Hypotonia, infantile, with psychomotor retardation and characteristic facies 1

Summary

Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 (MONDO:0024567) is a disease caused by NALCN (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: NALCN (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 89

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypotonia, infantile, with psychomotor retardation and characteristic facies 1
Mondo ID	MONDO:0024567
OMIM	615419
Orphanet	700336
UMLS	C3809454
MedGen	815784
GARD	0018457
Is cancer (heuristic)	no

Also known as: hypotonia, infantile, with psychomotor retardation and characteristic facies 1 · hypotonia, infantile, with psychomotor retardation and characteristic facies caused by mutation in NALCN · IHPRF1 · NALCN hypotonia, infantile, with psychomotor retardation and characteristic facies

Data availability: 89 ClinVar variants · 2 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 1

Related subtypes (2): hypotonia, infantile, with psychomotor retardation and characteristic facies 2, hypotonia, infantile, with psychomotor retardation and characteristic facies 3

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

89 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 27 pathogenic, 12 likely pathogenic, 6 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1323324	NM_052867.4(NALCN):c.1894C>T (p.Arg632Ter)	NALCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687235	NM_052867.4(NALCN):c.454C>T (p.Arg152Ter)	NALCN	Pathogenic	criteria provided, multiple submitters, no conflicts
1705481	NM_052867.4(NALCN):c.4447-2del	NALCN	Pathogenic	criteria provided, single submitter
2443941	NM_052867.4(NALCN):c.2022_2023del (p.Cys675fs)	NALCN	Pathogenic	no assertion criteria provided
3775266	NM_052867.4(NALCN):c.1269_1272dup (p.Phe425fs)	NALCN	Pathogenic	criteria provided, single submitter
3775336	NM_052867.4(NALCN):c.320G>A (p.Trp107Ter)	NALCN	Pathogenic	criteria provided, single submitter
3775602	NM_052867.4(NALCN):c.4796_4799del (p.Glu1599fs)	NALCN	Pathogenic	criteria provided, single submitter
4293634	NM_052867.4(NALCN):c.218dup (p.Leu74fs)	NALCN	Pathogenic	criteria provided, single submitter
489164	NM_052867.4(NALCN):c.2563C>T (p.Arg855Ter)	NALCN	Pathogenic	criteria provided, multiple submitters, no conflicts
522142	NM_052867.4(NALCN):c.4755+1G>T	NALCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522637	NM_052867.4(NALCN):c.3269G>A (p.Trp1090Ter)	NALCN	Pathogenic	criteria provided, single submitter
522758	NM_052867.4(NALCN):c.4236C>A (p.Tyr1412Ter)	NALCN	Pathogenic	criteria provided, single submitter
546191	NM_052867.4(NALCN):c.3490-2A>G	NALCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65422	NM_052867.4(NALCN):c.1924C>T (p.Gln642Ter)	NALCN	Pathogenic	no assertion criteria provided
684699	NM_052867.4(NALCN):c.3022C>T (p.Arg1008Ter)	NALCN	Pathogenic	criteria provided, multiple submitters, no conflicts
684700	NM_052867.4(NALCN):c.2629del (p.Gln877fs)	NALCN	Pathogenic	no assertion criteria provided
684701	NM_052867.4(NALCN):c.3056dup (p.Leu1019fs)	NALCN	Pathogenic	criteria provided, multiple submitters, no conflicts
684702	NM_052867.4(NALCN):c.4281C>A (p.Phe1427Leu)	NALCN	Pathogenic	no assertion criteria provided
684703	NM_052867.4(NALCN):c.4103+2T>C	NALCN	Pathogenic	no assertion criteria provided
684704	NM_052867.4(NALCN):c.3556C>T (p.Gln1186Ter)	NALCN	Pathogenic	no assertion criteria provided
684705	NM_052867.4(NALCN):c.2435dup (p.Glu813fs)	NALCN	Pathogenic	no assertion criteria provided
684706	NM_052867.4(NALCN):c.4333A>T (p.Ile1445Leu)	NALCN	Pathogenic	no assertion criteria provided
684707	NM_052867.4(NALCN):c.2889+3_2889+6del	NALCN	Pathogenic	no assertion criteria provided
684708	NM_052867.4(NALCN):c.4150C>T (p.Arg1384Ter)	NALCN	Pathogenic	criteria provided, multiple submitters, no conflicts
684709	NM_052867.4(NALCN):c.321G>A (p.Trp107Ter)	NALCN	Pathogenic	no assertion criteria provided
684710	NM_052867.4(NALCN):c.2758del (p.Ile920fs)	NALCN	Pathogenic	no assertion criteria provided
684711	NM_052867.4(NALCN):c.537del (p.Ile178_Trp179insTer)	NALCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88686	NM_052867.4(NALCN):c.1489del (p.Tyr497fs)	NALCN	Pathogenic	criteria provided, multiple submitters, no conflicts
88687	NM_052867.4(NALCN):c.3860G>T (p.Trp1287Leu)	NALCN	Pathogenic	no assertion criteria provided
915368	NM_052867.4(NALCN):c.1434+1G>A	NALCN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 15 · 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
NALCN	Definitive	Autosomal recessive	hypotonia, infantile, with psychomotor retardation and characteristic facies 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NALCN	Orphanet:1146	Distal arthrogryposis type 1
NALCN	Orphanet:1147	Sheldon-Hall syndrome
NALCN	Orphanet:2053	Freeman-Sheldon syndrome
NALCN	Orphanet:562528	Congenital limbs-face contractures-hypotonia-developmental delay syndrome
NALCN	Orphanet:700336	Hypotonia-speech impairment-severe cognitive delay syndrome due to NALCN deficiency
UNC80	Orphanet:700333	Hypotonia-speech impairment-severe cognitive delay syndrome due to UNC80 deficiency
TBCK	Orphanet:488632	TBCK-related encephalopathy-severe hypotonia-craniofacial dysmorphism syndrome
GLI2	Orphanet:220386	Semilobar holoprosencephaly
GLI2	Orphanet:280195	Septopreoptic holoprosencephaly
GLI2	Orphanet:280200	Microform holoprosencephaly
GLI2	Orphanet:420584	Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
GLI2	Orphanet:93924	Lobar holoprosencephaly
GLI2	Orphanet:93925	Alobar holoprosencephaly
GLI2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
GLI2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NALCN	HGNC:19082	ENSG00000102452	Q8IZF0	Sodium leak channel NALCN	gencc,clinvar
UNC80	HGNC:26582	ENSG00000144406	Q8N2C7	Protein unc-80 homolog	clinvar
TBCK	HGNC:28261	ENSG00000145348	Q8TEA7	TBC domain-containing protein kinase-like protein	clinvar
GLI2	HGNC:4318	ENSG00000074047	P10070	Zinc finger protein GLI2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NALCN	Sodium leak channel NALCN	Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability.
UNC80	Protein unc-80 homolog	Auxiliary subunit of the NALCN sodium channel complex, a voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability.
TBCK	TBC domain-containing protein kinase-like protein	Component of the FERRY complex (Five-subunit Endosomal Rab5 and RNA/ribosome intermediary).
GLI2	Zinc finger protein GLI2	Functions as a transcription regulator in the hedgehog (Hh) pathway.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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
Ion channel	1	27.9×	0.142
Kinase	1	6.9×	0.273
Transcription factor	1	2.1×	0.538
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NALCN	Ion channel	yes		Ion_trans_dom, Volt_channel_dom_sf, NALCN
UNC80	Other/Unknown	no		UNC80_N, UNC80_central, UNC80_C
TBCK	Kinase	yes		Rab-GAP-TBC_dom, Prot_kinase_dom, Rhodanese-like_dom
GLI2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	2
middle temporal gyrus	2
corpus callosum	1
cerebellar vermis	1
adrenal tissue	1
calcaneal tendon	1
kidney epithelium	1
germinal epithelium of ovary	1
tibia	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NALCN	201	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, corpus callosum
UNC80	166	broad	marker	cerebellar vermis, Brodmann (1909) area 23, middle temporal gyrus
TBCK	258	ubiquitous	marker	calcaneal tendon, kidney epithelium, adrenal tissue
GLI2	211	ubiquitous	marker	tibia, germinal epithelium of ovary, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLI2	3,112
NALCN	1,860
UNC80	1,665
TBCK	915

Intra-cohort edges

A	B	Sources
NALCN	UNC80	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NALCN	Q8IZF0	5
UNC80	Q8N2C7	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBCK	Q8TEA7	87.42
GLI2	P10070	42.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 4 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
Stimuli-sensing channels	2	90.6×	0.001	NALCN, UNC80
RUNX2 regulates chondrocyte maturation	1	761.3×	0.005	GLI2
GLI proteins bind promoters of Hh responsive genes to promote transcription	1	543.8×	0.005	GLI2
Degradation of GLI2 by the proteasome	1	74.6×	0.025	GLI2
Hedgehog ‘off’ state	1	59.5×	0.025	GLI2
Hedgehog ‘on’ state	1	52.9×	0.025	GLI2
Ion channel transport	1	32.0×	0.035	NALCN
Transport of small molecules	1	8.4×	0.115	NALCN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
monoatomic cation homeostasis	1	2106.5×	0.007	UNC80
ventral midline development	1	1404.3×	0.007	GLI2
floor plate formation	1	1404.3×	0.007	GLI2
spinal cord ventral commissure morphogenesis	1	1404.3×	0.007	GLI2
hindgut morphogenesis	1	1053.2×	0.007	GLI2
tube development	1	1053.2×	0.007	GLI2
positive regulation of synaptic transmission, cholinergic	1	842.6×	0.008	NALCN
cerebellar cortex morphogenesis	1	702.2×	0.008	GLI2
spinal cord dorsal/ventral patterning	1	526.6×	0.010	GLI2
ventral spinal cord development	1	468.1×	0.010	GLI2
epidermal cell differentiation	1	421.3×	0.010	GLI2
positive regulation of T cell differentiation in thymus	1	383.0×	0.010	GLI2
regulation of resting membrane potential	1	324.1×	0.011	NALCN
hindbrain development	1	280.9×	0.011	GLI2
osteoblast development	1	247.8×	0.011	GLI2
positive regulation of synaptic transmission, GABAergic	1	247.8×	0.011	NALCN
embryonic digestive tract development	1	247.8×	0.011	GLI2
regulation of TOR signaling	1	234.1×	0.011	TBCK
developmental growth	1	183.2×	0.013	GLI2
branching morphogenesis of an epithelial tube	1	183.2×	0.013	GLI2
proximal/distal pattern formation	1	162.0×	0.013	GLI2
pituitary gland development	1	162.0×	0.013	GLI2
mammary gland development	1	162.0×	0.013	GLI2
positive regulation of DNA replication	1	145.3×	0.013	GLI2
hair follicle morphogenesis	1	123.9×	0.015	GLI2
pattern specification process	1	117.0×	0.015	GLI2
odontogenesis of dentin-containing tooth	1	75.2×	0.023	GLI2
neuron development	1	63.8×	0.026	GLI2
calcium ion transmembrane transport	1	52.7×	0.029	NALCN
monoatomic ion transmembrane transport	1	52.0×	0.029	NALCN

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NALCN	0	0
UNC80	0	0
TBCK	0	0
GLI2	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
GLI2	6	Binding:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	NALCN
D	Druggable family + AlphaFold only, no drug	1	TBCK
E	Difficult family or no structure, no drug	2	UNC80, GLI2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NALCN	0	—
UNC80	0	—
TBCK	0	—
GLI2	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.