Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome

Summary

Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (MONDO:0019073) is a disease caused by SOX18 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SOX18 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 69

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypotrichosis-lymphedema-telangiectasia-renal defect syndrome
Mondo ID	MONDO:0019073
MeSH	C536825
OMIM	137940
DOID	DOID:0111360
UMLS	C4317151
MedGen	1373459
GARD	0002492
Is cancer (heuristic)	no

Also known as: HLTRS · hypotrichosis-lymphedema-telangiectasia-renal defect syndrome

Data availability: 69 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › hypotrichosis-lymphedema-telangiectasia syndrome (grouping) › hypotrichosis-lymphedema-telangiectasia-renal defect syndrome

Related subtypes (1): hypotrichosis-lymphedema-telangiectasia syndrome

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

69 retrieved; paginated sample, class counts are floors:

57 uncertain significance, 5 conflicting classifications of pathogenicity, 3 likely benign, 2 likely pathogenic, 1 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
433539	NM_018419.3(SOX18):c.712G>T (p.Glu238Ter)	SOX18	Pathogenic	criteria provided, single submitter
3587628	NM_018419.3(SOX18):c.917_947del (p.Leu306fs)	SOX18	Likely pathogenic	criteria provided, single submitter
8002	NM_018419.3(SOX18):c.720C>A (p.Cys240Ter)	SOX18	Likely pathogenic	criteria provided, single submitter
2070559	NM_018419.3(SOX18):c.853G>C (p.Gly285Arg)	SOX18	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2534625	NM_018419.3(SOX18):c.93C>G (p.Asp31Glu)	SOX18	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2743162	NM_018419.3(SOX18):c.553G>C (p.Glu185Gln)	SOX18	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3587651	NM_018419.3(SOX18):c.359-14C>G	SOX18	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
872265	NM_018419.3(SOX18):c.911C>A (p.Pro304Gln)	SOX18	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3237434	NM_018419.3(SOX18):c.166C>T (p.Arg56Cys)	LOC130066420	Uncertain significance	criteria provided, single submitter
3587658	NM_018419.3(SOX18):c.123_140dup (p.Ala47_Pro48insLeuAlaAlaProAlaAla)	LOC130066420	Uncertain significance	criteria provided, single submitter
2039484	NM_018419.3(SOX18):c.961G>A (p.Asp321Asn)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2069138	NM_018419.3(SOX18):c.71C>A (p.Pro24Gln)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2076665	NM_018419.3(SOX18):c.112G>T (p.Gly38Cys)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2148873	NM_018419.3(SOX18):c.601C>T (p.Pro201Ser)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2196021	NM_018419.3(SOX18):c.853G>A (p.Gly285Ser)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2231776	NM_018419.3(SOX18):c.664G>C (p.Gly222Arg)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2380634	NM_018419.3(SOX18):c.548C>T (p.Pro183Leu)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2474772	NM_018419.3(SOX18):c.88G>T (p.Ala30Ser)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2516120	NM_018419.3(SOX18):c.812G>A (p.Arg271Lys)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2609961	NM_018419.3(SOX18):c.748G>A (p.Ala250Thr)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2848825	NM_018419.3(SOX18):c.940C>A (p.Pro314Thr)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
2902243	NM_018419.3(SOX18):c.134C>T (p.Pro45Leu)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
3007794	NM_018419.3(SOX18):c.797T>G (p.Leu266Arg)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
3167754	NM_018419.3(SOX18):c.964G>T (p.Val322Leu)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
3321629	NM_018419.3(SOX18):c.1031C>T (p.Pro344Leu)	SOX18	Uncertain significance	criteria provided, multiple submitters, no conflicts
3346851	NM_018419.3(SOX18):c.800C>G (p.Ala267Gly)	SOX18	Uncertain significance	criteria provided, single submitter
3587623	NM_018419.3(SOX18):c.1151G>T (p.Gly384Val)	SOX18	Uncertain significance	criteria provided, single submitter
3587624	NM_018419.3(SOX18):c.1130A>G (p.Tyr377Cys)	SOX18	Uncertain significance	criteria provided, single submitter
3587625	NM_018419.3(SOX18):c.1087A>T (p.Ser363Cys)	SOX18	Uncertain significance	criteria provided, single submitter
3587626	NM_018419.3(SOX18):c.1069A>G (p.Met357Val)	SOX18	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 1 · 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
SOX18	Strong	Autosomal dominant	hypotrichosis-lymphedema-telangiectasia-renal defect syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX18	Orphanet:69735	Hypotrichosis-lymphedema-telangiectasia-renal defect 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
SOX18	HGNC:11194	ENSG00000203883	P35713	Transcription factor SOX-18	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOX18	Transcription factor SOX-18	Transcriptional activator that binds to the consensus sequence 5’-AACAAAG-3’ in the promoter of target genes and plays an essential role in embryonic cardiovascular development and lymphangiogenesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX18	Transcription factor	no		HMG_box_dom, Sox_C, Sox7/17/18_central

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
left uterine tube	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX18	165	broad	marker	apex of heart, right lung, left uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX18	1,525

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SOX18	P35713	63.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
stem cell fate specification	1	4213.0×	0.002	SOX18
endocardium formation	1	4213.0×	0.002	SOX18
hair cycle process	1	2808.7×	0.002	SOX18
endocardial cell differentiation	1	2808.7×	0.002	SOX18
lymphatic endothelial cell differentiation	1	2407.4×	0.002	SOX18
blood vessel endothelial cell migration	1	1404.3×	0.002	SOX18
regulation of stem cell proliferation	1	1404.3×	0.002	SOX18
lymphangiogenesis	1	1203.7×	0.002	SOX18
vasculature development	1	1123.5×	0.002	SOX18
embryonic heart tube development	1	766.0×	0.003	SOX18
establishment of endothelial barrier	1	766.0×	0.003	SOX18
cell maturation	1	443.5×	0.004	SOX18
hair follicle development	1	383.0×	0.004	SOX18
outflow tract morphogenesis	1	306.4×	0.005	SOX18
heart looping	1	267.5×	0.005	SOX18
vasculogenesis	1	255.3×	0.005	SOX18
in utero embryonic development	1	72.0×	0.018	SOX18
angiogenesis	1	62.4×	0.020	SOX18
negative regulation of DNA-templated transcription	1	31.6×	0.037	SOX18
positive regulation of DNA-templated transcription	1	27.9×	0.039	SOX18
negative regulation of transcription by RNA polymerase II	1	17.7×	0.059	SOX18
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	SOX18

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
SOX18	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
SOX18	11	Binding:11

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	SOX18

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)
SOX18	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.