Chediak-Higashi syndrome

Summary

Chediak-Higashi syndrome (MONDO:0008963) is a disease caused by LYST (GenCC Definitive), with 5 cohort genes and 12 clinical trials. Top therapeutic interventions include fludarabine phosphate and alefacept.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LYST (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 3,611
• Phenotypes (HPO): 76
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		500	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001010	Hypopigmentation of the skin	Very frequent (80-99%)
HP:0001881	Abnormal leukocyte morphology	Very frequent (80-99%)
HP:0001922	Vacuolated lymphocytes	Very frequent (80-99%)
HP:0002718	Recurrent bacterial infections	Very frequent (80-99%)
HP:0002719	Recurrent infections	Very frequent (80-99%)
HP:0012145	Abnormality of multiple cell lineages in the bone marrow	Very frequent (80-99%)
HP:0012156	Hemophagocytosis	Very frequent (80-99%)
HP:0031408	Increased proportion of CD25+ mast cells	Very frequent (80-99%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0000704	Periodontitis	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0000992	Cutaneous photosensitivity	Frequent (30-79%)
HP:0001410	Decreased liver function	Frequent (30-79%)
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001583	Rotary nystagmus	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001892	Abnormal bleeding	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002721	Immunodeficiency	Frequent (30-79%)
HP:0003281	Increased circulating ferritin concentration	Frequent (30-79%)
HP:0004527	Large clumps of pigment irregularly distributed along hair shaft	Frequent (30-79%)
HP:0005406	Recurrent bacterial skin infections	Frequent (30-79%)
HP:0005599	Hypopigmentation of hair	Frequent (30-79%)
HP:0007499	Recurrent staphylococcal infections	Frequent (30-79%)
HP:0007663	Reduced visual acuity	Frequent (30-79%)
HP:0007703	Abnormality of retinal pigmentation	Frequent (30-79%)
HP:0007730	Iris hypopigmentation	Frequent (30-79%)
HP:0011869	Abnormal platelet function	Frequent (30-79%)
HP:0011990	Abnormality of neutrophil physiology	Frequent (30-79%)
HP:0012176	Abnormal natural killer cell morphology	Frequent (30-79%)
HP:0020096	Recurrent streptococcal infections	Frequent (30-79%)
HP:0000225	Gingival bleeding	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000666	Horizontal nystagmus	Occasional (5-29%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000762	Decreased nerve conduction velocity	Occasional (5-29%)
HP:0000763	Sensory neuropathy	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0000969	Edema	Occasional (5-29%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001258	Spastic paraplegia	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Chediak-Higashi syndrome
Mondo ID	MONDO:0008963
MeSH	D002609
OMIM	214500
Orphanet	167
DOID	DOID:2935
ICD-10-CM	E70.330
NCIT	C2941
SNOMED CT	111396008
UMLS	C0007965
MedGen	3347
GARD	0006035
MedDRA	10008415
NORD	921
Is cancer (heuristic)	no

Also known as: ChC)diak-Higashi disease · ChC)diak-Higashi-Steinbrink syndrome · Chediak Higashi Syndrome · Chediak Higashi syndrome · Chediak-Higashi syndrome · CHS · Chédiak-Higashi disease · Chédiak-Higashi syndrome · Chédiak-Higashi-Steinbrink syndrome

Data availability: 3,611 ClinVar variants · 5 GenCC gene-disease records · 15 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › Chediak-Higashi syndrome

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

600 retrieved; paginated sample, class counts are floors:

424 uncertain significance, 126 likely benign, 20 pathogenic, 15 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 4 benign, 3 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069690	NM_000081.4(LYST):c.3433del (p.His1145fs)	LYST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075026	NM_000081.4(LYST):c.2832del (p.Ser945fs)	LYST	Pathogenic	criteria provided, single submitter
1075027	NM_000081.4(LYST):c.1406T>A (p.Leu469Ter)	LYST	Pathogenic	criteria provided, single submitter
1076173	NM_000081.4(LYST):c.985C>T (p.Arg329Ter)	LYST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1173104	NM_000081.4(LYST):c.4322_4325del (p.Glu1441fs)	LYST	Pathogenic	criteria provided, multiple submitters, no conflicts
1323257	NM_000081.4(LYST):c.1897A>T (p.Lys633Ter)	LYST	Pathogenic	criteria provided, multiple submitters, no conflicts
1323258	NM_000081.4(LYST):c.11002G>T (p.Glu3668Ter)	LYST	Pathogenic	criteria provided, multiple submitters, no conflicts
1323259	NM_000081.4(LYST):c.8358+2T>C	LYST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323261	NM_000081.4(LYST):c.10468G>T (p.Gly3490Ter)	LYST	Pathogenic	criteria provided, single submitter
1323262	NM_000081.4(LYST):c.7645C>T (p.Gln2549Ter)	LYST	Pathogenic	criteria provided, single submitter
1323263	NM_000081.4(LYST):c.9377_9389del (p.Gly3126fs)	LYST	Pathogenic	criteria provided, multiple submitters, no conflicts
1350886	NM_000081.4(LYST):c.575del (p.Phe191_Leu192insTer)	LYST	Pathogenic	criteria provided, single submitter
1361717	NM_000081.4(LYST):c.236_237del (p.Leu79fs)	LYST	Pathogenic	criteria provided, single submitter
1378721	NM_000081.4(LYST):c.6283C>T (p.Gln2095Ter)	LYST	Pathogenic	criteria provided, single submitter
1401196	NM_000081.4(LYST):c.4978C>T (p.Gln1660Ter)	LYST	Pathogenic	criteria provided, single submitter
1413390	NM_000081.4(LYST):c.5491C>T (p.Gln1831Ter)	LYST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1416537	NM_000081.4(LYST):c.9838C>T (p.Arg3280Ter)	LYST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1447041	NM_000081.4(LYST):c.10568_10569del (p.Val3523fs)	LYST	Pathogenic	criteria provided, single submitter
1452518	NM_000081.4(LYST):c.2962C>T (p.Arg988Ter)	LYST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452670	NM_000081.4(LYST):c.8691_8692del (p.Gln2898fs)	LYST	Pathogenic	criteria provided, single submitter
1452697	NM_000081.4(LYST):c.9449del (p.Asn3150fs)	LYST	Pathogenic	criteria provided, single submitter
1452929	NM_000081.4(LYST):c.3574G>T (p.Glu1192Ter)	LYST	Pathogenic	criteria provided, single submitter
1453205	NM_000081.4(LYST):c.6187del (p.Arg2063fs)	LYST	Pathogenic	criteria provided, single submitter
1454348	NM_000081.4(LYST):c.8536-1G>A	LYST	Pathogenic	criteria provided, single submitter
1457029	NC_000001.10:g.(?235826240)(235976381_?)del	LYST	Pathogenic	criteria provided, single submitter
1490158	NC_000001.10:g.(?235543365)(235922919_?)del	TBCE	Pathogenic	criteria provided, single submitter
1067292	NC_000001.10:g.(?235950490)(235964407_?)dup	LYST	Likely pathogenic	criteria provided, single submitter
1479341	NM_000081.4(LYST):c.5923-1G>A	LYST	Likely pathogenic	criteria provided, single submitter
1480650	NM_000081.4(LYST):c.9044+1G>A	LYST	Likely pathogenic	criteria provided, single submitter
1020286	NM_000081.4(LYST):c.9616G>C (p.Asp3206His)	LYST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 13 · 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
LYST	Definitive	Autosomal recessive	Chediak-Higashi syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LYST	Orphanet:167	Chédiak-Higashi syndrome
LYST	Orphanet:352723	Attenuated Chédiak-Higashi syndrome
TBCE	Orphanet:2323	Sanjad-Sakati syndrome
TBCE	Orphanet:496756	Early-onset progressive encephalopathy-spastic ataxia-distal spinal muscular atrophy syndrome
TBCE	Orphanet:93324	Autosomal recessive Kenny-Caffey syndrome
ACTN2	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTN2	Orphanet:708129	Autosomal recessive ACTN2-related distal myopathy
ACTN2	Orphanet:708133	Autosomal dominant ACTN2-related distal myopathy
B3GALNT2	Orphanet:588	Muscle-eye-brain disease
B3GALNT2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
B3GALNT2	Orphanet:899	Walker-Warburg syndrome
SMCHD1	Orphanet:2250	Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
SMCHD1	Orphanet:269	Facioscapulohumeral dystrophy

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
LYST	HGNC:1968	ENSG00000143669	Q99698	Lysosomal-trafficking regulator	gencc,clinvar
TBCE	HGNC:11582	ENSG00000284770	Q15813	Tubulin-specific chaperone E	clinvar
ACTN2	HGNC:164	ENSG00000077522	P35609	Alpha-actinin-2	clinvar
B3GALNT2	HGNC:28596	ENSG00000162885	Q8NCR0	UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2	clinvar
SMCHD1	HGNC:29090	ENSG00000101596	A6NHR9	Structural maintenance of chromosomes flexible hinge domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LYST	Lysosomal-trafficking regulator	Adapter protein that regulates and/or fission of intracellular vesicles such as lysosomes.
TBCE	Tubulin-specific chaperone E	Tubulin-folding protein; involved in the second step of the tubulin folding pathway and in the regulation of tubulin heterodimer dissociation.
ACTN2	Alpha-actinin-2	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
B3GALNT2	UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2	Beta-1,3-N-acetylgalactosaminyltransferase that synthesizes a unique carbohydrate structure, GalNAc-beta-1-3GlcNAc, on N- and O-glycans.
SMCHD1	Structural maintenance of chromosomes flexible hinge domain-containing protein 1	Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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
Scaffold/PPI	1	3.5×	0.530
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LYST	Scaffold/PPI	no		BEACH_dom, WD40_rpt, PH-like_dom_sf
TBCE	Other/Unknown	no		Ubiquitin-like_dom, CAP-Gly_domain, Ubiquitin-like_domsf
ACTN2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
B3GALNT2	Enzyme (other)	yes	2.4.1.313	Glyco_trans_31
SMCHD1	Other/Unknown	no		SMC_hinge, SMC_hinge_sf, HATPase_C_sf

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	2
leukocyte	1
monocyte	1
mononuclear cell	1
cortical plate	1
ventricular zone	1
skeletal muscle tissue of biceps brachii	1
skeletal muscle tissue of rectus abdominis	1
adrenal tissue	1
body of pancreas	1
skeletal muscle tissue	1
blood	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LYST	278	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
TBCE	134	ubiquitous	yes	ventricular zone, hindlimb stylopod muscle, cortical plate
ACTN2	226	broad	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle
B3GALNT2	141	ubiquitous	marker	body of pancreas, skeletal muscle tissue, adrenal tissue
SMCHD1	290	ubiquitous	marker	calcaneal tendon, colonic epithelium, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTN2	2,781
SMCHD1	1,888
LYST	1,556
TBCE	1,068
B3GALNT2	748

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTN2	P35609	16
TBCE	Q15813	6
SMCHD1	A6NHR9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
B3GALNT2	Q8NCR0	86.81
LYST	Q99698

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. 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
DAG1 core M3 glycosylations	1	634.4×	0.023	B3GALNT2
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	1	292.8×	0.023	ACTN2
Ras activation upon Ca2+ influx through NMDA receptor	1	190.3×	0.023	ACTN2
Unblocking of NMDA receptors, glutamate binding and activation	1	181.3×	0.023	ACTN2
Negative regulation of NMDA receptor-mediated neuronal transmission	1	181.3×	0.023	ACTN2
Nephrin family interactions	1	158.6×	0.023	ACTN2
Post-chaperonin tubulin folding pathway	1	158.6×	0.023	TBCE
Long-term potentiation	1	158.6×	0.023	ACTN2
Striated Muscle Contraction	1	102.9×	0.031	ACTN2
Protein folding	1	86.5×	0.031	TBCE
Assembly and cell surface presentation of NMDA receptors	1	84.6×	0.031	ACTN2
Post NMDA receptor activation events	1	68.0×	0.035	ACTN2
Activation of NMDA receptors and postsynaptic events	1	61.4×	0.036	ACTN2
Response to elevated platelet cytosolic Ca2+	1	54.4×	0.036	ACTN2
Metabolism of proteins	2	8.2×	0.036	TBCE, B3GALNT2
O-linked glycosylation	1	48.2×	0.037	B3GALNT2
Cell-Cell communication	1	45.9×	0.037	ACTN2
MAPK1/MAPK3 signaling	1	43.8×	0.037	ACTN2
Platelet activation, signaling and aggregation	1	35.2×	0.041	ACTN2
MAPK family signaling cascades	1	34.3×	0.041	ACTN2
Neurotransmitter receptors and postsynaptic signal transmission	1	33.4×	0.041	ACTN2
Platelet degranulation	1	29.3×	0.045	ACTN2
Muscle contraction	1	25.7×	0.047	ACTN2
Transmission across Chemical Synapses	1	25.4×	0.047	ACTN2
RAF/MAP kinase cascade	1	20.4×	0.056	ACTN2
Neuronal System	1	14.8×	0.074	ACTN2
Hemostasis	1	12.0×	0.087	ACTN2
Post-translational protein modification	1	6.4×	0.154	B3GALNT2
Signal Transduction	1	3.4×	0.267	ACTN2

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
actin filament uncapping	1	3370.4×	0.009	ACTN2
muscle atrophy	1	1685.2×	0.009	TBCE
mast cell secretory granule organization	1	1685.2×	0.009	LYST
phospholipase C-activating angiotensin-activated signaling pathway	1	1123.5×	0.009	ACTN2
microspike assembly	1	842.6×	0.009	ACTN2
peripheral nervous system neuron axonogenesis	1	842.6×	0.009	TBCE
post-chaperonin tubulin folding pathway	1	561.7×	0.009	TBCE
endosome to lysosome transport via multivesicular body sorting pathway	1	561.7×	0.009	LYST
positive regulation of endocytic recycling	1	561.7×	0.009	ACTN2
nose development	1	481.5×	0.009	SMCHD1
autosome genomic imprinting	1	481.5×	0.009	SMCHD1
positive regulation of potassium ion transport	1	421.3×	0.009	ACTN2
negative regulation of potassium ion transport	1	374.5×	0.010	ACTN2
tubulin complex assembly	1	337.0×	0.010	TBCE
dosage compensation by inactivation of X chromosome	1	306.4×	0.010	SMCHD1
negative regulation of protein localization to cell surface	1	259.3×	0.012	ACTN2
leukocyte chemotaxis	1	210.7×	0.013	LYST
positive regulation of double-strand break repair via nonhomologous end joining	1	198.3×	0.013	SMCHD1
muscle cell development	1	187.2×	0.013	ACTN2
random inactivation of X chromosome	1	187.2×	0.013	SMCHD1
developmental growth	1	146.5×	0.015	TBCE
pigmentation	1	140.4×	0.015	LYST
melanosome organization	1	129.6×	0.015	LYST
cardiac muscle cell development	1	124.8×	0.015	ACTN2
negative regulation of double-strand break repair via homologous recombination	1	124.8×	0.015	SMCHD1
defense response to protozoan	1	120.4×	0.015	LYST
chromosome organization	1	116.2×	0.015	SMCHD1
focal adhesion assembly	1	105.3×	0.016	ACTN2
natural killer cell mediated cytotoxicity	1	86.4×	0.019	LYST
sarcomere organization	1	76.6×	0.021	ACTN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMCHD1	1	2
LYST	0	0
TBCE	0	0
ACTN2	0	0
B3GALNT2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SMCHD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SMCHD1	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
B3GALNT2	2.4.1.313	protein O-mannose beta-1,3-N-acetylgalactosaminyltransferase

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	SMCHD1

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	1	SMCHD1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	B3GALNT2
E	Difficult family or no structure, no drug	3	LYST, TBCE, ACTN2

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)
LYST	0	—
TBCE	0	—
ACTN2	0	—
B3GALNT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE2	2
PHASE2/PHASE3	1
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00176826	PHASE2/PHASE3	TERMINATED	T-Cell Depletion and Stem Cell Transplant for Immune Deficiencies and Histiocytic Disorders
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT00730314	PHASE1/PHASE2	COMPLETED	Unrelated Hematopoietic Stem Cell Transplantation(HSCT) for Genetic Diseases of Blood Cells
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT00005917	Not specified	RECRUITING	Study of Chediak-Higashi Syndrome
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT00005933	Not specified	COMPLETED	Learning and Behavior Problems in Children With Chronic Granulomatous Disease and Related Disorders
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
NCT00006056	Not specified	UNKNOWN	Pilot Study of Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients With Life Threatening Hemophagocytic Disorders
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	2
ALEFACEPT	4	1