Familial primary hypomagnesemia with normocalciuria and normocalcemia

Summary

Familial primary hypomagnesemia with normocalciuria and normocalcemia (MONDO:0018101) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial primary hypomagnesemia with normocalciuria and normocalcemia
Mondo ID	MONDO:0018101
Orphanet	34527
SNOMED CT	725031005
UMLS	C4510731
MedGen	1390277
GARD	0025127
Is cancer (heuristic)	no

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › familial primary hypomagnesemia › familial primary hypomagnesemia with normocalcuria › familial primary hypomagnesemia with normocalciuria and normocalcemia

Related subtypes (2): intestinal hypomagnesemia 1, isolated autosomal dominant hypomagnesemia, Glaudemans type

Subtypes (3): renal hypomagnesemia 4, renal hypomagnesemia 6, hypomagnesemia, seizures, and intellectual disability

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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
CNNM2	Definitive	Semidominant	hypomagnesemia, seizures, and intellectual disability 1	7
EGF	Supportive	Autosomal dominant	familial primary hypomagnesemia with normocalciuria and normocalcemia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CNNM2	Orphanet:620363	Primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome
EGF	Orphanet:210159	Adult hepatocellular carcinoma
EGF	Orphanet:620368	EGF-related primary hypomagnesemia with intellectual disability

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
CNNM2	HGNC:103	ENSG00000148842	Q9H8M5	Metal transporter CNNM2	gencc
EGF	HGNC:3229	ENSG00000138798	P01133	Pro-epidermal growth factor	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CNNM2	Metal transporter CNNM2	Divalent metal cation transporter.
EGF	Pro-epidermal growth factor	EGF stimulates the growth of various epidermal and epithelial tissues in vivo and in vitro and of some fibroblasts in cell culture.

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)
CNNM2	Other/Unknown	no		CBS_dom, CNNM, RmlC-like_jellyroll
EGF	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF

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
oocyte	1
right adrenal gland	1
secondary oocyte	1
body of pancreas	1
hindlimb stylopod muscle	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CNNM2	234	ubiquitous	marker	secondary oocyte, oocyte, right adrenal gland
EGF	215	broad	marker	renal medulla, body of pancreas, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EGF	8,267
CNNM2	1,230

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EGF	P01133	13
CNNM2	Q9H8M5	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. 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
PLCG1 events in ERBB2 signaling	1	2855.0×	0.004	EGF
Inhibition of Signaling by Overexpressed EGFR	1	1268.9×	0.004	EGF
EGFR interacts with phospholipase C-gamma	1	1142.0×	0.004	EGF
NFE2L2 regulating tumorigenic genes	1	951.7×	0.004	EGF
ERBB2 Activates PTK6 Signaling	1	815.7×	0.004	EGF
GRB2 events in EGFR signaling	1	761.3×	0.004	EGF
SHC1 events in EGFR signaling	1	713.8×	0.004	EGF
Constitutive Signaling by EGFRvIII	1	713.8×	0.004	EGF
ERBB2 Regulates Cell Motility	1	713.8×	0.004	EGF
PI3K events in ERBB2 signaling	1	671.8×	0.004	EGF
Signaling by ERBB2 ECD mutants	1	671.8×	0.004	EGF
GAB1 signalosome	1	634.4×	0.004	EGF
GRB2 events in ERBB2 signaling	1	634.4×	0.004	EGF
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	601.0×	0.004	EGF
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	571.0×	0.004	EGF
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	543.8×	0.004	EGF
SHC1 events in ERBB2 signaling	1	475.8×	0.004	EGF
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.004	EGF
Signaling by ERBB2 TMD/JMD mutants	1	475.8×	0.004	EGF
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	456.8×	0.004	EGF
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	439.2×	0.004	EGF
Signaling by ERBB2 KD Mutants	1	423.0×	0.004	EGF
Downregulation of ERBB2 signaling	1	380.7×	0.004	EGF
Signaling by ERBB2	1	346.1×	0.004	EGF
EGFR downregulation	1	346.1×	0.004	EGF
Signaling by EGFR	1	326.3×	0.004	EGF
Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin	1	278.5×	0.005	EGF
Signaling by ERBB4	1	271.9×	0.005	EGF
Extra-nuclear estrogen signaling	1	170.4×	0.007	EGF
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.009	EGF

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
positive regulation of hyaluronan biosynthetic process	1	2106.5×	0.004	EGF
positive regulation of cerebellar granule cell precursor proliferation	1	1685.2×	0.004	EGF
negative regulation of secretion	1	1685.2×	0.004	EGF
negative regulation of cholesterol efflux	1	1404.3×	0.004	EGF
positive regulation of epithelial tube formation	1	1404.3×	0.004	EGF
regulation of calcium ion import	1	1053.2×	0.004	EGF
positive regulation of peptidyl-threonine phosphorylation	1	936.2×	0.004	EGF
magnesium ion homeostasis	1	936.2×	0.004	CNNM2
ubiquitin-dependent endocytosis	1	936.2×	0.004	EGF
ERBB2-EGFR signaling pathway	1	842.6×	0.004	EGF
positive regulation of protein localization to early endosome	1	842.6×	0.004	EGF
regulation of protein localization to cell surface	1	842.6×	0.004	EGF
cerebellar granule cell precursor proliferation	1	766.0×	0.004	EGF
regulation of receptor signaling pathway via JAK-STAT	1	702.2×	0.004	EGF
positive regulation of DNA binding	1	601.9×	0.004	EGF
mammary gland alveolus development	1	495.6×	0.005	EGF
positive regulation of phosphorylation	1	421.3×	0.005	EGF
negative regulation of epidermal growth factor receptor signaling pathway	1	383.0×	0.005	EGF
branching morphogenesis of an epithelial tube	1	366.4×	0.005	EGF
positive regulation of receptor internalization	1	351.1×	0.005	EGF
positive regulation of ubiquitin-dependent protein catabolic process	1	280.9×	0.006	EGF
positive regulation of mitotic nuclear division	1	271.8×	0.006	EGF
ERK1 and ERK2 cascade	1	159.0×	0.010	EGF
epithelial cell proliferation	1	156.0×	0.010	EGF
positive regulation of endothelial cell migration	1	125.8×	0.011	EGF
epidermal growth factor receptor signaling pathway	1	123.9×	0.011	EGF
positive regulation of endothelial cell proliferation	1	115.4×	0.012	EGF
positive regulation of canonical Wnt signaling pathway	1	77.3×	0.017	EGF
positive regulation of MAPK cascade	1	40.3×	0.031	EGF
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	39.2×	0.031	EGF

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CNNM2	0	0
EGF	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
EGF	5	Binding:5

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	CNNM2, EGF

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)
CNNM2	0	—
EGF	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.