van Maldergem syndrome 1

Summary

van Maldergem syndrome 1 (MONDO:0011070) is a disease caused by DCHS1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: DCHS1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 78

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	van Maldergem syndrome 1
Mondo ID	MONDO:0011070
OMIM	601390
DOID	DOID:0080585
UMLS	C4551950
MedGen	1644627
GARD	0024770
Is cancer (heuristic)	no

Also known as: DCHS1 van Maldergem syndrome · van Maldergem syndrome 1 · van Maldergem syndrome caused by mutation in DCHS1 · Van Maldergem syndrome type 1 · VMLDS1

Data availability: 78 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › van Maldergem syndrome › van Maldergem syndrome 1

Related subtypes (1): van Maldergem 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

78 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 15 conflicting classifications of pathogenicity, 6 pathogenic, 6 benign, 3 likely pathogenic, 3 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1177398	NM_003737.4(DCHS1):c.2225T>A (p.Leu742Ter)	DCHS1	Pathogenic	criteria provided, single submitter
1188839	NM_003737.4(DCHS1):c.1964del (p.Phe655fs)	DCHS1	Pathogenic	no assertion criteria provided
2499546	NM_003737.4(DCHS1):c.163C>T (p.Gln55Ter)	DCHS1	Pathogenic	criteria provided, single submitter
88997	NM_003737.4(DCHS1):c.2503G>T (p.Gly835Ter)	DCHS1	Pathogenic	no assertion criteria provided
88998	NM_003737.4(DCHS1):c.2543del (p.Thr848fs)	DCHS1	Pathogenic	no assertion criteria provided
88999	NM_003737.4(DCHS1):c.7109A>T (p.Asn2370Ile)	DCHS1	Pathogenic	no assertion criteria provided
3237376	NM_003737.4:c.[6115G>A];[2597G>A]		Likely pathogenic	criteria provided, single submitter
1710069	NM_003737.4(DCHS1):c.2500C>T (p.Arg834Ter)	DCHS1	Likely pathogenic	criteria provided, single submitter
3377407	NM_003737.4(DCHS1):c.7204G>A (p.Asp2402Asn)	DCHS1	Likely pathogenic	criteria provided, single submitter
1028155	NM_003737.4(DCHS1):c.590C>T (p.Pro197Leu)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049154	NM_003737.4(DCHS1):c.1595C>T (p.Thr532Met)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1049586	NM_003737.4(DCHS1):c.3769A>G (p.Thr1257Ala)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1107906	NM_003737.4(DCHS1):c.8302C>T (p.Arg2768Cys)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1297585	NM_003737.4(DCHS1):c.8186A>T (p.His2729Leu)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1464387	NM_003737.4(DCHS1):c.6233G>A (p.Arg2078His)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1545746	NM_003737.4(DCHS1):c.6467T>A (p.Val2156Glu)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2069398	NM_003737.4(DCHS1):c.6189G>C (p.Glu2063Asp)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2895933	NM_003737.4(DCHS1):c.1282C>T (p.Arg428Trp)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289966	NM_003737.4(DCHS1):c.4072G>A (p.Glu1358Lys)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2985193	NM_003737.4(DCHS1):c.8612G>A (p.Arg2871Gln)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
426125	NM_003737.4(DCHS1):c.2699C>T (p.Thr900Met)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
437929	NM_003737.4(DCHS1):c.2382G>C (p.Gln794His)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451612	NM_003737.4(DCHS1):c.704G>A (p.Arg235Gln)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
977877	NM_003737.4(DCHS1):c.5972G>A (p.Arg1991His)	DCHS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028648	NM_003737.4(DCHS1):c.6956A>C (p.Gln2319Pro)	DCHS1	Uncertain significance	criteria provided, single submitter
1028649	NM_003737.4(DCHS1):c.868G>T (p.Val290Leu)	DCHS1	Uncertain significance	criteria provided, single submitter
1188838	NM_003737.4(DCHS1):c.2055T>G (p.Phe685Leu)	DCHS1	Uncertain significance	criteria provided, single submitter
1303837	NM_003737.4(DCHS1):c.5918G>A (p.Gly1973Asp)	DCHS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1363973	NM_003737.4(DCHS1):c.2932C>T (p.Arg978Cys)	DCHS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1391575	NM_003737.4(DCHS1):c.8449G>C (p.Ala2817Pro)	DCHS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
DCHS1	Strong	Autosomal recessive	van Maldergem syndrome 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DCHS1	Orphanet:314679	Cerebrofacioarticular syndrome
DCHS1	Orphanet:741	Familial mitral valve prolapse
FAT4	Orphanet:2136	Hennekam syndrome
FAT4	Orphanet:314679	Cerebrofacioarticular 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
DCHS1	HGNC:13681	ENSG00000166341	Q96JQ0	Protocadherin-16	gencc,clinvar
FAT4	HGNC:23109	ENSG00000196159	Q6V0I7	Protocadherin Fat 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DCHS1	Protocadherin-16	Calcium-dependent cell-adhesion protein.
FAT4	Protocadherin Fat 4	Cadherins are calcium-dependent cell adhesion proteins.

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)
DCHS1	Other/Unknown	no		Cadherin-like_dom, Cadherin-like_sf, Cadherin_CS
FAT4	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Laminin_G

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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	2
ganglionic eminence	1
tendon of biceps brachii	1
blood vessel layer	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DCHS1	259	broad	marker	tendon of biceps brachii, ganglionic eminence, cortical plate
FAT4	231	ubiquitous	marker	calcaneal tendon, cortical plate, blood vessel layer

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FAT4	1,932
DCHS1	1,356

Intra-cohort edges

A	B	Sources
DCHS1	FAT4	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DCHS1	Q96JQ0	2
FAT4	Q6V0I7	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hippo signaling	2	732.7×	4e-05	DCHS1, FAT4
heterophilic cell-cell adhesion	2	337.0×	1e-04	DCHS1, FAT4
neurogenesis	2	208.1×	2e-04	DCHS1, FAT4
homophilic cell-cell adhesion	2	140.4×	3e-04	DCHS1, FAT4
mitral valve formation	1	2808.7×	0.001	DCHS1
condensed mesenchymal cell proliferation	1	2808.7×	0.001	DCHS1
cell migration involved in endocardial cushion formation	1	2106.5×	0.001	DCHS1
septin cytoskeleton organization	1	2106.5×	0.001	DCHS1
ossification involved in bone maturation	1	702.2×	0.004	DCHS1
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	561.7×	0.004	DCHS1
post-anal tail morphogenesis	1	366.4×	0.006	DCHS1
neural tube development	1	263.3×	0.006	DCHS1
digestive tract development	1	263.3×	0.006	DCHS1
calcium-dependent cell-cell adhesion	1	240.7×	0.006	DCHS1
pattern specification process	1	234.1×	0.006	DCHS1
cochlea development	1	234.1×	0.006	DCHS1
cell-cell adhesion mediated by cadherin	1	205.5×	0.007	FAT4
branching involved in ureteric bud morphogenesis	1	183.2×	0.007	DCHS1
cerebral cortex development	1	102.8×	0.012	FAT4
epithelial cell differentiation	1	87.8×	0.014	FAT4
axonogenesis	1	80.2×	0.014	FAT4
protein localization to plasma membrane	1	54.4×	0.020	DCHS1
gene expression	1	39.9×	0.026	DCHS1
cell migration	1	30.8×	0.032	DCHS1

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
DCHS1	0	0
FAT4	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	DCHS1, FAT4

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)
DCHS1	0	—
FAT4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.