brachydactyly type E2

Summary

brachydactyly type E2 (MONDO:0013244) is a disease caused by PTHLH (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PTHLH (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	brachydactyly type E2
Mondo ID	MONDO:0013244
OMIM	613382
DOID	DOID:0110976
UMLS	C3150644
MedGen	461994
GARD	0015654
Is cancer (heuristic)	no

Also known as: BDE2 · brachydactyly type E caused by mutation in PTHLH · brachydactyly type E2 · brachydactyly, type E2 · PTHLH brachydactyly type E

Data availability: 11 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › brachydactyly › brachydactyly type E › brachydactyly type E2

Related subtypes (2): brachydactyly type E1, brachydactyly, type E, with atrial septal defect, type 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

11 retrieved; paginated sample, class counts are floors:

7 pathogenic, 3 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1192234	NM_198965.2(PTHLH):c.44T>G (p.Leu15Arg)	PTHLH	Pathogenic	criteria provided, single submitter
13738	NM_198965.2(PTHLH):c.179T>C (p.Leu60Pro)	PTHLH	Pathogenic	no assertion criteria provided
13739	NM_198965.2(PTHLH):c.131T>C (p.Leu44Pro)	PTHLH	Pathogenic	no assertion criteria provided
13740	NM_198965.2(PTHLH):c.534A>G (p.Ter178Trp)	PTHLH	Pathogenic	no assertion criteria provided
13741	NM_198965.2(PTHLH):c.358A>T (p.Lys120Ter)	PTHLH	Pathogenic	no assertion criteria provided
3362250	NM_198965.2(PTHLH):c.166C>T (p.Arg56Ter)	PTHLH	Pathogenic	criteria provided, single submitter
3894530	NM_198965.2(PTHLH):c.4C>T (p.Gln2Ter)	PTHLH	Pathogenic	criteria provided, single submitter
3256666	NM_198965.2(PTHLH):c.276dup (p.Val93fs)	PTHLH	Likely pathogenic	criteria provided, single submitter
3376415	NM_198965.2(PTHLH):c.54C>G (p.Tyr18Ter)	PTHLH	Likely pathogenic	criteria provided, single submitter
3382184	NM_198965.2(PTHLH):c.463_464del (p.Ser155fs)	PTHLH	Likely pathogenic	criteria provided, single submitter
1247849	NM_198965.2(PTHLH):c.-22-36A>T	PTHLH	Benign	criteria provided, multiple submitters, no conflicts

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
PTHLH	Definitive	Autosomal dominant	brachydactyly type E2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTHLH	Orphanet:93387	Brachydactyly type E

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
PTHLH	HGNC:9607	ENSG00000087494	P12272	Parathyroid hormone-related protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTHLH	Parathyroid hormone-related protein	Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport.

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)
PTHLH	Other/Unknown	no		PTH/PTH-rel, PTH-rel

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
periodontal ligament	1
primordial germ cell in gonad	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTHLH	202	broad	marker	periodontal ligament, primordial germ cell in gonad, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTHLH	1,599

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTHLH	P12272	11

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
Class B/2 (Secretin family receptors)	1	190.3×	0.011	PTHLH
G alpha (s) signalling events	1	73.2×	0.014	PTHLH

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
adenylate cyclase-activating G protein-coupled cAMP receptor signaling pathway	1	8426.0×	0.001	PTHLH
negative regulation of chondrocyte development	1	5617.3×	0.001	PTHLH
cAMP metabolic process	1	4213.0×	0.001	PTHLH
regulation of chondrocyte differentiation	1	1404.3×	0.003	PTHLH
osteoblast development	1	991.3×	0.003	PTHLH
negative regulation of chondrocyte differentiation	1	674.1×	0.004	PTHLH
bone mineralization	1	271.8×	0.008	PTHLH
female pregnancy	1	210.7×	0.008	PTHLH
epidermis development	1	210.7×	0.008	PTHLH
skeletal system development	1	125.8×	0.012	PTHLH
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	113.1×	0.012	PTHLH
regulation of gene expression	1	83.4×	0.015	PTHLH
cell-cell signaling	1	69.6×	0.017	PTHLH
negative regulation of cell population proliferation	1	42.1×	0.025	PTHLH
positive regulation of cell population proliferation	1	33.6×	0.030	PTHLH

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

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)
PTHLH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.