Neurodevelopmental disorder with hypotonia, neuropathy, and deafness
diseaseOn this page
Also known as NEDHND
Summary
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MONDO:0060496) is a disease caused by SPTBN4 (GenCC Definitive), with 2 cohort genes.
At a glance
- Causal gene: SPTBN4 (GenCC Definitive)
- Cohort genes: 2
- ClinVar variants: 66
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | neurodevelopmental disorder with hypotonia, neuropathy, and deafness |
| Mondo ID | MONDO:0060496 |
| OMIM | 617519 |
| UMLS | C4479603 |
| MedGen | 1382171 |
| GARD | 0027987 |
| Is cancer (heuristic) | no |
Also known as: NEDHND · neurodevelopmental disorder with hypotonia, neuropathy, and deafness
Data availability: 66 ClinVar variants · 5 GenCC gene-disease records.
Disease family
Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › neurodevelopmental disorder with hypotonia, neuropathy, and deafness
Related subtypes (275): microcephaly and chorioretinopathy, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, autosomal dominant primary microcephaly, Prader-Willi syndrome, Smith-Magenis syndrome, microcephalic osteodysplastic primordial dwarfism type I, microcephalic osteodysplastic primordial dwarfism type II, microcephalic osteodysplastic primordial dwarfism, type 3, CK syndrome, orofaciodigital syndrome I, Rett syndrome, Wieacker-Wolff syndrome, Amish lethal microcephaly, cerebral palsy, spastic quadriplegic, 2, Pitt-Hopkins-like syndrome 2, developmental delay with autism spectrum disorder and gait instability, complex cortical dysplasia with other brain malformations 5, AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome, intellectual disability, autosomal dominant 29, Au-Kline syndrome, cerebellar atrophy, visual impairment, and psychomotor retardation;, neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, cerebral palsy, spastic quadriplegic, 3, Okur-Chung neurodevelopmental syndrome, Harel-Yoon syndrome, neurodevelopmental disorder with hypotonia, seizures, and absent language, alternating hemiplegia of childhood, autosomal recessive primary microcephaly, Rubinstein-Taybi syndrome, neurodevelopmental disorder with cerebellar atrophy and with or without seizures, neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities, neurodevelopmental disorder with hypotonia, microcephaly, and seizures, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, neurodevelopmental disorder with language impairment and behavioral abnormalities, neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities, neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, neurodevelopmental disorder with or without early-onset generalized epilepsy, neurodevelopmental disorder with or without autism or seizures, neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism, neurodevelopmental disorder with dysmorphic facies and variable seizures, squalene synthase deficiency, intellectual developmental disorder and retinitis pigmentosa; IDDRP, neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, Houge-Janssens syndrome 3, neurodevelopmental disorder with central and peripheral motor dysfunction, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, neurodevelopmental disorder with impaired speech and hyperkinetic movements, developmental delay with variable intellectual impairment and behavioral abnormalities, neurodevelopmental disorder with or without variable brain abnormalities; NEDBA, neurodevelopmental disorder with seizures and speech and walking impairment, neurodevelopmental disorder with microcephaly and structural brain anomalies, neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, neurodevelopmental disorder with visual defects and brain anomalies, neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, neurodevelopmental disorder with cerebellar hypoplasia and spasticity, neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies, neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies, neurodevelopmental disorder with absent language and variable seizures, neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia, neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, Poirier-Bienvenu neurodevelopmental syndrome, neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements, neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation, neurodevelopmental disorder with microcephaly and dysmorphic facies, neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies, neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, neurodevelopmental disorder with speech impairment and dysmorphic facies, neurodevelopmental disorder with alopecia and brain abnormalities, neurodevelopmental disorder with seizures and brain atrophy, neurodevelopmental disorder with microcephaly, seizures, and brain atrophy, Delpire-McNeill syndrome, neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, developmental delay and seizures with or without movement abnormalities, Stankiewicz-Isidor syndrome, neurodevelopmental disorder with midbrain and hindbrain malformations, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies, neurodevelopmental disorder with involuntary movements, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities, neurodevelopmental disorder with microcephaly, ataxia, and seizures, neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, neurodevelopmental disorder with severe motor impairment and absent language, neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, neurodevelopmental disorder with or without seizures and gait abnormalities, neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features, neurodevelopmental disorder with poor language and loss of hand skills, neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, neurodevelopmental disorder with spasticity and poor growth, neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, FOXG1 disorder, genetic developmental and epileptic encephalopathy, X-linked complex neurodevelopmental disorder, PPP2R1A-related intellectual disability, intellectual disability, autosomal dominant, CACNA1A-related complex neurodevelopmental disorder, X-linked intellectual disability, PAX5-related B lymphopenia and autism spectrum disorder, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, KCNH1 associated disorder, AFG2B-related complex neurodevelopmental disorder with motor features and hearing loss, intellectual disability, autosomal recessive, FAT4-related neurodevelopmental disorder, SOX11-related complex neurodevelopmental disorder with or without congenital anomalies, microcephaly with lissencephaly and/or hydranencephaly, MYH10-related neurodevelopmental disorder with congenital anomalies, CNOT9-related developmental disorder with seizures, HMGB1-related brachyphalangy, polydactyly and tibial aplasia syndrome, ATXN7L3-related developmental delay, hypotonia and facial dysmorphism, DIP2C-related developmental disorder with speech delay, EPB41L3-related developmental disorder with delayed myelination and seizures, GABRA4-related neurodevelopmental disorder with seizures, GABRD-related neurodevelopmental disorder with epilepsy, KCNK3-related developmental delay with sleep apnea, RFX3-related neurodevelopmental disorder with autism and other behavioural abnormalities, RFX4-related neurodevelopmental disorder with autism and other behavioural abnormalities, KDM2B-related neurodevelopmental disorder, TRA2B-related neurodevelopmental disorder, WDR5-related neurodevelopmental disorder, ARF3-related neurodevelopmental disorder, CBX1-related neurodevelopmental disorder, DDX17-related neurodevelopmental disorder, FEZF2-related neurodevelopmental disorder, HDAC3-related neurodevelopmental disorder, DEAF1-associated neurodevelopmental disorder, SYNCRIP-related neurodevelopmental disorder, HNRNPC-related neurodevelopmental disorder, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability, SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth, neurodevelopmental disorder with gait disturbance, dysmorphic facies, and behavioral abnormalities, X-linked, Alzahrani-Kuwahara syndrome, neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia, Hiatt-Neu-Cooper neurodevelopmental syndrome, neurodevelopmental disorder with seizures and gingival overgrowth, neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, neurodevelopmental disorder with infantile epileptic spasms, neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities, neurodevelopmental disorder with motor and speech delay and behavioral abnormalities, neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, neurodevelopmental disorder with hypotonia and dysmorphic facies, neurodevelopmental disorder with hypotonia and brain abnormalities, neurodevelopmental disorder with impaired language and ataxia and with or without seizures, neurodevelopmental disorder with hearing loss and spasticity, neurodevelopmental disorder with hypotonia and gross motor and speech delay, neurodevelopmental disorder with hyperkinetic movements and dyskinesia, neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, Marbach-Schaaf neurodevelopmental syndrome, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, Brunet-Wagner neurodevelopmental syndrome, Ferguson-Bonni neurodevelopmental syndrome, neurodevelopmental disorder with or without variable movement or behavioral abnormalities, neurodevelopmental disorder with central hypotonia and dysmorphic facies, neurodevelopmental disorder with neuromuscular and skeletal abnormalities, Chilton-Okur-Chung neurodevelopmental syndrome, neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, parenti-mignot neurodevelopmental syndrome, neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, Dentici-Novelli neurodevelopmental syndrome, neurodevelopmental disorder with poor growth and skeletal anomalies, neurodevelopmental disorder with language delay and seizures, neurodevelopmental disorder with dystonia and seizures, Dworschak-Punetha neurodevelopmental syndrome, neurodevelopmental disorder with epilepsy and brain atrophy, neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, neurodevelopmental disorder with speech delay and variable ocular anomalies, neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, neurodevelopmental disorder with spasticity, seizures, and brain abnormalities, neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, neurodevelopmental disorder with microcephaly, short stature, and speech delay, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties, neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-pelger-huet anomaly, neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, neurodevelopmental disorder with eye movement abnormalities and ataxia, neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, neurodevelopmental disorder with speech impairment and with or without seizures, neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities, neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, neurodevelopmental disorder with poor growth and behavioral abnormalities, neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, neurodevelopmental disorder with microcephaly and movement abnormalities, neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies, neurodevelopmental disorder with language delay and variable cognitive abnormalities, neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction, Hao-Fountain syndrome due to USP7 mutation, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, neurodevelopmental disorder with hyperkinetic movements, seizures, and structural brain abnormalities, neurodevelopmental disorder with hypotonia and characteristic brain abnormalities, neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, Jeffries-Lakhani neurodevelopmental syndrome, neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder, neurodevelopmental disorder plus optic atrophy, neurodevelopmental disorder with progressive movement abnormalities, aplasia cutis-enamel dysplasia syndrome, neurodevelopmental disorder with hypotonia and seizures, El Hayek-Chahrour neurodevelopmental disorder, neurodevelopmental disorder with hypotonia, feeding difficulties, facial dysmorphism, and brain abnormalities, neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language, otofacial neurodevelopmental syndrome, neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, Kariminejad neurodevelopmental syndrome, Karayol-Borroto-Haghshenas neurodevelopmental syndrome, neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, neurodevelopmental disorder with variable familial hypercholanemia, intellectual developmental disorder with polymicrogyria and seizures, neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia, neurodevelopmental disorder with progressive spasticity and brain abnormalities, neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, neurodevelopmental disorder with white matter abnormalities and gait disturbance, neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, neurodevelopmental disorder with poor or absent speech, dysmorphic facies, and behavioral abnormalities, neurodevelopmental disorder with ataxia and brain abnormalities, neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, Li-Takada-Miyake syndrome, neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, Nil-Deshwar neurodevelopmental syndrome, Popov-Chang syndrome, neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, Dursun-Ozgul neurodevelopmental syndrome, neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, neurodevelopmental disorder with speech delay and behavioral abnormalities, Harel-Tora neurodevelopmental syndrome, neurocardiorenal malformation syndrome, neurodevelopmental disorder with behavioral abnormalities and childhood-onset spastic paraplegia, neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities, neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, Ramond-Elliott neurodevelopmental syndrome, microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, neurodevelopmental disorder with hypotonia, epilepsy, and absent speech, neurodevelopmental disorder with speech delay, movement abnormalities, and seizures, neurodevelopmental disorder with spasticity, thin corpus callosum, and decreased brain white matter, neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities, neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, PIP5K1C-related neurodevelopmental disorder, KCND2-related neurodevelopmental disorder with or without seizures, PRPF19-related neurodevelopmental disorder, CTR9-related neurodevelopmental disorder, CAMK2D-related neurodevelopmental disorder and dilated cardiomyopathy, PPFIA3-related neurodevelopmental disorder, dyneinopathy, MYCBP2-related developmental delay with corpus callosum defects, GRIN-related complex neurodevelopmental disorder, RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity, TSEN2-related neurodevelopmental disorder with or without thrombotic microangiopathy
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
66 retrieved; paginated sample, class counts are floors:
25 uncertain significance, 15 likely pathogenic, 11 benign, 10 pathogenic, 5 conflicting classifications of pathogenicity
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 559548 | NM_020971.3(SPTBN4):c.7303C>T (p.Arg2435Cys) | LOC130064467 | Pathogenic | no assertion criteria provided |
| 1030745 | NM_020971.3(SPTBN4):c.3589C>T (p.Gln1197Ter) | SPTBN4 | Pathogenic | criteria provided, single submitter |
| 2572987 | NM_020971.3(SPTBN4):c.6016C>T (p.Arg2006Ter) | SPTBN4 | Pathogenic | criteria provided, single submitter |
| 3254916 | NM_020971.3(SPTBN4):c.5173C>T (p.Gln1725Ter) | SPTBN4 | Pathogenic | criteria provided, single submitter |
| 3390929 | NM_020971.3(SPTBN4):c.2265G>A (p.Trp755Ter) | SPTBN4 | Pathogenic | criteria provided, single submitter |
| 375254 | NM_020971.3(SPTBN4):c.1597C>T (p.Gln533Ter) | SPTBN4 | Pathogenic | no assertion criteria provided |
| 559545 | NM_020971.3(SPTBN4):c.3820G>T (p.Glu1274Ter) | SPTBN4 | Pathogenic | criteria provided, single submitter |
| 987745 | NM_020971.3(SPTBN4):c.3375_3393del (p.Asp1126fs) | SPTBN4 | Pathogenic | criteria provided, single submitter |
| 987746 | NM_020971.3(SPTBN4):c.1149dup (p.Asn384fs) | SPTBN4 | Pathogenic | criteria provided, single submitter |
| 988586 | NM_020971.3(SPTBN4):c.1249del (p.Leu417fs) | SPTBN4 | Pathogenic | criteria provided, single submitter |
| 1709124 | NM_020971.3(SPTBN4):c.7149del (p.Pro2384fs) | LOC130064467 | Likely pathogenic | criteria provided, single submitter |
| 1878626 | NM_020971.3(SPTBN4):c.1897del (p.Ala633fs) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 2441659 | NM_020971.3(SPTBN4):c.1906C>T (p.Arg636Ter) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 2503813 | NM_020971.3(SPTBN4):c.4960C>T (p.Gln1654Ter) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 3065352 | NM_020971.3(SPTBN4):c.2903+2T>C | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 3362455 | NM_020971.3(SPTBN4):c.1217T>C (p.Leu406Pro) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 3362729 | NM_020971.3(SPTBN4):c.2535_2554del (p.Gly846fs) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 3392510 | NM_020971.3(SPTBN4):c.2326_2341dup (p.Asp781delinsAlaProValArgArgTer) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 3775463 | NM_020971.3(SPTBN4):c.3948+1G>A | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 3776278 | NM_020971.3(SPTBN4):c.6826G>T (p.Glu2276Ter) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 4073460 | NM_020971.3(SPTBN4):c.1795del (p.Leu599fs) | SPTBN4 | Likely pathogenic | no assertion criteria provided |
| 4813047 | NM_020971.3(SPTBN4):c.1090C>T (p.Gln364Ter) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 559549 | NM_020971.3(SPTBN4):c.7453del (p.Ala2485fs) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 800778 | NM_020971.3(SPTBN4):c.4584+1G>T | SPTBN4 | Likely pathogenic | no assertion criteria provided |
| 987747 | NM_020971.3(SPTBN4):c.737G>C (p.Arg246Pro) | SPTBN4 | Likely pathogenic | criteria provided, single submitter |
| 1325615 | NM_020971.3(SPTBN4):c.6113A>G (p.Asp2038Gly) | SPTBN4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1806026 | NM_020971.3(SPTBN4):c.4862T>A (p.Phe1621Tyr) | SPTBN4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 2222677 | NM_020971.3(SPTBN4):c.5099G>A (p.Arg1700Gln) | SPTBN4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 2377072 | NM_020971.3(SPTBN4):c.2875C>T (p.Arg959Cys) | SPTBN4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 2407221 | NM_020971.3(SPTBN4):c.1156C>T (p.Arg386Cys) | SPTBN4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 5 · Orphanet: 5 · 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 |
|---|---|---|---|---|
| SPTBN4 | Definitive | Autosomal recessive | neurodevelopmental disorder with hypotonia, neuropathy, and deafness | 5 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| ITGB4 | Orphanet:1114 | Aplasia cutis congenita |
| ITGB4 | Orphanet:158684 | Epidermolysis bullosa simplex with pyloric atresia |
| ITGB4 | Orphanet:251393 | Localized junctional epidermolysis bullosa |
| ITGB4 | Orphanet:79402 | Intermediate generalized junctional epidermolysis bullosa |
| ITGB4 | Orphanet:79403 | Junctional epidermolysis bullosa with pyloric atresia |
Cohort genes → proteins
2 cohort genes, 2 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 2 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| SPTBN4 | HGNC:14896 | ENSG00000160460 | Q9H254 | Spectrin beta chain, non-erythrocytic 4 | gencc,clinvar |
| ITGB4 | HGNC:6158 | ENSG00000132470 | P16144 | Integrin beta-4 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| ITGB4 | Integrin beta-4 | Integrin alpha-6/beta-4 is a receptor for laminin. |
Protein-family classification
Druggable: 1 · Difficult: 1 · Unknown: 0 · 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 |
|---|---|---|---|
| Antibody/Immunoglobulin | 1 | 14.6× | 0.112 |
| Scaffold/PPI | 1 | 8.6× | 0.112 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| SPTBN4 | Scaffold/PPI | no | Actinin_actin-bd_CS, PH_dom-spectrin-type, CH_dom | |
| ITGB4 | Antibody/Immunoglobulin | yes | EGF, Integrin_bsu_VWA, Calx_beta |
Expression context
Cohort genes with no expression data: 0.
2 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) | 2 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| cerebellar cortex | 1 |
| cerebellar hemisphere | 1 |
| right hemisphere of cerebellum | 1 |
| minor salivary gland | 1 |
| skin of leg | 1 |
| tibial nerve | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| SPTBN4 | 203 | broad | marker | right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex |
| ITGB4 | 267 | broad | marker | tibial nerve, minor salivary gland, skin of leg |
Protein interactions among cohort
Intra-cohort edges: 0.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| ITGB4 | 2,536 |
| SPTBN4 | 1,669 |
Structural data
PDB: 1 · AlphaFold-only: 1 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| ITGB4 | P16144 | 13 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| SPTBN4 | Q9H254 | 72.50 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Type I hemidesmosome assembly | 1 | 519.1× | 0.026 | ITGB4 |
| Collagen formation | 1 | 228.4× | 0.026 | ITGB4 |
| Syndecan interactions | 1 | 211.5× | 0.026 | ITGB4 |
| Laminin interactions | 1 | 190.3× | 0.026 | ITGB4 |
| Interaction between L1 and Ankyrins | 1 | 184.2× | 0.026 | SPTBN4 |
| Developmental Biology | 2 | 14.5× | 0.026 | SPTBN4, ITGB4 |
| Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin | 1 | 139.3× | 0.027 | ITGB4 |
| NCAM signaling for neurite out-growth | 1 | 135.9× | 0.027 | SPTBN4 |
| Developmental Cell Lineages | 1 | 112.0× | 0.028 | ITGB4 |
| Assembly of collagen fibrils and other multimeric structures | 1 | 100.2× | 0.028 | ITGB4 |
| Cell junction organization | 1 | 93.6× | 0.028 | ITGB4 |
| Non-integrin membrane-ECM interactions | 1 | 77.2× | 0.029 | ITGB4 |
| Cell-Cell communication | 1 | 68.8× | 0.029 | ITGB4 |
| ER to Golgi Anterograde Transport | 1 | 66.4× | 0.029 | SPTBN4 |
| MAPK1/MAPK3 signaling | 1 | 65.6× | 0.029 | SPTBN4 |
| L1CAM interactions | 1 | 60.1× | 0.030 | SPTBN4 |
| COPI-mediated anterograde transport | 1 | 54.9× | 0.030 | SPTBN4 |
| MAPK family signaling cascades | 1 | 51.4× | 0.030 | SPTBN4 |
| Transport to the Golgi and subsequent modification | 1 | 51.4× | 0.030 | SPTBN4 |
| Extracellular matrix organization | 1 | 31.6× | 0.043 | ITGB4 |
| RAF/MAP kinase cascade | 1 | 30.5× | 0.043 | SPTBN4 |
| Asparagine N-linked glycosylation | 1 | 30.1× | 0.043 | SPTBN4 |
| Axon guidance | 1 | 22.6× | 0.055 | SPTBN4 |
| Nervous system development | 1 | 21.5× | 0.056 | SPTBN4 |
| Membrane Trafficking | 1 | 18.5× | 0.062 | SPTBN4 |
| Vesicle-mediated transport | 1 | 17.4× | 0.063 | SPTBN4 |
| Post-translational protein modification | 1 | 9.6× | 0.109 | SPTBN4 |
| Metabolism of proteins | 1 | 6.2× | 0.161 | SPTBN4 |
| Signal Transduction | 1 | 5.1× | 0.187 | SPTBN4 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| peripheral nervous system myelin formation | 1 | 2808.7× | 0.005 | ITGB4 |
| hemidesmosome assembly | 1 | 1203.7× | 0.005 | ITGB4 |
| nail development | 1 | 1203.7× | 0.005 | ITGB4 |
| clustering of voltage-gated sodium channels | 1 | 1203.7× | 0.005 | SPTBN4 |
| trophoblast cell migration | 1 | 1203.7× | 0.005 | ITGB4 |
| central nervous system projection neuron axonogenesis | 1 | 936.2× | 0.005 | SPTBN4 |
| cardiac conduction | 1 | 842.6× | 0.005 | SPTBN4 |
| mesodermal cell differentiation | 1 | 766.0× | 0.005 | ITGB4 |
| actin filament capping | 1 | 766.0× | 0.005 | SPTBN4 |
| skin morphogenesis | 1 | 702.2× | 0.005 | ITGB4 |
| negative regulation of heart rate | 1 | 648.1× | 0.005 | SPTBN4 |
| regulation of sodium ion transport | 1 | 468.1× | 0.006 | SPTBN4 |
| cell adhesion mediated by integrin | 1 | 337.0× | 0.007 | ITGB4 |
| transmission of nerve impulse | 1 | 324.1× | 0.007 | SPTBN4 |
| filopodium assembly | 1 | 324.1× | 0.007 | ITGB4 |
| neuromuscular junction development | 1 | 263.3× | 0.007 | SPTBN4 |
| neuromuscular process | 1 | 263.3× | 0.007 | SPTBN4 |
| adult walking behavior | 1 | 247.8× | 0.007 | SPTBN4 |
| positive regulation of multicellular organism growth | 1 | 247.8× | 0.007 | SPTBN4 |
| cell motility | 1 | 200.6× | 0.008 | ITGB4 |
| fertilization | 1 | 156.0× | 0.010 | SPTBN4 |
| response to wounding | 1 | 110.9× | 0.014 | ITGB4 |
| cell-matrix adhesion | 1 | 81.8× | 0.017 | ITGB4 |
| integrin-mediated signaling pathway | 1 | 80.2× | 0.017 | ITGB4 |
| axonogenesis | 1 | 80.2× | 0.017 | SPTBN4 |
| protein-containing complex assembly | 1 | 56.9× | 0.022 | SPTBN4 |
| autophagy | 1 | 55.1× | 0.022 | ITGB4 |
| protein localization to plasma membrane | 1 | 54.4× | 0.022 | SPTBN4 |
| cell-cell adhesion | 1 | 50.8× | 0.022 | ITGB4 |
| sensory perception of sound | 1 | 50.5× | 0.022 | SPTBN4 |
Therapeutics
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2
Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| SPTBN4 | 0 | 0 |
| ITGB4 | 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 |
|---|---|---|
| ITGB4 | 2 | Binding:2 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 2; 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 | ITGB4 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 1 | SPTBN4 |
Undrugged target profiles
2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| SPTBN4 | 0 | — |
| ITGB4 | 2 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.