Lethal osteosclerotic bone dysplasia

Summary

Lethal osteosclerotic bone dysplasia (MONDO:0009821) is a disease caused by FAM20C (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FAM20C (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 53
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000270	Delayed cranial suture closure	Very frequent (80-99%)
HP:0000278	Retrognathia	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000457	Depressed nasal ridge	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0009099	Median cleft palate	Very frequent (80-99%)
HP:0000169	Gingival fibromatosis	Frequent (30-79%)
HP:0000212	Gingival overgrowth	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0009939	Mandibular aplasia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal osteosclerotic bone dysplasia
Mondo ID	MONDO:0009821
MeSH	C535282, C564916
OMIM	259660, 259775
Orphanet	1832
ICD-11	1306493470
UMLS	C1850106
MedGen	342416
GARD	0000282
Is cancer (heuristic)	no

Also known as: combination of microcephaly, exophthalmos, hypoplastic nose and midface, gum hyperplasia, cleft palate, apparently low-set ears, and osteosclerosis · lethal osteosclerotic bone dysplasia · osteomalacia, sclerosing, with cerebral calcification · osteosclerotic bone dysplasia, lethal · RAINE syndrome · Raine syndrome · RNS

Data availability: 53 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › neonatal osteosclerotic dysplasia › lethal osteosclerotic bone dysplasia

Related subtypes (4): Caffey disease, chondrodysplasia Blomstrand type, desmosterolosis, dysplastic cortical hyperostosis

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

53 retrieved; paginated sample, class counts are floors:

14 pathogenic, 13 benign, 12 uncertain significance, 6 conflicting classifications of pathogenicity, 4 benign/likely benign, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1023	NM_020223.4(FAM20C):c.1093G>C (p.Gly365Arg)	FAM20C	Pathogenic	no assertion criteria provided
1024	NM_020223.4(FAM20C):c.1163T>G (p.Leu388Arg)	FAM20C	Pathogenic	no assertion criteria provided
1026	NM_020223.4(FAM20C):c.957-3C>G	FAM20C	Pathogenic	no assertion criteria provided
1027	NM_020223.4(FAM20C):c.1136G>A (p.Gly379Glu)	FAM20C	Pathogenic	no assertion criteria provided
1028	NM_020223.4(FAM20C):c.1364-2A>G	FAM20C	Pathogenic	no assertion criteria provided
1029	NM_020223.4(FAM20C):c.956+5G>C	FAM20C	Pathogenic	no assertion criteria provided
1030	NM_020223.4(FAM20C):c.1446-1G>A	FAM20C	Pathogenic	no assertion criteria provided
1676667	NM_020223.4(FAM20C):c.1094G>A (p.Gly365Asp)	FAM20C	Pathogenic	no assertion criteria provided
1676668	NG_033970.2:g.(8164_21328)_(21408_56449)del	FAM20C	Pathogenic	no assertion criteria provided
2637599	NM_020223.4(FAM20C):c.474del (p.Ser159fs)	FAM20C	Pathogenic	criteria provided, single submitter
3061677	NM_020223.4(FAM20C):c.1445G>A (p.Gly482Glu)	FAM20C	Pathogenic	criteria provided, single submitter
30876	NM_020223.4(FAM20C):c.737T>A (p.Ile246Asn)	FAM20C	Pathogenic	no assertion criteria provided
30878	NM_020223.4(FAM20C):c.982C>T (p.Pro328Ser)	FAM20C	Pathogenic	no assertion criteria provided
4538529	NM_020223.4(FAM20C):c.307_308dup (p.Ser104fs)	FAM20C	Pathogenic	criteria provided, single submitter
3068037	NM_020223.4(FAM20C):c.1331T>G (p.Val444Gly)	FAM20C	Likely pathogenic	criteria provided, single submitter
30875	NM_020223.4(FAM20C):c.1351G>A (p.Asp451Asn)	FAM20C	Likely pathogenic	criteria provided, single submitter
4278334	NM_020223.4(FAM20C):c.1276T>C (p.Cys426Arg)	FAM20C	Likely pathogenic	criteria provided, single submitter
4538528	GRCh37/hg19 7p22.3(chr7:170366-229852)x1	FAM20C	Likely pathogenic	no assertion criteria provided
1625813	NM_020223.4(FAM20C):c.1072+53_1072+88del	FAM20C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1649913	NM_020223.4(FAM20C):c.600G>C (p.Pro200=)	FAM20C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2063547	NM_020223.4(FAM20C):c.608C>T (p.Pro203Leu)	FAM20C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289269	NM_020223.4(FAM20C):c.1228T>A (p.Ser410Thr)	FAM20C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3370792	NM_020223.4(FAM20C):c.1487C>T (p.Pro496Leu)	FAM20C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
720953	NM_020223.4(FAM20C):c.731C>T (p.Pro244Leu)	FAM20C	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1025	NM_020223.4(FAM20C):c.1645C>T (p.Arg549Trp)	FAM20C	Uncertain significance	criteria provided, single submitter
1045368	NM_020223.4(FAM20C):c.458G>A (p.Gly153Asp)	FAM20C	Uncertain significance	criteria provided, multiple submitters, no conflicts
1333203	NM_020223.4(FAM20C):c.838G>A (p.Gly280Arg)	FAM20C	Uncertain significance	criteria provided, single submitter
1369846	NM_020223.4(FAM20C):c.1651C>T (p.Arg551Cys)	FAM20C	Uncertain significance	criteria provided, multiple submitters, no conflicts
30877	NM_020223.4(FAM20C):c.796G>A (p.Gly266Arg)	FAM20C	Uncertain significance	criteria provided, single submitter
3594525	NM_020223.4(FAM20C):c.1330G>A (p.Val444Ile)	FAM20C	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
FAM20C	Definitive	Autosomal recessive	lethal osteosclerotic bone dysplasia	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FAM20C	Orphanet:1832	Osteosclerotic bone dysplasia

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
FAM20C	HGNC:22140	ENSG00000177706	Q8IXL6	Extracellular serine/threonine protein kinase FAM20C	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FAM20C	Extracellular serine/threonine protein kinase FAM20C	Golgi serine/threonine protein kinase that phosphorylates secretory pathway proteins within Ser-x-Glu/pSer motifs and plays a key role in biomineralization of bones and teeth.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAM20C	Other/Unknown	no		FAM20_C, FAM20

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
adult mammalian kidney	1
lower esophagus muscularis layer	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAM20C	134	ubiquitous	marker	right lobe of liver, adult mammalian kidney, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FAM20C	1,530

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAM20C	Q8IXL6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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
Post-translational protein phosphorylation	1	100.2×	0.012	FAM20C
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	FAM20C

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
regulation of phosphorus metabolic process	1	16852.0×	7e-04	FAM20C
osteoclast maturation	1	8426.0×	7e-04	FAM20C
regulation of fibroblast growth factor receptor signaling pathway	1	2407.4×	0.001	FAM20C
odontoblast differentiation	1	2106.5×	0.001	FAM20C
dentinogenesis	1	2106.5×	0.001	FAM20C
enamel mineralization	1	1203.7×	0.002	FAM20C
biomineral tissue development	1	648.1×	0.002	FAM20C
post-translational protein modification	1	421.3×	0.003	FAM20C
positive regulation of bone mineralization	1	391.9×	0.003	FAM20C
positive regulation of osteoblast differentiation	1	224.7×	0.005	FAM20C
protein phosphorylation	1	68.0×	0.015	FAM20C

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
FAM20C	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
FAM20C	2	Binding:2

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	FAM20C

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)
FAM20C	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.