Osteocraniostenosis

Summary

Osteocraniostenosis (MONDO:0011215) is a disease caused by FAM111A (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FAM111A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	osteocraniostenosis
Mondo ID	MONDO:0011215
MeSH	C537291
OMIM	602361
Orphanet	2763
ICD-11	539409723
SNOMED CT	722109008
UMLS	C1865639
MedGen	356331
GARD	0003396
Is cancer (heuristic)	no

Also known as: GCLEB · gracile bone dysplasia · Osteocraniosplenic syndrome · osteocraniostenosis · skeletal dysplasia lethal with gracile bones

Data availability: 14 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 › skeletal dysplasia › primordial dwarfism and slender bone disorder › osteocraniostenosis

Related subtypes (25): microcephalic osteodysplastic primordial dwarfism type II, Lowry-Wood syndrome, Hallermann-Streiff syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, microcephalic primordial dwarfism, Toriello type, 3M syndrome 1, Seckel syndrome 2, 3M syndrome 2, Seckel syndrome 5, 3M syndrome 3, IMAGe syndrome, short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome, microcephalic primordial dwarfism, Alazami type, Rothmund-Thomson syndrome type 3, Seckel syndrome 8, microcephaly 13, primary, autosomal recessive, short stature, microcephaly, and endocrine dysfunction, Roifman syndrome, Seckel syndrome 9, Seckel syndrome 10, Kenny-Caffey syndrome, microcephalic osteodysplastic primordial dwarfism types I and III, microcephalic primordial dwarfism due to RTTN deficiency, microcephalic osteodysplastic dysplasia, Saul-Wilson type, intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

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

14 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 4 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic, 1 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
56810	NM_001312909.2(FAM111A):c.1706G>A (p.Arg569His)	FAM111A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56811	NM_001312909.2(FAM111A):c.1020TTC[2] (p.Ser343del)	FAM111A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
56813	NM_001312909.2(FAM111A):c.1583A>G (p.Asp528Gly)	FAM111A	Pathogenic/Likely pathogenic	no assertion criteria provided
56815	NM_001312909.2(FAM111A):c.1579C>A (p.Pro527Thr)	FAM111A	Pathogenic	criteria provided, single submitter
56814	NM_001312909.2(FAM111A):c.1012A>G (p.Thr338Ala)	LOC130005740	Pathogenic/Likely pathogenic	no assertion criteria provided
982416	NM_001312909.2(FAM111A):c.931A>T (p.Ile311Phe)	FAM111A	Likely pathogenic	criteria provided, single submitter
2311301	NM_001312909.2(FAM111A):c.873_874del (p.Leu292fs)	FAM111A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031325	NM_001312909.2(FAM111A):c.1818G>A (p.Met606Ile)	FAM111A	Uncertain significance	criteria provided, single submitter
1031326	NM_001312909.2(FAM111A):c.533C>T (p.Ser178Leu)	FAM111A	Uncertain significance	criteria provided, single submitter
1937870	NM_001312909.2(FAM111A):c.377T>C (p.Met126Thr)	FAM111A	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891676	NM_001312909.2(FAM111A):c.860G>T (p.Arg287Ile)	FAM111A	Uncertain significance	criteria provided, single submitter
4277390	NM_001312909.2(FAM111A):c.1622C>T (p.Ser541Phe)	FAM111A	Uncertain significance	criteria provided, single submitter
930855	NM_001312909.2(FAM111A):c.1138A>G (p.Ile380Val)	FAM111A	Uncertain significance	criteria provided, single submitter
708105	NM_001312909.2(FAM111A):c.1758G>A (p.Lys586=)	FAM111A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
FAM111A	Strong	Autosomal dominant	osteocraniostenosis	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FAM111A	Orphanet:2763	Osteocraniostenosis
FAM111A	Orphanet:93325	Autosomal dominant Kenny-Caffey 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
FAM111A	HGNC:24725	ENSG00000166801	Q96PZ2	Serine protease FAM111A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FAM111A	Serine protease FAM111A	Single-stranded DNA-binding serine protease that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAM111A	Protease	yes		Peptidase_S1_PA,

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
granulocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAM111A	267	ubiquitous	marker	monocyte, mononuclear cell, granulocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FAM111A	926

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAM111A	Q96PZ2	2

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
protein-DNA covalent cross-linking repair	1	1685.2×	0.004	FAM111A
protein autoprocessing	1	648.1×	0.005	FAM111A
replication fork processing	1	421.3×	0.005	FAM111A
negative regulation of viral genome replication	1	374.5×	0.005	FAM111A
DNA replication	1	165.2×	0.008	FAM111A
DNA damage response	1	53.5×	0.022	FAM111A
proteolysis	1	34.2×	0.029	FAM111A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
FAM111A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	FAM111A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
FAM111A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.