Hypotonia, infantile, with psychomotor retardation and characteristic facies 2

Summary

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (MONDO:0014777) is a disease caused by UNC80 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: UNC80 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 181

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 2
Mondo ID	MONDO:0014777
OMIM	616801
Orphanet	700333
UMLS	C4225203
MedGen	907651
GARD	0018458
Is cancer (heuristic)	no

Also known as: hypotonia, infantile, with psychomotor retardation and characteristic facies 2 · hypotonia, infantile, with psychomotor retardation and characteristic facies 2; IHPRF2 · hypotonia, infantile, with psychomotor retardation and characteristic facies caused by mutation in UNC80 · hypotonia, infantile, with psychomotor retardation and characteristic facies type 2 · IHPRF2 · UNC80 hypotonia, infantile, with psychomotor retardation and characteristic facies

Data availability: 181 ClinVar variants · 4 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 2

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

181 retrieved; paginated sample, class counts are floors:

84 uncertain significance, 24 pathogenic, 19 conflicting classifications of pathogenicity, 16 benign/likely benign, 16 likely pathogenic, 9 pathogenic/likely pathogenic, 8 benign, 4 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
219188	NM_001371986.1(UNC80):c.3787C>T (p.Arg1263Ter)	LOC121725110	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
684714	NM_001371986.1(UNC80):c.1681_1682del (p.Thr561fs)	LOC122861286	Pathogenic	no assertion criteria provided
1028448	NM_001371986.1(UNC80):c.1696C>T (p.Arg566Ter)	UNC80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028452	NM_001371986.1(UNC80):c.3042-1G>T	UNC80	Pathogenic	criteria provided, single submitter
1323741	NM_001371986.1(UNC80):c.2914C>T (p.Gln972Ter)	UNC80	Pathogenic	criteria provided, single submitter
1323742	NM_001371986.1(UNC80):c.2331+1G>T	UNC80	Pathogenic	criteria provided, single submitter
1373605	NM_001371986.1(UNC80):c.286C>T (p.Arg96Ter)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
1456340	NM_001371986.1(UNC80):c.7645C>T (p.Arg2549Ter)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
1457621	NM_001371986.1(UNC80):c.4063C>T (p.Arg1355Ter)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
1521559	NM_001371986.1(UNC80):c.4110+1G>C	UNC80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699471	NM_001371986.1(UNC80):c.6976C>T (p.Gln2326Ter)	UNC80	Pathogenic	criteria provided, single submitter
219189	NM_001371986.1(UNC80):c.1078C>T (p.Arg360Ter)	UNC80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
222017	NM_001371986.1(UNC80):c.151C>T (p.Arg51Ter)	UNC80	Pathogenic	criteria provided, single submitter
2788446	NM_001371986.1(UNC80):c.3328C>T (p.Arg1110Ter)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
2791845	NM_001371986.1(UNC80):c.6475C>T (p.Arg2159Ter)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
2883996	NM_001371986.1(UNC80):c.3226C>T (p.Arg1076Ter)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
2920703	NM_001371986.1(UNC80):c.6337C>T (p.Arg2113Ter)	UNC80	Pathogenic	criteria provided, single submitter
422552	NM_001371986.1(UNC80):c.6373C>T (p.Arg2125Ter)	UNC80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292419	NM_001371986.1(UNC80):c.7056del (p.Ala2353fs)	UNC80	Pathogenic	criteria provided, single submitter
431143	NM_001371986.1(UNC80):c.2399del (p.Leu800fs)	UNC80	Pathogenic	criteria provided, single submitter
431144	NM_001371986.1(UNC80):c.4144G>T (p.Glu1382Ter)	UNC80	Pathogenic	criteria provided, single submitter
488633	NM_001371986.1(UNC80):c.8771_8772del (p.Lys2924fs)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
505011	NM_001371986.1(UNC80):c.1513C>T (p.Arg505Ter)	UNC80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
684712	NM_001371986.1(UNC80):c.8314C>T (p.Arg2772Ter)	UNC80	Pathogenic	criteria provided, single submitter
684713	NM_001371986.1(UNC80):c.520C>T (p.Arg174Ter)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
684715	NM_001371986.1(UNC80):c.5869C>T (p.Arg1957Ter)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
801862	NM_001371986.1(UNC80):c.3358-1G>C	UNC80	Pathogenic	criteria provided, single submitter
801863	NM_001371986.1(UNC80):c.3853C>T (p.Arg1285Ter)	UNC80	Pathogenic	criteria provided, multiple submitters, no conflicts
829816	NM_001371986.1(UNC80):c.1357del (p.Arg453fs)	UNC80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
829817	NM_001371986.1(UNC80):c.7700_7701del (p.Thr2567fs)	UNC80	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
UNC80	Definitive	Autosomal recessive	hypotonia, infantile, with psychomotor retardation and characteristic facies 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UNC80	Orphanet:700333	Hypotonia-speech impairment-severe cognitive delay syndrome due to UNC80 deficiency

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
UNC80	HGNC:26582	ENSG00000144406	Q8N2C7	Protein unc-80 homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

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)
UNC80	Other/Unknown	no		UNC80_N, UNC80_central, UNC80_C

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
Brodmann (1909) area 23	1
cerebellar vermis	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UNC80	166	broad	marker	cerebellar vermis, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UNC80	1,665

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UNC80	Q8N2C7	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Stimuli-sensing channels	1	135.9×	0.007	UNC80

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
monoatomic cation homeostasis	1	8426.0×	1e-04	UNC80

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
UNC80	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	UNC80

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)
UNC80	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.