Childhood apraxia of speech

Summary

Childhood apraxia of speech (MONDO:0011184) is a disease caused by FOXP2 (GenCC Strong), with 5 cohort genes and 16 clinical trials. Top therapeutic interventions include levocarnitine and methylphenidate hydrochloride.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FOXP2 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 182
• Phenotypes (HPO): 23
• Clinical trials: 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		22	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0002474	Expressive language delay	Frequent (30-79%)
HP:0002546	Incomprehensible speech	Frequent (30-79%)
HP:0006977	Grammar-specific speech disorder	Frequent (30-79%)
HP:0007010	Poor fine motor coordination	Frequent (30-79%)
HP:0010863	Receptive language delay	Frequent (30-79%)
HP:0011098	Speech apraxia	Frequent (30-79%)
HP:0031434	Abnormal speech prosody	Frequent (30-79%)
HP:0002307	Drooling	Occasional (5-29%)
HP:0002339	Abnormal caudate nucleus morphology	Occasional (5-29%)
HP:0002340	Caudate atrophy	Occasional (5-29%)
HP:0007015	Poor gross motor coordination	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012434	Delayed social development	Occasional (5-29%)
HP:0000176	Submucous cleft hard palate	Very rare (<1-4%)
HP:0000396	Overfolded helix	Very rare (<1-4%)
HP:0000729	Autistic behavior	Very rare (<1-4%)
HP:0002705	High, narrow palate	Very rare (<1-4%)
HP:0011228	Horizontal eyebrow	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	childhood apraxia of speech
Mondo ID	MONDO:0011184
OMIM	602081
Orphanet	209908
DOID	DOID:0111275
ICD-11	1590154825
SNOMED CT	229703009
UMLS	C0750927
MedGen	152917
GARD	0012889
Is cancer (heuristic)	no

Also known as: articulatory apraxia · CAS · childhood apraxia of speech · das · developmental apraxia of speech · developmental verbal apraxia · developmental verbal dyspraxia · SPCH1 · speech and language disorder with orofacial dyspraxia · speech-language disorder 1 · speech-language disorder type 1 · speech-language disorder-1

Data availability: 182 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › specific learning disability › specific language disorder › childhood apraxia of speech

Related subtypes (1): familial developmental dysphasia

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

182 retrieved; paginated sample, class counts are floors:

69 uncertain significance, 41 benign, 30 pathogenic, 10 conflicting classifications of pathogenicity, 9 likely pathogenic, 9 benign/likely benign, 6 not provided, 6 likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
242972	NC_000007.13:g.(20954043_21001537)_(114528369_114556605)inv	ADAM22	Pathogenic	no assertion criteria provided
1065476	NM_014491.4(FOXP2):c.586C>T (p.Gln196Ter)	FOXP2	Pathogenic	criteria provided, single submitter
1098279	NM_014491.4(FOXP2):c.559C>T (p.Gln187Ter)	FOXP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1119985	NM_014491.4(FOXP2):c.1432C>T (p.Arg478Ter)	FOXP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1119990	NM_014491.4(FOXP2):c.1690C>T (p.Arg564Ter)	FOXP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1710219	NM_014491.4(FOXP2):c.1540del (p.Arg514fs)	FOXP2	Pathogenic	no assertion criteria provided
242953	t(3;7)(q23;q31.2)	FOXP2	Pathogenic	no assertion criteria provided
242954	t(5;7)(q22;q31.2)	FOXP2	Pathogenic	no assertion criteria provided
242955	t(7;13)(q31.1;q13.2)	FOXP2	Pathogenic	no assertion criteria provided
242957	NC_000007.12:g.111781517_120142536del	FOXP2	Pathogenic	no assertion criteria provided
242958	7q31.1-q31.2, 6.5 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242959	7q31.1-q31.3, 14.8 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242960	7q31.1-q31.2, 1.57 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242961	7q31.1-q31.2, 9.1 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242962	7q31.1-q31.3, 16 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242963	7q31.1-q31.3, 11 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242964	7q31.1-q31.3, 15 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242965	NC_000007.12:g.112946520_114520576del	FOXP2	Pathogenic	no assertion criteria provided
242966	7q31.2-q32, 13 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242967	7q31.2-q32, 14 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242968	7q31.2-q32, 15 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242969	7q31.2-q32, 26 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242970	7q22-q31.3 deletion (15 Mb)	FOXP2	Pathogenic	no assertion criteria provided
242971	7q22-q31.33, 22 Mb deletion	FOXP2	Pathogenic	no assertion criteria provided
242973	Uniparental disomy of chromosome 7	FOXP2	Pathogenic	no assertion criteria provided
3764648	NM_014491.4(FOXP2):c.1126C>T (p.Arg376Ter)	FOXP2	Pathogenic	criteria provided, multiple submitters, no conflicts
4819020	NM_014491.4(FOXP2):c.307C>T (p.Gln103Ter)	FOXP2	Pathogenic	criteria provided, single submitter
5067	NM_014491.4(FOXP2):c.1658G>A (p.Arg553His)	FOXP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5068	NM_014491.4(FOXP2):c.982C>T (p.Arg328Ter)	FOXP2	Pathogenic	criteria provided, multiple submitters, no conflicts
617625	NM_014491.4(FOXP2):c.1426C>T (p.Arg476Ter)	FOXP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
FOXP2	Strong	Autosomal dominant	childhood apraxia of speech	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXP2	Orphanet:209908	Isolated childhood apraxia of speech
FOXP2	Orphanet:251061	7q31 microdeletion syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXP2	HGNC:13875	ENSG00000128573	O15409	Forkhead box protein P2	gencc,clinvar
IMMP2L	HGNC:14598	ENSG00000184903	Q96T52	Mitochondrial inner membrane protease subunit 2	clinvar
CDH18	HGNC:1757	ENSG00000145526	Q13634	Cadherin-18	clinvar
ADAM22	HGNC:201	ENSG00000008277	Q9P0K1	Disintegrin and metalloproteinase domain-containing protein 22	clinvar
ZGRF1	HGNC:25654	ENSG00000138658	Q86YA3	5’-3’ DNA helicase ZGRF1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXP2	Forkhead box protein P2	Transcriptional repressor that may play a role in the specification and differentiation of lung epithelium.
IMMP2L	Mitochondrial inner membrane protease subunit 2	Catalyzes the removal of transit peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space.
CDH18	Cadherin-18	Cadherins are calcium-dependent cell adhesion proteins.
ADAM22	Disintegrin and metalloproteinase domain-containing protein 22	Probable ligand for integrin in the brain.
ZGRF1	5’-3’ DNA helicase ZGRF1	5’-3’ DNA helicase which is recruited to sites of DNA damage and promotes repair of replication-blocking DNA lesions through stimulation of homologous recombination (HR).

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.4

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
Protease	2	14.7×	0.021
Transcription factor	2	3.3×	0.171
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXP2	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, FOXP-CC
IMMP2L	Protease	yes		Pept_S26A_signal_pept_1, Peptidase_S26, Pept_S26A_signal_pept_1_CS
CDH18	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
ADAM22	Protease	yes		EGF, Peptidase_M12B, Disintegrin_dom
ZGRF1	Transcription factor	no		Znf_GRF, ZGRF1-like_N, P-loop_NTPase

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibialis anterior	2
middle temporal gyrus	2
buccal mucosa cell	1
mucosa of paranasal sinus	1
calcaneal tendon	1
deltoid	1
cerebellar vermis	1
paraflocculus	1
lateral nuclear group of thalamus	1
pons	1
ganglionic eminence	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXP2	237	broad	marker	buccal mucosa cell, tibialis anterior, mucosa of paranasal sinus
IMMP2L	223	ubiquitous	marker	tibialis anterior, deltoid, calcaneal tendon
CDH18	170	broad	marker	middle temporal gyrus, cerebellar vermis, paraflocculus
ADAM22	221	ubiquitous	yes	lateral nuclear group of thalamus, middle temporal gyrus, pons
ZGRF1	224	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOXP2	2,557
IMMP2L	1,975
ZGRF1	1,640
ADAM22	1,137
CDH18	889

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADAM22	Q9P0K1	10
FOXP2	O15409	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IMMP2L	Q96T52	87.66
CDH18	Q13634	77.57
ZGRF1	Q86YA3	50.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Positive Regulation of CDH1 Gene Transcription	1	317.2×	0.013	FOXP2
LGI-ADAM interactions	1	271.9×	0.013	ADAM22
Adherens junctions interactions	1	82.8×	0.021	CDH18
Cell-cell junction organization	1	82.8×	0.021	CDH18
Cell junction organization	1	62.4×	0.022	CDH18
Cell-Cell communication	1	45.9×	0.025	CDH18
Developmental Biology	1	4.8×	0.194	ADAM22

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
caudate nucleus development	1	3370.4×	0.004	FOXP2
putamen development	1	3370.4×	0.004	FOXP2
cerebellum vasculature development	1	3370.4×	0.004	IMMP2L
ovulation	1	842.6×	0.010	IMMP2L
recombinational repair	1	674.1×	0.010	ZGRF1
epithelial cell proliferation involved in lung morphogenesis	1	674.1×	0.010	FOXP2
mitochondrial respiratory chain complex assembly	1	561.7×	0.010	IMMP2L
positive regulation of epithelial cell proliferation involved in lung morphogenesis	1	481.5×	0.010	FOXP2
obsolete protein processing involved in protein targeting to mitochondrion	1	421.3×	0.010	IMMP2L
vocal learning	1	421.3×	0.010	FOXP2
righting reflex	1	374.5×	0.011	FOXP2
obsolete signal peptide processing	1	280.9×	0.013	IMMP2L
positive regulation of synaptic transmission	1	224.7×	0.014	ADAM22
cerebellar Purkinje cell differentiation	1	210.7×	0.014	FOXP2
smooth muscle tissue development	1	210.7×	0.014	FOXP2
superoxide metabolic process	1	198.3×	0.014	IMMP2L
vocalization behavior	1	177.4×	0.014	FOXP2
respiratory electron transport chain	1	168.5×	0.014	IMMP2L
positive regulation of mesenchymal cell proliferation	1	120.4×	0.019	FOXP2
blood circulation	1	102.1×	0.020	IMMP2L
adherens junction organization	1	102.1×	0.020	CDH18
calcium-dependent cell-cell adhesion	1	96.3×	0.021	CDH18
cell-cell junction assembly	1	88.7×	0.021	CDH18
cell-cell adhesion mediated by cadherin	1	82.2×	0.022	CDH18
ovarian follicle development	1	78.4×	0.022	IMMP2L
negative regulation of cell adhesion	1	76.6×	0.022	ADAM22
camera-type eye development	1	71.7×	0.022	FOXP2
lung alveolus development	1	70.2×	0.022	FOXP2
skeletal muscle tissue development	1	58.1×	0.026	FOXP2
post-embryonic development	1	41.1×	0.034	FOXP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 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
FOXP2	0	0
IMMP2L	0	0
CDH18	0	0
ADAM22	0	0
ZGRF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	1	ADAM22
D	Druggable family + AlphaFold only, no drug	1	IMMP2L
E	Difficult family or no structure, no drug	3	FOXP2, CDH18, ZGRF1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXP2	0	—
IMMP2L	0	—
CDH18	0	—
ADAM22	0	—
ZGRF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 16.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	13
PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07216001	PHASE2	NOT_YET_RECRUITING	Role of Omega-DEK in Childhood Apraxia of Speech
NCT05185583	PHASE2	COMPLETED	Methylphenidate in Childhood Apraxia of Speech
NCT03903120	PHASE1	COMPLETED	ASSIST: Treatment for Childhood Apraxia of Speech
NCT04642053	Not specified	RECRUITING	A Randomized Control Trial of Motor-based Intervention for CAS
NCT05066178	Not specified	RECRUITING	Speech Treatment for Minimally Verbal Children With ASD and CAS
NCT05675306	Not specified	ACTIVE_NOT_RECRUITING	Dose Frequency RCT on DTTC in Children With CAS
NCT05916222	Not specified	RECRUITING	The Effects of Caregiver Training on DTTC Treatment Outcomes in CAS
NCT07087249	Not specified	NOT_YET_RECRUITING	Efficacy of Ultrasound Biofeedback in Brazilian Childhood Apraxia of Speech
NCT07526246	Not specified	NOT_YET_RECRUITING	Motor-based Intervention for Childhood Apraxia of Speech: DTTC-Connect
NCT01097161	Not specified	COMPLETED	Stuttering and Apraxia of Speech: the Efficacy of an Intervention Program
NCT02022410	Not specified	COMPLETED	CAS and Length of Hospital Stay After TKA
NCT03238677	Not specified	COMPLETED	Treating Childhood Apraxia of Speech
NCT03700151	Not specified	UNKNOWN	Efficacy of an Intervention for the Children With Severe Speech Sounds Disorders
NCT04825145	Not specified	COMPLETED	Preeclampsia and Contact Activation
NCT04832503	Not specified	COMPLETED	Childhood Apraxia of Speech: Experience Dependent Changes Induced by Treatment
NCT06385470	Not specified	UNKNOWN	Treatment of Cantonese Speakers With Childhood Apraxia of Speech

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEVOCARNITINE	4	1
METHYLPHENIDATE HYDROCHLORIDE	4	1