Neonatal severe primary hyperparathyroidism

Summary

Neonatal severe primary hyperparathyroidism (MONDO:0009397) is a disease caused by CASR (GenCC Strong), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: CASR (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 280
• Phenotypes (HPO): 10
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000774	Narrow chest	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0100530	Abnormality of calcium-phosphate metabolism	Very frequent (80-99%)
HP:0000820	Abnormality of the thyroid gland	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0003355	Aminoaciduria	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neonatal severe primary hyperparathyroidism
Mondo ID	MONDO:0009397
MeSH	C563375
OMIM	239200
Orphanet	417
ICD-11	1929875111
NCIT	C131853
SNOMED CT	715218009
UMLS	C1832615
MedGen	331326
GARD	0002838
Is cancer (heuristic)	no

Also known as: hyperparathyroidism, neonatal · hyperparathyroidism, neonatal severe · neonatal severe hyperparathyroidism · NSHPT

Data availability: 280 ClinVar variants · 4 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › parathyroid gland disorder › hyperparathyroidism › primary hyperparathyroidism › familial primary hyperparathyroidism › neonatal severe primary hyperparathyroidism

Related subtypes (4): multiple endocrine neoplasia type 1, hyperparathyroidism 2 with jaw tumors, familial isolated hyperparathyroidism, hyperparathyroidism, primary, caused by water clear cell hyperplasia

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

280 retrieved; paginated sample, class counts are floors:

110 uncertain significance, 79 conflicting classifications of pathogenicity, 22 likely benign, 21 pathogenic, 17 pathogenic/likely pathogenic, 13 benign, 11 benign/likely benign, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066880	NM_000388.4(CASR):c.1525G>C (p.Gly509Arg)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1177515	NM_000388.4(CASR):c.209G>A (p.Trp70Ter)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
1475268	NM_000388.4(CASR):c.2495T>C (p.Phe832Ser)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1698608	NM_000388.4(CASR):c.2065G>A (p.Val689Met)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
237763	NM_000388.4(CASR):c.2039G>A (p.Arg680His)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280428	NM_000388.4(CASR):c.1630C>T (p.Arg544Ter)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
280657	NM_000388.4(CASR):c.108dup (p.Leu37fs)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
35787	NM_000388.4(CASR):c.206G>A (p.Arg69His)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372315	NM_000388.4(CASR):c.73C>T (p.Arg25Ter)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374153	NM_000388.4(CASR):c.2449G>A (p.Val817Ile)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
379931	NM_000388.4(CASR):c.2405A>G (p.Asn802Ser)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
410347	NM_000388.4(CASR):c.2038C>T (p.Arg680Cys)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
431804	NM_000388.4(CASR):c.658C>T (p.Arg220Trp)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4687113	NM_000388.4(CASR):c.490C>T (p.Gln164Ter)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
4687520	NM_000388.4(CASR):c.1031_1034delinsT (p.His344_Asn345delinsLeu)	CASR	Pathogenic	criteria provided, single submitter
4847861	NM_000388.4(CASR):c.2260C>T (p.Gln754Ter)	CASR	Pathogenic	criteria provided, single submitter
532618	NM_000388.4(CASR):c.679C>T (p.Arg227Ter)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
60667	NM_000388.4(CASR):c.662C>T (p.Pro221Leu)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
8313	NM_000388.4(CASR):c.889G>A (p.Glu297Lys)	CASR	Pathogenic	criteria provided, single submitter
8314	NM_000388.4(CASR):c.554G>A (p.Arg185Gln)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
8315	NM_000388.4(CASR):c.380A>C (p.Glu127Ala)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
8316	NM_000388.4:c.2628_2629insAlu	CASR	Pathogenic	no assertion criteria provided
8317	NM_000388.4(CASR):c.680G>T (p.Arg227Leu)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
8318	NM_000388.4(CASR):c.1745G>A (p.Cys582Tyr)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts
8319	NM_000388.4(CASR):c.2241_2242delinsT (p.Pro748fs)	CASR	Pathogenic	no assertion criteria provided
8329	NM_000388.4(CASR):c.2009G>A (p.Gly670Glu)	CASR	Pathogenic	no assertion criteria provided
8331	NM_000388.4(CASR):c.680G>A (p.Arg227Gln)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8332	NM_000388.4(CASR):c.413C>T (p.Thr138Met)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8335	NM_000388.4(CASR):c.196C>T (p.Arg66Cys)	CASR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8341	NM_000388.4(CASR):c.1942C>T (p.Arg648Ter)	CASR	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 6 · 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
CASR	Strong	Autosomal dominant	neonatal severe primary hyperparathyroidism	11
TRPV6	Strong	Autosomal recessive	hyperparathyroidism, transient neonatal	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CASR	Orphanet:417	Neonatal severe primary hyperparathyroidism
CASR	Orphanet:428	Autosomal dominant hypocalcemia
CASR	Orphanet:676	Autosomal dominant hereditary chronic pancreatitis
CASR	Orphanet:93372	Familial hypocalciuric hypercalcemia type 1
TRPV6	Orphanet:417	Neonatal severe primary hyperparathyroidism
TRPV6	Orphanet:676	Autosomal dominant hereditary chronic pancreatitis

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
CASR	HGNC:1514	ENSG00000036828	P41180	Extracellular calcium-sensing receptor	gencc,clinvar
TRPV6	HGNC:14006	ENSG00000165125	Q9H1D0	Transient receptor potential cation channel subfamily V member 6	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CASR	Extracellular calcium-sensing receptor	G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis.
TRPV6	Transient receptor potential cation channel subfamily V member 6	Calcium selective cation channel that mediates Ca(2+) uptake in various tissues, including the intestine.

Protein-family classification

Druggable: 2 · 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
Ion channel	1	55.8×	0.036
GPCR	1	12.0×	0.082

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CASR	GPCR	yes		GPCR_3_Ca_sens_rcpt-rel, GPCR_3, ANF_lig-bd_rcpt
TRPV6	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TRPV5/TRPV6

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
hair follicle	1
islet of Langerhans	1
body of pancreas	1
duodenum	1
pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CASR	63	tissue_specific	marker	islet of Langerhans, diaphragm, hair follicle
TRPV6	125	tissue_specific	marker	body of pancreas, pancreas, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASR	2,692
TRPV6	1,197

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASR	P41180	31
TRPV6	Q9H1D0	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TRP channels	1	203.9×	0.027	TRPV6
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	146.4×	0.027	CASR
GPCR ligand binding	1	32.1×	0.058	CASR
G alpha (q) signalling events	1	28.7×	0.058	CASR
GPCR downstream signalling	1	21.7×	0.058	CASR
Signaling by GPCR	1	20.0×	0.058	CASR
G alpha (i) signalling events	1	19.5×	0.058	CASR
Signal Transduction	1	5.1×	0.187	CASR

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
parathyroid hormone secretion	1	4213.0×	0.005	TRPV6
regulation of presynaptic membrane potential	1	4213.0×	0.005	CASR
chemosensory behavior	1	1685.2×	0.006	CASR
bile acid secretion	1	1685.2×	0.006	CASR
response to fibroblast growth factor	1	1053.2×	0.006	CASR
fat pad development	1	842.6×	0.006	CASR
cellular response to peptide	1	842.6×	0.006	CASR
cellular response to vitamin D	1	766.0×	0.006	CASR
positive regulation of positive chemotaxis	1	702.2×	0.006	CASR
detection of calcium ion	1	561.7×	0.006	CASR
cellular response to hepatocyte growth factor stimulus	1	561.7×	0.006	CASR
regulation of calcium ion-dependent exocytosis	1	468.1×	0.006	TRPV6
positive regulation of calcium ion import	1	468.1×	0.006	CASR
cellular response to low-density lipoprotein particle stimulus	1	443.5×	0.006	CASR
regulation of calcium ion transport	1	401.2×	0.006	CASR
branching morphogenesis of an epithelial tube	1	366.4×	0.007	CASR
positive regulation of vasoconstriction	1	300.9×	0.007	CASR
positive regulation of NLRP3 inflammasome complex assembly	1	290.6×	0.007	CASR
calcium ion import across plasma membrane	1	271.8×	0.008	TRPV6
calcium ion homeostasis	1	221.7×	0.009	TRPV6
vasodilation	1	183.2×	0.010	CASR
response to calcium ion	1	159.0×	0.011	TRPV6
JNK cascade	1	135.9×	0.012	CASR
cellular response to glucose stimulus	1	133.8×	0.012	CASR
positive regulation of insulin secretion	1	127.7×	0.012	CASR
response to ischemia	1	125.8×	0.012	CASR
chloride transmembrane transport	1	118.7×	0.012	CASR
ossification	1	113.9×	0.012	CASR
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1	109.4×	0.012	CASR
calcium ion transmembrane transport	1	105.3×	0.012	TRPV6

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CASR	CINACALCET HYDROCHLORIDE
TRPV6	ECONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASR	10	4
TRPV6	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CINACALCET HYDROCHLORIDE	4	CASR
CINACALCET	4	CASR
ECONAZOLE	4	TRPV6
ENCALERET	3	CASR
EVOCALCET	3	CASR
SB-423562	2	CASR
RONACALERET	2	CASR
TECALCET HYDROCHLORIDE	2	CASR
FENDILINE	2	CASR
TECALCET	2	CASR
TETRAHYDROCANNABIVARIN	2	TRPV6
ATF-936	1	CASR
SOR-C13	1	TRPV6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CASR	45	Functional:32, Binding:13
TRPV6	32	Binding:32

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

13 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.

Compound	Max phase	Cohort target (bioactivity)
CINACALCET HYDROCHLORIDE	4	CASR
CINACALCET	4	CASR
ECONAZOLE	4	TRPV6
ENCALERET	3	CASR
EVOCALCET	3	CASR
SB-423562	2	CASR
RONACALERET	2	CASR
TECALCET HYDROCHLORIDE	2	CASR
FENDILINE	2	CASR
TECALCET	2	CASR
TETRAHYDROCANNABIVARIN	2	TRPV6
ATF-936	1	CASR
SOR-C13	1	TRPV6

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CASR, TRPV6
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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns