcription)	1	17.8×	0.063	ACTL6B
Generic Transcription Pathway	1	15.1×	0.066	ACTL6B

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
neuron maturation	1	802.5×	0.005	ACTL6B
regulation of G0 to G1 transition	1	674.1×	0.005	ACTL6B
regulation of nucleotide-excision repair	1	601.9×	0.005	ACTL6B
regulation of mitotic metaphase/anaphase transition	1	495.6×	0.005	ACTL6B
positive regulation of T cell differentiation	1	455.5×	0.005	ACTL6B
dendrite development	1	391.9×	0.005	ACTL6B
positive regulation of myoblast differentiation	1	366.4×	0.005	ACTL6B
positive regulation of stem cell population maintenance	1	343.9×	0.005	ACTL6B
positive regulation of double-strand break repair	1	343.9×	0.005	ACTL6B
regulation of G1/S transition of mitotic cell cycle	1	306.4×	0.005	ACTL6B
negative regulation of cell differentiation	1	285.6×	0.005	ACTL6B
positive regulation of cell differentiation	1	267.5×	0.005	ACTL6B
chromatin organization	1	99.1×	0.013	ACTL6B
chromatin remodeling	1	73.0×	0.017	ACTL6B
nervous system development	1	45.9×	0.025	ACTL6B
positive regulation of cell population proliferation	1	33.6×	0.032	ACTL6B
regulation of transcription by RNA polymerase II	1	11.7×	0.086	ACTL6B

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
ACTL6B	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	ACTL6B

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)
ACTL6B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.