Ritscher-Schinzel syndrome 4

Summary

Ritscher-Schinzel syndrome 4 (MONDO:0030331) is a disease caused by DPYSL5 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: DPYSL5 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Ritscher-Schinzel syndrome 4
Mondo ID	MONDO:0030331
OMIM	619435
UMLS	C5561939
MedGen	1794149
GARD	0025541
Is cancer (heuristic)	no

Also known as: Ritscher-Schinzel syndrome 4 · RTSC4

Data availability: 19 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › Ritscher-Schinzel syndrome › Ritscher-Schinzel syndrome 4

Related subtypes (3): Ritscher-Schinzel syndrome 1, Ritscher-Schinzel syndrome 2, Ritscher-Schinzel syndrome 3

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

19 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 2 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1184280	NM_020134.4(DPYSL5):c.121G>A (p.Glu41Lys)	DPYSL5	Pathogenic	criteria provided, multiple submitters, no conflicts
246520	NM_006415.4(SPTLC1):c.58G>T (p.Ala20Ser)	SPTLC1	Pathogenic	criteria provided, multiple submitters, no conflicts
3901970	NM_020134.4(DPYSL5):c.73G>A (p.Glu25Lys)	DPYSL5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2431728	NM_020134.4(DPYSL5):c.395T>C (p.Val132Ala)	DPYSL5	Uncertain significance	criteria provided, single submitter
2441716	NM_020134.4(DPYSL5):c.323C>T (p.Ser108Phe)	DPYSL5	Uncertain significance	criteria provided, single submitter
2582573	NM_020134.4(DPYSL5):c.-122G>T	DPYSL5	Uncertain significance	criteria provided, single submitter
2688970	NM_020134.4(DPYSL5):c.158C>G (p.Ala53Gly)	DPYSL5	Uncertain significance	criteria provided, single submitter
3068160	NM_020134.4(DPYSL5):c.1139A>G (p.Asn380Ser)	DPYSL5	Uncertain significance	criteria provided, single submitter
3257726	NM_020134.4(DPYSL5):c.692G>A (p.Arg231His)	DPYSL5	Uncertain significance	criteria provided, single submitter
3362820	NM_020134.4(DPYSL5):c.332A>C (p.Asp111Ala)	DPYSL5	Uncertain significance	criteria provided, single submitter
3382737	NM_020134.4(DPYSL5):c.625G>A (p.Gly209Arg)	DPYSL5	Uncertain significance	criteria provided, single submitter
3901969	NM_020134.4(DPYSL5):c.335C>T (p.Ala112Val)	DPYSL5	Uncertain significance	criteria provided, single submitter
4014776	NM_020134.4(DPYSL5):c.1069G>A (p.Val357Ile)	DPYSL5	Uncertain significance	criteria provided, multiple submitters, no conflicts
4292691	NM_020134.4(DPYSL5):c.133C>T (p.Pro45Ser)	DPYSL5	Uncertain significance	criteria provided, single submitter
4540431	NM_020134.4(DPYSL5):c.493G>T (p.Asp165Tyr)	DPYSL5	Uncertain significance	criteria provided, single submitter
4796477	NM_020134.4(DPYSL5):c.1652G>A (p.Arg551Gln)	DPYSL5	Uncertain significance	criteria provided, single submitter
4846780	NM_020134.4(DPYSL5):c.1196A>T (p.Asp399Val)	DPYSL5	Uncertain significance	criteria provided, single submitter
632587	NM_020134.4(DPYSL5):c.139G>A (p.Gly47Arg)	DPYSL5	Uncertain significance	criteria provided, single submitter
1330199	GRCh37/hg19 2p23.3(chr2:26860458-27346266)x1	EMILIN1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 5 · 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
DPYSL5	Strong	Autosomal dominant	Ritscher-Schinzel syndrome 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DPYSL5	Orphanet:528084	Non-specific syndromic intellectual disability
DPYSL5	Orphanet:7	3C syndrome
SPTLC1	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPTLC1	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
EMILIN1	Orphanet:485418	EMILIN-1-related connective tissue disease

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
DPYSL5	HGNC:20637	ENSG00000157851	Q9BPU6	Dihydropyrimidinase-related protein 5	gencc,clinvar
SPTLC1	HGNC:11277	ENSG00000090054	O15269	Serine palmitoyltransferase 1	clinvar
EMILIN1	HGNC:19880	ENSG00000138080	Q9Y6C2	EMILIN-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DPYSL5	Dihydropyrimidinase-related protein 5	Involved in the negative regulation of dendrite outgrowth.
SPTLC1	Serine palmitoyltransferase 1	Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-…
EMILIN1	EMILIN-1	Involved in elastic and collagen fibers formation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DPYSL5	Other/Unknown	no		Amidohydro-rel, Metal-dep_hydrolase_composite, Hydantoinase/dihydroPyrase
SPTLC1	Enzyme (other)	yes	2.3.1.50	Aminotransferase_I/II_large, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
EMILIN1	Other/Unknown	no		C1q_dom, Collagen, Tumour_necrosis_fac-like_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
ganglionic eminence	1
ventricular zone	1
epithelium of esophagus	1
esophagus squamous epithelium	1
oral cavity	1
body of uterus	1
left uterine tube	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DPYSL5	133	broad	marker	cortical plate, ganglionic eminence, ventricular zone
SPTLC1	300	ubiquitous	marker	esophagus squamous epithelium, oral cavity, epithelium of esophagus
EMILIN1	206	ubiquitous	marker	right coronary artery, body of uterus, left uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPTLC1	3,288
DPYSL5	1,690
EMILIN1	1,254

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPTLC1	O15269	17
DPYSL5	Q9BPU6	3
EMILIN1	Q9Y6C2	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
CRMPs in Sema3A signaling	1	211.5×	0.021	DPYSL5
Molecules associated with elastic fibres	1	102.9×	0.021	EMILIN1
Sphingolipid de novo biosynthesis	1	95.2×	0.021	SPTLC1
Sphingolipid metabolism	1	56.0×	0.027	SPTLC1
Metabolism of lipids	1	10.5×	0.111	SPTLC1
Metabolism	1	3.9×	0.237	SPTLC1

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
regulation of fat cell apoptotic process	1	5617.3×	0.004	SPTLC1
sphinganine biosynthetic process	1	2808.7×	0.004	SPTLC1
negative regulation of cell activation	1	2808.7×	0.004	EMILIN1
negative regulation of collagen fibril organization	1	2808.7×	0.004	EMILIN1
positive regulation of lipophagy	1	1123.5×	0.007	SPTLC1
negative regulation of macrophage migration	1	936.2×	0.007	EMILIN1
negative regulation of dendrite morphogenesis	1	624.1×	0.007	DPYSL5
positive regulation of defense response to bacterium	1	624.1×	0.007	EMILIN1
positive regulation of extracellular matrix assembly	1	624.1×	0.007	EMILIN1
elastic fiber assembly	1	510.7×	0.007	EMILIN1
sphingomyelin biosynthetic process	1	468.1×	0.007	SPTLC1
negative regulation of vascular endothelial growth factor receptor signaling pathway	1	432.1×	0.007	EMILIN1
negative regulation of vascular endothelial growth factor signaling pathway	1	432.1×	0.007	EMILIN1
positive regulation of platelet aggregation	1	432.1×	0.007	EMILIN1
positive regulation of blood coagulation	1	374.5×	0.007	EMILIN1
negative regulation of collagen biosynthetic process	1	374.5×	0.007	EMILIN1
sphingosine biosynthetic process	1	351.1×	0.007	SPTLC1
sphingolipid metabolic process	1	330.4×	0.007	SPTLC1
cell adhesion mediated by integrin	1	224.7×	0.009	EMILIN1
negative regulation of SMAD protein signal transduction	1	200.6×	0.010	EMILIN1
positive regulation of cell-substrate adhesion	1	165.2×	0.012	EMILIN1
aortic valve morphogenesis	1	144.0×	0.012	EMILIN1
ceramide biosynthetic process	1	140.4×	0.012	SPTLC1
sphingolipid biosynthetic process	1	119.5×	0.014	SPTLC1
regulation of blood pressure	1	73.9×	0.021	EMILIN1
negative regulation of ERK1 and ERK2 cascade	1	72.0×	0.021	EMILIN1
negative regulation of transforming growth factor beta receptor signaling pathway	1	57.9×	0.025	EMILIN1
negative regulation of angiogenesis	1	56.2×	0.025	EMILIN1
cell-matrix adhesion	1	54.5×	0.025	EMILIN1
regulation of cell population proliferation	1	38.5×	0.033	EMILIN1

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
DPYSL5	0	0
SPTLC1	0	0
EMILIN1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SPTLC1	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SPTLC1	2.3.1.50	serine C-palmitoyltransferase

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	1	SPTLC1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	DPYSL5, EMILIN1

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)
DPYSL5	0	—
SPTLC1	4	—
EMILIN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.