Hydrolethalus syndrome 1

Summary

Hydrolethalus syndrome 1 (MONDO:0009365) is a disease caused by HYLS1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: HYLS1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hydrolethalus syndrome 1
Mondo ID	MONDO:0009365
MeSH	C565504
OMIM	236680
DOID	DOID:0111355
UMLS	C1856016
MedGen	343455
GARD	0015182
Is cancer (heuristic)	no

Also known as: HLS1 · hydrolethalus syndrome · hydrolethalus syndrome 1 · hydrolethalus syndrome caused by mutation in HYLS1 · hydrolethalus syndrome type 1 · HYLS1 hydrolethalus syndrome

Data availability: 24 ClinVar variants · 4 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 › hydrolethalus syndrome › hydrolethalus syndrome 1

Related subtypes (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

24 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 7 likely pathogenic, 1 pathogenic, 1 benign, 1 conflicting classifications of pathogenicity

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
3599137	NM_001134793.2(HYLS1):c.194del (p.Pro65fs)	HYLS1	Likely pathogenic	criteria provided, single submitter
3599138	NM_001134793.2(HYLS1):c.400dup (p.Arg134fs)	HYLS1	Likely pathogenic	criteria provided, single submitter
3599140	NM_001134793.2(HYLS1):c.550C>T (p.Gln184Ter)	HYLS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3599135	NM_001134793.2(HYLS1):c.130C>T (p.Gln44Ter)	PUS3	Likely pathogenic	criteria provided, single submitter
3599139	NM_001134793.2(HYLS1):c.415C>T (p.Gln139Ter)	PUS3	Likely pathogenic	criteria provided, single submitter
3599141	NM_001134793.2(HYLS1):c.807_808del (p.Lys270fs)	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
303364	NM_001134793.2(HYLS1):c.298C>T (p.Arg100Cys)	HYLS1	Uncertain significance	criteria provided, single submitter
3859179	NM_001134793.2(HYLS1):c.499C>G (p.Gln167Glu)	HYLS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
554542	NM_001134793.2(HYLS1):c.851_859del (p.Ala284_Gly286del)	HYLS1	Uncertain significance	no assertion criteria provided
555336	NM_001134793.2(HYLS1):c.145_147del (p.Asp49del)	HYLS1	Uncertain significance	no assertion criteria provided
556120	NM_001134793.2(HYLS1):c.73_78del (p.Thr25_Ala26del)	HYLS1	Uncertain significance	no assertion criteria provided
557646	NM_001134793.2(HYLS1):c.220_221del (p.Glu74fs)	HYLS1	Uncertain significance	no assertion criteria provided
992017	NM_001134793.2(HYLS1):c.547G>A (p.Glu183Lys)	HYLS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1331389	NM_001134793.2(HYLS1):c.546C>G (p.Tyr182Ter)	PUS3	Uncertain significance	criteria provided, multiple submitters, no conflicts
550484	NM_001134793.2(HYLS1):c.893CTT[1] (p.Ser299del)	PUS3	Uncertain significance	no assertion criteria provided
554866	NM_001134793.2(HYLS1):c.284_286dup (p.Lys95_Arg96insLys)	PUS3	Uncertain significance	no assertion criteria provided
554935	NM_001134793.2(HYLS1):c.536_544del (p.Ser179_Ala181del)	PUS3	Uncertain significance	no assertion criteria provided
555374	NM_001134793.2(HYLS1):c.167_169del (p.Val56del)	PUS3	Uncertain significance	no assertion criteria provided
556505	NM_001134793.2(HYLS1):c.459del (p.Lys153fs)	PUS3	Uncertain significance	no assertion criteria provided
992019	NM_001134793.2(HYLS1):c.725G>A (p.Arg242Gln)	PUS3	Uncertain significance	criteria provided, single submitter
303363	NM_001134793.2(HYLS1):c.91T>C (p.Cys31Arg)	PUS3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HYLS1	Orphanet:2189	Hydrolethalus
HYLS1	Orphanet:475	Isolated Joubert syndrome
PUS3	Orphanet:488627	Severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability 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
HYLS1	HGNC:26558	ENSG00000198331	Q96M11	Centriolar and ciliogenesis-associated protein HYLS1	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.
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: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HYLS1	Other/Unknown	no		HYLS1, HYLS1_C_dom, Centriolar_ciliogenesis_assoc
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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sperm	2
oocyte	1
secondary oocyte	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
PUS3	284	ubiquitous	yes	buccal mucosa cell, islet of Langerhans, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PUS3	2,132
HYLS1	453

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PUS3	Q9BZE2	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HYLS1	Q96M11	66.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA modification in the nucleus and cytosol	1	292.8×	0.003	PUS3

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
tRNA pseudouridine synthesis	1	1404.3×	0.002	PUS3
mRNA pseudouridine synthesis	1	842.6×	0.002	PUS3
tRNA modification	1	300.9×	0.004	PUS3
cilium assembly	1	36.8×	0.027	HYLS1

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
HYLS1	0	0
PUS3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	2	HYLS1, PUS3

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)
HYLS1	0	—
PUS3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.