Seckel syndrome 6

Summary

Seckel syndrome 6 (MONDO:0013871) is a disease caused by CEP63 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CEP63 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 19

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Seckel syndrome 6
Mondo ID	MONDO:0013871
OMIM	614728
DOID	DOID:0070006
UMLS	C3553582
MedGen	766496
GARD	0024958
Is cancer (heuristic)	no

Also known as: CEP63 Seckel syndrome · SCKL6 · Seckel syndrome 6 · Seckel syndrome caused by mutation in CEP63 · Seckel syndrome type 6

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

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Seckel syndrome › Seckel syndrome 6

Related subtypes (11): Seckel syndrome 1, intrauterine growth retardation with increased mitomycin c sensitivity, Seckel syndrome 2, Seckel syndrome 4, Seckel syndrome 5, Seckel syndrome 7, Seckel syndrome 8, microcephaly 13, primary, autosomal recessive, Seckel syndrome 9, Seckel syndrome 10, Seckel syndrome 11

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:

6 uncertain significance, 6 likely pathogenic, 3 conflicting classifications of pathogenicity, 2 pathogenic, 1 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
2581612	NM_001353108.3(CEP63):c.490C>T (p.Gln164Ter)	CEP63	Pathogenic	criteria provided, single submitter
35517	NM_001353108.3(CEP63):c.129G>A (p.Trp43Ter)	CEP63	Pathogenic	no assertion criteria provided
1120220	NM_001353108.3(CEP63):c.1125T>G (p.Tyr375Ter)	CEP63	Likely pathogenic	criteria provided, single submitter
1120221	NM_001353108.3(CEP63):c.595del (p.Glu199fs)	CEP63	Likely pathogenic	criteria provided, single submitter
225312	NM_001353108.3(CEP63):c.182_185dup (p.Lys62delinsAsnTer)	CEP63	Likely pathogenic	criteria provided, single submitter
2431057	NM_001353108.3(CEP63):c.1835del (p.Ser611_Leu612insTer)	CEP63	Likely pathogenic	criteria provided, single submitter
4845915	NM_001353108.3(CEP63):c.790-1G>A	CEP63	Likely pathogenic	criteria provided, single submitter
977835	NM_001353108.3(CEP63):c.790-2A>G	CEP63	Likely pathogenic	criteria provided, single submitter
1593774	NM_001353108.3(CEP63):c.1368A>G (p.Ala456=)	CEP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210698	NM_001353108.3(CEP63):c.1068-1G>A	CEP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210705	NM_001353108.3(CEP63):c.989_992del (p.Asp330fs)	CEP63	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030913	NM_001353108.3(CEP63):c.1657A>G (p.Lys553Glu)	CEP63	Uncertain significance	criteria provided, multiple submitters, no conflicts
2505567	NM_001353108.3(CEP63):c.790-11C>G	CEP63	Uncertain significance	criteria provided, single submitter
377098	NM_001353108.3(CEP63):c.668A>G (p.Asn223Ser)	CEP63	Uncertain significance	criteria provided, multiple submitters, no conflicts
434752	NM_001353108.3(CEP63):c.1973C>A (p.Pro658His)	CEP63	Uncertain significance	criteria provided, multiple submitters, no conflicts
434753	NM_001353108.3(CEP63):c.935G>A (p.Arg312Gln)	CEP63	Uncertain significance	criteria provided, multiple submitters, no conflicts
3898046	NM_000182.5(HADHA):c.2119G>C (p.Gly707Arg)	GAREM2	Uncertain significance	criteria provided, single submitter
1209686	NM_001042384.2(CEP63):c.1330-16A>G	CEP63	Benign	criteria provided, multiple submitters, no conflicts
3764490	NM_001353108.3(CEP63):c.1783del (p.Val595fs)	CEP63	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CEP63	Strong	Autosomal recessive	Seckel syndrome 6	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CEP63	Orphanet:808	Seckel 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
CEP63	HGNC:25815	ENSG00000182923	Q96MT8	Centrosomal protein of 63 kDa	gencc,clinvar
GAREM2	HGNC:27172	ENSG00000157833	Q75VX8	GRB2-associated and regulator of MAPK protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CEP63	Centrosomal protein of 63 kDa	Required for normal spindle assembly.
GAREM2	GRB2-associated and regulator of MAPK protein 2	Probable adapter protein that may provide a link between cell surface epidermal growth factor receptor and the MAPK/ERK signaling pathway.

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)
CEP63	Other/Unknown	no		CEP63/Deup1_N, CEP63/Deup1_CC
GAREM2	Other/Unknown	no		SAM/pointed_sf, CABIT_dom, GAREM

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
cortical plate	1
caudate nucleus	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CEP63	282	ubiquitous	marker	calcaneal tendon, colonic epithelium, cortical plate
GAREM2	187	ubiquitous	yes	ventricular zone, ganglionic eminence, caudate nucleus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CEP63	1,437
GAREM2	667

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CEP63	Q96MT8	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GAREM2	Q75VX8	61.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Centrosome maturation	1	253.8×	0.013	CEP63
Loss of Nlp from mitotic centrosomes	1	158.6×	0.013	CEP63
Loss of proteins required for interphase microtubule organization from the centrosome	1	158.6×	0.013	CEP63
AURKA Activation by TPX2	1	152.3×	0.013	CEP63
Recruitment of mitotic centrosome proteins and complexes	1	135.9×	0.013	CEP63
Regulation of PLK1 Activity at G2/M Transition	1	126.9×	0.013	CEP63
Mitotic G2-G2/M phases	1	126.9×	0.013	CEP63
G2/M Transition	1	126.9×	0.013	CEP63
Recruitment of NuMA to mitotic centrosomes	1	116.5×	0.013	CEP63
Anchoring of the basal body to the plasma membrane	1	113.1×	0.013	CEP63
Cilium Assembly	1	108.8×	0.013	CEP63
Mitotic Prometaphase	1	69.2×	0.017	CEP63
Organelle biogenesis and maintenance	1	66.0×	0.017	CEP63
M Phase	1	66.0×	0.017	CEP63
Cell Cycle, Mitotic	1	48.2×	0.022	CEP63
Cell Cycle	1	36.0×	0.028	CEP63

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
negative regulation of protein K63-linked ubiquitination	1	2106.5×	0.004	CEP63
de novo centriole assembly involved in multi-ciliated epithelial cell differentiation	1	1685.2×	0.004	CEP63
response to stress	1	1203.7×	0.004	GAREM2
signal transduction in response to DNA damage	1	401.2×	0.007	CEP63
centriole replication	1	366.4×	0.007	CEP63
neuron projection extension	1	263.3×	0.007	GAREM2
negative regulation of innate immune response	1	255.3×	0.007	CEP63
spindle assembly	1	221.7×	0.007	CEP63
DNA damage checkpoint signaling	1	195.9×	0.007	CEP63
cognition	1	142.8×	0.009	GAREM2
social behavior	1	135.9×	0.009	GAREM2
protein stabilization	1	33.4×	0.032	CEP63
cell division	1	23.1×	0.043	CEP63

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
CEP63	0	0
GAREM2	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	CEP63, GAREM2

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)
CEP63	0	—
GAREM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.