Hypotonia, infantile, with psychomotor retardation and characteristic facies 3

Summary

Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 (MONDO:0014823) is a disease caused by TBCK (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TBCK (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 116
• Phenotypes (HPO): 73

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

73 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001319	Neonatal hypotonia	Very frequent (80-99%)
HP:0003323	Progressive muscle weakness	Very frequent (80-99%)
HP:0003444	EMG: chronic denervation signs	Very frequent (80-99%)
HP:0006829	Severe muscular hypotonia	Very frequent (80-99%)
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0002093	Respiratory insufficiency	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002283	Global brain atrophy	Frequent (30-79%)
HP:0002518	Abnormal periventricular white matter morphology	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0003119	Abnormal circulating lipid concentration	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0031165	Multifocal seizures	Frequent (30-79%)
HP:0000158	Macroglossia	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000286	Epicanthus	Occasional (5-29%)
HP:0000337	Broad forehead	Occasional (5-29%)
HP:0000340	Sloping forehead	Occasional (5-29%)
HP:0000414	Bulbous nose	Occasional (5-29%)
HP:0000574	Thick eyebrow	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0001007	Hirsutism	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0002045	Hypothermia	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002705	High, narrow palate	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0009826	Limb undergrowth	Occasional (5-29%)
HP:0010804	Tented upper lip vermilion	Occasional (5-29%)
HP:0011198	EEG with generalized epileptiform discharges	Occasional (5-29%)
HP:0100288	EMG: myokymic discharges	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0000011	Neurogenic bladder	Very rare (<1-4%)
HP:0000028	Cryptorchidism	Very rare (<1-4%)
HP:0000252	Microcephaly	Very rare (<1-4%)
HP:0000303	Mandibular prognathia	Very rare (<1-4%)
HP:0000343	Long philtrum	Very rare (<1-4%)
HP:0000407	Sensorineural hearing impairment	Very rare (<1-4%)
HP:0000431	Wide nasal bridge	Very rare (<1-4%)
HP:0000470	Short neck	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypotonia, infantile, with psychomotor retardation and characteristic facies 3
Mondo ID	MONDO:0014823
OMIM	616900
Orphanet	488632
DOID	DOID:0060935
UMLS	C5567480
MedGen	1798903
GARD	0017896
Is cancer (heuristic)	no

Also known as: hypotonia, infantile, with psychomotor retardation and characteristic facies 3 · IHPRF3 · TBCK ID-syndrome · TBCK syndrome · TBCK-related encephalopathy

Data availability: 116 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › hypotonia, infantile, with psychomotor retardation and characteristic facies › hypotonia, infantile, with psychomotor retardation and characteristic facies 3

Related subtypes (2): hypotonia, infantile, with psychomotor retardation and characteristic facies 2, hypotonia, infantile, with psychomotor retardation and characteristic facies 1

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

116 retrieved; paginated sample, class counts are floors:

33 pathogenic, 24 uncertain significance, 22 likely pathogenic, 21 pathogenic/likely pathogenic, 13 conflicting classifications of pathogenicity, 2 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033752	NM_001163435.3(TBCK):c.381+1G>A	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1033753	NM_001163435.3(TBCK):c.531dup (p.Pro178fs)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1175036	NM_001163435.3(TBCK):c.1635G>A (p.Trp545Ter)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1180828	NM_001163435.3(TBCK):c.247C>T (p.Arg83Ter)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1185558	NM_001163435.3(TBCK):c.737_738del (p.Val246fs)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1305149	NM_001163435.3(TBCK):c.2252del (p.Pro751fs)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325175	NM_001163435.3(TBCK):c.1290del (p.Arg431fs)	TBCK	Pathogenic	criteria provided, multiple submitters, no conflicts
1327511	NM_001163435.3(TBCK):c.2060_2235del (p.Glu687fs)	TBCK	Pathogenic	no assertion criteria provided
1327512	NM_001163435.3(TBCK):c.2130C>G (p.Tyr710Ter)	TBCK	Pathogenic	criteria provided, single submitter
1375645	NM_001163435.3(TBCK):c.196C>T (p.Arg66Ter)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460053	NM_001163435.3(TBCK):c.2479G>T (p.Glu827Ter)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1488790	NM_001163435.3(TBCK):c.382-2A>G	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1678860	NM_001163435.3(TBCK):c.1108C>T (p.Arg370Ter)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1696868	NM_001163435.3(TBCK):c.2154del (p.Lys718fs)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183338	NM_001163435.3(TBCK):c.1897+1G>A	TBCK	Pathogenic	criteria provided, multiple submitters, no conflicts
1912543	NM_001163435.3(TBCK):c.186_189dup (p.His64fs)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2008265	NM_001163435.3(TBCK):c.663T>A (p.Cys221Ter)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2059019	NM_001163435.3(TBCK):c.538_568del (p.Pro180fs)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2104638	NM_001163435.3(TBCK):c.2025del (p.Phe675fs)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2125261	NM_001163435.3(TBCK):c.1058del (p.Cys353fs)	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2128154	NM_001163435.3(TBCK):c.1938del (p.Leu647fs)	TBCK	Pathogenic	criteria provided, multiple submitters, no conflicts
225235	NM_001163435.3(TBCK):c.376C>T (p.Arg126Ter)	TBCK	Pathogenic	criteria provided, multiple submitters, no conflicts
225236	NM_001163435.3(TBCK):c.1363A>T (p.Lys455Ter)	TBCK	Pathogenic	criteria provided, multiple submitters, no conflicts
225238	NM_001163435.3(TBCK):c.831_832insTA (p.Pro278fs)	TBCK	Pathogenic	criteria provided, single submitter
225239	NM_001163435.3(TBCK):c.2060-2A>G	TBCK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225240	NM_001163435.3(TBCK):c.803_806del (p.Met268fs)	TBCK	Pathogenic	criteria provided, multiple submitters, no conflicts
225241	NM_001163435.3(TBCK):c.1370del (p.Asn457fs)	TBCK	Pathogenic	criteria provided, multiple submitters, no conflicts
2579177	GRCh38/hg38 4q24(chr4:106170998-106171368)x0	TBCK	Pathogenic	criteria provided, single submitter
3233781	NC_000004.11:g.(107169464_107170077)_(107183370_107216250)del	TBCK	Pathogenic	criteria provided, single submitter
3362618	NM_001163435.3(TBCK):c.305delinsCATTTGAGGTTCTTC (p.Gln102fs)	TBCK	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
TBCK	Definitive	Autosomal recessive	hypotonia, infantile, with psychomotor retardation and characteristic facies 3	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBCK	Orphanet:488632	TBCK-related encephalopathy-severe hypotonia-craniofacial dysmorphism 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
TBCK	HGNC:28261	ENSG00000145348	Q8TEA7	TBC domain-containing protein kinase-like protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBCK	TBC domain-containing protein kinase-like protein	Component of the FERRY complex (Five-subunit Endosomal Rab5 and RNA/ribosome intermediary).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBCK	Kinase	yes		Rab-GAP-TBC_dom, Prot_kinase_dom, Rhodanese-like_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
adrenal tissue	1
calcaneal tendon	1
kidney epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBCK	258	ubiquitous	marker	calcaneal tendon, kidney epithelium, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBCK	915

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBCK	Q8TEA7	87.42

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 TOR signaling	1	936.2×	0.003	TBCK
cell population proliferation	1	102.8×	0.013	TBCK
actin cytoskeleton organization	1	79.1×	0.013	TBCK

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
TBCK	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	1	TBCK
E	Difficult family or no structure, no drug	0

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)
TBCK	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.