Hydrolethalus syndrome

Summary

Hydrolethalus syndrome (MONDO:0006037) is a disease with 3 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Finland) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 59
• Phenotypes (HPO): 28

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	5	Finland	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated
Point prevalence	<1 / 1 000 000		Finland	Not yet validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000238	Hydrocephalus	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0001162	Postaxial hand polydactyly	Very frequent (80-99%)
HP:0001274	Agenesis of corpus callosum	Very frequent (80-99%)
HP:0001331	Absent septum pellucidum	Very frequent (80-99%)
HP:0001561	Polyhydramnios	Very frequent (80-99%)
HP:0001622	Premature birth	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000176	Submucous cleft hard palate	Frequent (30-79%)
HP:0000193	Bifid uvula	Frequent (30-79%)
HP:0000369	Low-set ears	Frequent (30-79%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0001601	Laryngomalacia	Frequent (30-79%)
HP:0002086	Abnormality of the respiratory system	Frequent (30-79%)
HP:0004408	Abnormality of the sense of smell	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0030690	Gingival cleft	Frequent (30-79%)
HP:0100333	Unilateral cleft lip	Frequent (30-79%)
HP:0100682	Tracheal atresia	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000528	Anophthalmia	Occasional (5-29%)
HP:0000568	Microphthalmia	Occasional (5-29%)
HP:0002139	Arrhinencephaly	Occasional (5-29%)
HP:0002323	Anencephaly	Occasional (5-29%)
HP:0002983	Micromelia	Occasional (5-29%)
HP:0011027	Abnormality of the fallopian tube	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hydrolethalus syndrome
Mondo ID	MONDO:0006037
MeSH	C536079
OMIM	236680
Orphanet	2189
DOID	DOID:0050779
SNOMED CT	721232000
UMLS	C2931104
MedGen	419335
GARD	0006683
Is cancer (heuristic)	no

Also known as: HLS

Data availability: 59 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, 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, autosomal recessive Kenny-Caffey 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

Subtypes (2): hydrolethalus syndrome 1, hydrolethalus syndrome 2

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

59 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 15 likely pathogenic, 12 likely benign, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1143	NM_031307.4(PUS3):c.-47+3170T>C	HYLS1	Pathogenic	criteria provided, multiple submitters, no conflicts
3599136	NM_001134793.2(HYLS1):c.181C>T (p.Arg61Ter)	HYLS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599140	NM_001134793.2(HYLS1):c.550C>T (p.Gln184Ter)	HYLS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4069616	NM_001134793.2(HYLS1):c.520dup (p.Arg174fs)	HYLS1	Likely pathogenic	criteria provided, single submitter
4069623	NM_001134793.2(HYLS1):c.657C>G (p.Tyr219Ter)	HYLS1	Likely pathogenic	criteria provided, single submitter
4076610	NM_001134793.2(HYLS1):c.613C>T (p.Arg205Ter)	HYLS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4816848	NM_001134793.2(HYLS1):c.15_16insAA (p.Pro6fs)	HYLS1	Likely pathogenic	criteria provided, single submitter
4816849	NM_001134793.2(HYLS1):c.169del (p.Ala57fs)	HYLS1	Likely pathogenic	criteria provided, single submitter
4816851	NM_001134793.2(HYLS1):c.197dup (p.Gln67fs)	HYLS1	Likely pathogenic	criteria provided, single submitter
4816852	NM_001134793.2(HYLS1):c.25_26del (p.Gln9fs)	HYLS1	Likely pathogenic	criteria provided, single submitter
4816854	NM_001134793.2(HYLS1):c.31del (p.Trp11fs)	HYLS1	Likely pathogenic	criteria provided, single submitter
4816855	NM_001134793.2(HYLS1):c.652G>T (p.Glu218Ter)	HYLS1	Likely pathogenic	criteria provided, single submitter
4816857	NM_001134793.2(HYLS1):c.724C>T (p.Arg242Ter)	HYLS1	Likely pathogenic	criteria provided, single submitter
4816850	NM_001134793.2(HYLS1):c.182delinsCA (p.Arg61fs)	PUS3	Likely pathogenic	criteria provided, single submitter
4816853	NM_001134793.2(HYLS1):c.316_319delinsTAACAGATGAGTAACAGAT (p.Glu106_Val107delinsTer)	PUS3	Likely pathogenic	criteria provided, single submitter
4816856	NM_001134793.2(HYLS1):c.674C>G (p.Ser225Ter)	PUS3	Likely pathogenic	criteria provided, single submitter
557012	NM_001134793.2(HYLS1):c.55C>T (p.Arg19Ter)	HYLS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
718029	NM_001134793.2(HYLS1):c.662G>A (p.Arg221Gln)	HYLS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283923	NM_198525.3(KIF7):c.1177G>T (p.Gly393Cys)	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
303364	NM_001134793.2(HYLS1):c.298C>T (p.Arg100Cys)	HYLS1	Uncertain significance	criteria provided, single submitter
4036981	NM_001134793.2(HYLS1):c.892C>T (p.Pro298Ser)	HYLS1	Uncertain significance	criteria provided, single submitter
4069610	NM_001134793.2(HYLS1):c.379G>A (p.Asp127Asn)	HYLS1	Uncertain significance	no assertion criteria provided
4069612	NM_001134793.2(HYLS1):c.568A>C (p.Ser190Arg)	HYLS1	Uncertain significance	no assertion criteria provided
4069613	NM_001134793.2(HYLS1):c.118A>G (p.Arg40Gly)	HYLS1	Uncertain significance	no assertion criteria provided
4069614	NM_001134793.2(HYLS1):c.774A>T (p.Ile258=)	HYLS1	Uncertain significance	no assertion criteria provided
4069615	NM_001134793.2(HYLS1):c.201A>G (p.Gln67=)	HYLS1	Uncertain significance	no assertion criteria provided
4069617	NM_001134793.2(HYLS1):c.383T>C (p.Leu128Pro)	HYLS1	Uncertain significance	no assertion criteria provided
4069618	NM_001134793.2(HYLS1):c.724C>G (p.Arg242Gly)	HYLS1	Uncertain significance	no assertion criteria provided
4069619	NM_001134793.2(HYLS1):c.-3G>A	HYLS1	Uncertain significance	no assertion criteria provided
4069620	NM_001134793.2(HYLS1):c.677T>A (p.Ile226Lys)	HYLS1	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 7 · 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
HYLS1	Definitive	Autosomal recessive	hydrolethalus syndrome 1	6
KIF7	Strong	Autosomal recessive	hydrolethalus syndrome 2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HYLS1	Orphanet:2189	Hydrolethalus
HYLS1	Orphanet:475	Isolated Joubert syndrome
KIF7	Orphanet:166024	Multiple epiphyseal dysplasia-macrocephaly-facial dysmorphism syndrome
KIF7	Orphanet:2189	Hydrolethalus
KIF7	Orphanet:2754	Orofaciodigital syndrome type 6
KIF7	Orphanet:36	Acrocallosal syndrome
PUS3	Orphanet:488627	Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HYLS1	HGNC:26558	ENSG00000198331	Q96M11	Centriolar and ciliogenesis-associated protein HYLS1	gencc,clinvar
KIF7	HGNC:30497	ENSG00000166813	Q2M1P5	Kinesin-like protein KIF7	gencc,clinvar
PUS3	HGNC:25461	ENSG00000110060	Q9BZE2	tRNA pseudouridine(38/39) synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HYLS1	Centriolar and ciliogenesis-associated protein HYLS1	Plays a role in ciliogenesis.
KIF7	Kinesin-like protein KIF7	Essential for hedgehog signaling regulation: acts both as a negative and positive regulator of sonic hedgehog (Shh) and Indian hedgehog (Ihh) pathways, acting downstream of SMO, through both SUFU-dependent and -independent mechanisms.
PUS3	tRNA pseudouridine(38/39) synthase	Formation of pseudouridine at position 39 in the anticodon stem and loop of transfer RNAs.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HYLS1	Other/Unknown	no		HYLS1, HYLS1_C_dom, Centriolar_ciliogenesis_assoc
KIF7	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
PUS3	Other/Unknown	no		PsdUridine_synth_TruA, TruA/RsuA/RluB/E/F_N, PsdUridine_synth_TruA_C

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sperm	2
oocyte	1
secondary oocyte	1
cardiac muscle of right atrium	1
kidney epithelium	1
left ventricle myocardium	1
buccal mucosa cell	1
islet of Langerhans	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HYLS1	205	ubiquitous	yes	oocyte, secondary oocyte, sperm
KIF7	165	ubiquitous	yes	kidney epithelium, cardiac muscle of right atrium, left ventricle myocardium
PUS3	284	ubiquitous	yes	buccal mucosa cell, islet of Langerhans, sperm

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PUS3	2,132
KIF7	1,655
HYLS1	453

Intra-cohort edges

A	B	Sources
HYLS1	KIF7	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PUS3	Q9BZE2	6
KIF7	Q2M1P5	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HYLS1	Q96M11	66.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 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
tRNA modification in the nucleus and cytosol	1	146.4×	0.016	PUS3
Signaling by Hedgehog	1	92.1×	0.016	KIF7
Hedgehog ‘off’ state	1	89.2×	0.016	KIF7
Hedgehog ‘on’ state	1	79.3×	0.016	KIF7
Signal Transduction	1	5.1×	0.187	KIF7

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tRNA pseudouridine synthesis	1	936.2×	0.006	PUS3
mRNA pseudouridine synthesis	1	561.7×	0.006	PUS3
tRNA modification	1	200.6×	0.010	PUS3
negative regulation of smoothened signaling pathway	1	151.8×	0.010	KIF7
positive regulation of smoothened signaling pathway	1	140.4×	0.010	KIF7
microtubule-based movement	1	98.5×	0.012	KIF7
cilium assembly	1	24.5×	0.040	HYLS1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HYLS1	0	0
KIF7	0	0
PUS3	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
KIF7	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	HYLS1, KIF7, PUS3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HYLS1	0	—
KIF7	5	—
PUS3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.