Hydrolethalus syndrome 2

Summary

Hydrolethalus syndrome 2 (MONDO:0013585) is a disease caused by KIF7 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: KIF7 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 312

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hydrolethalus syndrome 2
Mondo ID	MONDO:0013585
OMIM	614120
DOID	DOID:0111356
UMLS	C3279899
MedGen	481529
GARD	0015759
Is cancer (heuristic)	no

Also known as: HLS2 · hydrolethalus syndrome 2 · hydrolethalus syndrome caused by mutation in KIF7 · hydrolethalus syndrome type 2 · KIF7 hydrolethalus syndrome

Data availability: 312 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 › hydrolethalus syndrome › hydrolethalus syndrome 2

Related subtypes (1): hydrolethalus syndrome 1

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

312 retrieved; paginated sample, class counts are floors:

247 uncertain significance, 23 conflicting classifications of pathogenicity, 14 likely pathogenic, 12 benign, 9 pathogenic/likely pathogenic, 4 benign/likely benign, 2 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1201620	NM_198525.3(KIF7):c.1149dup (p.Ile384fs)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297573	NM_198525.3(KIF7):c.3235C>T (p.Gln1079Ter)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1380985	NM_198525.3(KIF7):c.1248del (p.Asp417fs)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454843	NM_198525.3(KIF7):c.2560_2570del (p.Ala854fs)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195441	NM_198525.3(KIF7):c.61C>T (p.Arg21Ter)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3023369	NM_198525.3(KIF7):c.350_353dup (p.Ile119fs)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30895	NM_198525.3(KIF7):c.2896_2897del (p.Ala966fs)	KIF7	Pathogenic	criteria provided, multiple submitters, no conflicts
3891489	NM_198525.3(KIF7):c.2515C>T (p.Gln839Ter)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520764	NM_198525.3(KIF7):c.328+2T>G	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
587434	NM_198525.3(KIF7):c.67C>T (p.Arg23Ter)	KIF7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988539	NM_198525.3(KIF7):c.1019dup (p.Asn341fs)	KIF7	Pathogenic	criteria provided, multiple submitters, no conflicts
1306220	NM_198525.3(KIF7):c.1443+2T>C	KIF7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334544	NM_198525.3(KIF7):c.1561-1G>A	KIF7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2048811	NM_198525.3(KIF7):c.1789-2A>G	KIF7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3578015	NM_198525.3(KIF7):c.3838_3886del (p.Ser1280fs)	KIF7	Likely pathogenic	criteria provided, single submitter
3578040	NM_198525.3(KIF7):c.3195C>A (p.Cys1065Ter)	KIF7	Likely pathogenic	criteria provided, single submitter
3578060	NM_198525.3(KIF7):c.2869G>T (p.Glu957Ter)	KIF7	Likely pathogenic	criteria provided, single submitter
3578062	NM_198525.3(KIF7):c.2758G>T (p.Glu920Ter)	KIF7	Likely pathogenic	criteria provided, single submitter
3578063	NM_198525.3(KIF7):c.2718+1G>A	KIF7	Likely pathogenic	criteria provided, single submitter
3578066	NM_198525.3(KIF7):c.2618del (p.Gln873fs)	KIF7	Likely pathogenic	criteria provided, single submitter
3578092	NM_198525.3(KIF7):c.1703del (p.Leu568fs)	KIF7	Likely pathogenic	criteria provided, single submitter
3578109	NM_198525.3(KIF7):c.1295_1307dup (p.Lys439fs)	KIF7	Likely pathogenic	criteria provided, single submitter
3578124	NM_198525.3(KIF7):c.923+2T>G	KIF7	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3578129	NM_198525.3(KIF7):c.719_720insT (p.Gln242fs)	KIF7	Likely pathogenic	criteria provided, single submitter
4845879	NM_198525.3(KIF7):c.417_420del (p.Cys139fs)	KIF7	Likely pathogenic	criteria provided, single submitter
1024840	NM_198525.3(KIF7):c.50G>A (p.Arg17Gln)	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1119022	NM_198525.3(KIF7):c.329-26_329-13del	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1401610	NM_198525.3(KIF7):c.2345G>A (p.Arg782Gln)	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1624285	NM_198525.3(KIF7):c.2896-9T>C	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1934832	NM_198525.3(KIF7):c.690C>T (p.Arg230=)	KIF7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · 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
KIF7	Strong	Autosomal recessive	hydrolethalus syndrome 2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KIF7	HGNC:30497	ENSG00000166813	Q2M1P5	Kinesin-like protein KIF7	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KIF7	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac muscle of right atrium	1
kidney epithelium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KIF7	165	ubiquitous	yes	kidney epithelium, cardiac muscle of right atrium, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF7	1,655

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KIF7	Q2M1P5	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 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
Signaling by Hedgehog	1	184.2×	0.008	KIF7
Hedgehog ‘off’ state	1	178.4×	0.008	KIF7
Hedgehog ‘on’ state	1	158.6×	0.008	KIF7
Signal Transduction	1	10.2×	0.098	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of smoothened signaling pathway	1	455.5×	0.003	KIF7
positive regulation of smoothened signaling pathway	1	421.3×	0.003	KIF7
microtubule-based movement	1	295.6×	0.003	KIF7

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KIF7	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: 1; 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	1	KIF7

Undrugged target profiles

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

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.