autosomal recessive Kenny-Caffey syndrome

Summary

autosomal recessive Kenny-Caffey syndrome (MONDO:0009486) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 23
• Phenotypes (HPO): 22

Clinical features

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0002199	Hypocalcemic seizures	Very frequent (80-99%)
HP:0002901	Hypocalcemia	Very frequent (80-99%)
HP:0008198	Congenital hypoparathyroidism	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000270	Delayed cranial suture closure	Frequent (30-79%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000670	Carious teeth	Frequent (30-79%)
HP:0000883	Thin ribs	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001773	Short foot	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0003472	Hypocalcemic tetany	Frequent (30-79%)
HP:0004331	Decreased skull ossification	Frequent (30-79%)
HP:0005450	Calvarial osteosclerosis	Frequent (30-79%)
HP:0005791	Cortical thickening of long bone diaphyses	Frequent (30-79%)
HP:0006470	Thin long bone diaphyses	Frequent (30-79%)
HP:0006645	Thin clavicles	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0100254	Stenosis of the medullary cavity of the long bones	Frequent (30-79%)
HP:0200055	Small hand	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive Kenny-Caffey syndrome
Mondo ID	MONDO:0009486
MeSH	C537021
OMIM	244460
Orphanet	93324
DOID	DOID:0080722
NCIT	C130992
UMLS	C1855648
MedGen	340923
GARD	0008367
Is cancer (heuristic)	no

Also known as: KCS1 · Kenny-Caffey syndrome type 1 · Kenny-Caffey syndrome, autosomal recessive · Kenny-Caffey syndrome, type 1

Data availability: 23 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive Kenny-Caffey syndrome

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

23 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 7 likely pathogenic, 5 pathogenic/likely pathogenic, 4 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
225483	NM_003193.5(TBCE):c.143_144del (p.Lys48fs)	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2743364	NM_003193.5(TBCE):c.433A>T (p.Lys145Ter)	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5290	NM_003193.5(TBCE):c.155_166del (p.Ser52_Gly55del)	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631595	NM_003193.5(TBCE):c.100+1G>A	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804381	NM_003193.5(TBCE):c.355_356del (p.Ile119fs)	TBCE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297492	NM_003193.5(TBCE):c.101-1G>C	TBCE	Likely pathogenic	criteria provided, single submitter
3581407	NM_003193.5(TBCE):c.34C>T (p.Arg12Ter)	TBCE	Likely pathogenic	criteria provided, single submitter
3581420	NM_003193.5(TBCE):c.185+1G>C	TBCE	Likely pathogenic	criteria provided, single submitter
3581427	NM_003193.5(TBCE):c.561-2A>G	TBCE	Likely pathogenic	criteria provided, single submitter
3581430	NM_003193.5(TBCE):c.736del (p.Arg246fs)	TBCE	Likely pathogenic	criteria provided, single submitter
3581434	NM_003193.5(TBCE):c.1116+1G>T	TBCE	Likely pathogenic	criteria provided, single submitter
870974	NM_003193.5(TBCE):c.1038del (p.Glu347fs)	TBCE	Likely pathogenic	criteria provided, multiple submitters, no conflicts
282266	NM_003193.5(TBCE):c.1465C>A (p.Leu489Ile)	B3GALNT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520625	NM_003193.5(TBCE):c.1491_1491+4dup	B3GALNT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193652	NM_003193.5(TBCE):c.847A>T (p.Ile283Phe)	TBCE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2189908	NM_003193.5(TBCE):c.371+2_371+8dup	TBCE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033981	NM_003193.5(TBCE):c.71G>A (p.Arg24His)	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1386786	NM_003193.5(TBCE):c.581C>T (p.Pro194Leu)	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1449541	NM_003193.5(TBCE):c.898+6T>C	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1709569	NM_003193.5(TBCE):c.786T>G (p.Asn262Lys)	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
3581423	NM_003193.5(TBCE):c.389A>G (p.Gln130Arg)	TBCE	Uncertain significance	criteria provided, single submitter
3892603	NM_003193.5(TBCE):c.1112G>A (p.Cys371Tyr)	TBCE	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892605	NM_003193.5(TBCE):c.661-1147A>G	TBCE	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
TBCE	Moderate	Autosomal recessive	autosomal recessive Kenny-Caffey syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
B3GALNT2	Orphanet:588	Muscle-eye-brain disease
B3GALNT2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
B3GALNT2	Orphanet:899	Walker-Warburg syndrome

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
TBCE	HGNC:11582	ENSG00000284770	Q15813	Tubulin-specific chaperone E	gencc,clinvar
B3GALNT2	HGNC:28596	ENSG00000162885	Q8NCR0	UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBCE	Other/Unknown	no		Ubiquitin-like_dom, CAP-Gly_domain, Ubiquitin-like_domsf
B3GALNT2	Enzyme (other)	yes	2.4.1.313	Glyco_trans_31

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
hindlimb stylopod muscle	1
ventricular zone	1
adrenal tissue	1
body of pancreas	1
skeletal muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBCE	134	ubiquitous	yes	ventricular zone, hindlimb stylopod muscle, cortical plate
B3GALNT2	141	ubiquitous	marker	body of pancreas, skeletal muscle tissue, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBCE	1,068
B3GALNT2	748

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBCE	Q15813	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
B3GALNT2	Q8NCR0	86.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
DAG1 core M3 glycosylations	1	951.7×	0.006	B3GALNT2
Post-chaperonin tubulin folding pathway	1	237.9×	0.012	TBCE
Protein folding	1	129.8×	0.012	TBCE
Metabolism of proteins	2	12.4×	0.012	TBCE, B3GALNT2
O-linked glycosylation	1	72.3×	0.017	B3GALNT2
Post-translational protein modification	1	9.6×	0.101	B3GALNT2

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
muscle atrophy	1	4213.0×	0.003	TBCE
peripheral nervous system neuron axonogenesis	1	2106.5×	0.003	TBCE
post-chaperonin tubulin folding pathway	1	1404.3×	0.003	TBCE
tubulin complex assembly	1	842.6×	0.004	TBCE
developmental growth	1	366.4×	0.007	TBCE
glycoprotein biosynthetic process	1	168.5×	0.011	B3GALNT2
adult locomotory behavior	1	150.5×	0.011	TBCE
mitotic spindle organization	1	135.9×	0.011	TBCE
protein O-linked glycosylation	1	112.3×	0.012	B3GALNT2
post-embryonic development	1	102.8×	0.012	TBCE
microtubule cytoskeleton organization	1	60.6×	0.018	TBCE
protein folding	1	51.7×	0.019	TBCE

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
TBCE	0	0
B3GALNT2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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: 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	0
D	Druggable family + AlphaFold only, no drug	1	B3GALNT2
E	Difficult family or no structure, no drug	1	TBCE

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)
TBCE	0	—
B3GALNT2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.