Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

Summary

Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome (MONDO:0008915) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 194
• Phenotypes (HPO): 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

7 HPO clinical features (Orphanet curated; top 7 by frequency):

HPO ID	Term	Frequency
HP:0000147	Polycystic ovaries	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0000815	Hypergonadotropic hypogonadism	Very frequent (80-99%)
HP:0000826	Precocious puberty	Very frequent (80-99%)
HP:0001644	Dilated cardiomyopathy	Very frequent (80-99%)
HP:0100362	Aplasia of the phalanges of the 3rd toe	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
Mondo ID	MONDO:0008915
OMIM	212112
Orphanet	2229
DOID	DOID:0111584
NCIT	C174217
SNOMED CT	719451006
UMLS	C0796031
MedGen	162901
GARD	0003373
Is cancer (heuristic)	no

Also known as: cardiogenital syndrome · dilated cardiomyopathy with hypergonadotropic hypogonadism · Malouf syndrome · Najjar syndrome

Data availability: 194 ClinVar variants · 1 GenCC gene-disease record · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › male reproductive system disorder › dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome

Related subtypes (25): benign male reproductive system neoplasm, hematocele of tunica vaginalis testis, male genital organ stricture, male genital organ vascular disease, penile disorder, testicular disorder, prostate disorder, epididymitis, hydrocele, male infertility, male genital tuberculosis, spermatocele, cryptorchidism, diphallia, postorgasmic illness syndrome, penoscrotal transposition, congenital bilateral absence of vas deferens, posterior hypospadias, isolated micropenis, male reproductive system neoplasm, fournier gangrene, congenital agenesis of the scrotum, scrotal disorder, congenital megaprepuce, epididymis disease

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

194 retrieved; paginated sample, class counts are floors:

98 uncertain significance, 56 conflicting classifications of pathogenicity, 17 likely benign, 7 pathogenic/likely pathogenic, 6 pathogenic, 6 benign/likely benign, 2 likely pathogenic, 1 benign, 1 uncertain significance/uncertain risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
14489	NM_170707.4(LMNA):c.1444C>T (p.Arg482Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14495	NM_170707.4(LMNA):c.1130G>A (p.Arg377His)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
14506	NM_170707.4(LMNA):c.169G>C (p.Ala57Pro)	LMNA	Pathogenic	no assertion criteria provided
1457399	NM_170707.4(LMNA):c.822del (p.Arg275fs)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18457	NM_170707.4(LMNA):c.176T>G (p.Leu59Arg)	LMNA	Pathogenic	no assertion criteria provided
200941	NM_170707.4(LMNA):c.768G>A (p.Val256=)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595598	NM_170707.4(LMNA):c.5del (p.Glu2fs)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
36473	NM_170707.4(LMNA):c.1003C>T (p.Arg335Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
48096	NM_170707.4(LMNA):c.961C>T (p.Arg321Ter)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
66762	NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66800	NM_170707.4(LMNA):c.1294C>T (p.Gln432Ter)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66853	NM_170707.4(LMNA):c.1608+1G>A	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
66931	NM_170707.4(LMNA):c.746G>A (p.Arg249Gln)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341358	NM_170707.4(LMNA):c.168C>G (p.Asn56Lys)	LMNA	Likely pathogenic	criteria provided, single submitter
1343751	NM_170707.4(LMNA):c.1646_1647del (p.Val549fs)	LMNA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
48078	NM_170707.4(LMNA):c.749C>T (p.Ala250Val)	LMNA	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1029259	NM_170707.4(LMNA):c.187A>C (p.Ile63Leu)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1284657	NM_170707.4(LMNA):c.1786_1800del (p.Asp596_Ala600del)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14486	NM_170707.4(LMNA):c.1445G>A (p.Arg482Gln)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14494	NM_170707.4(LMNA):c.1745G>A (p.Arg582His)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14498	NM_170707.4(LMNA):c.892C>T (p.Arg298Cys)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14499	NM_170707.4(LMNA):c.1580G>A (p.Arg527His)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14517	NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14519	NM_170707.4(LMNA):c.1195C>T (p.Arg399Cys)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14520	NM_170707.4(LMNA):c.1318G>A (p.Val440Met)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14527	NM_170707.4(LMNA):c.1930C>T (p.Arg644Cys)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1501721	NM_170707.4(LMNA):c.11C>A (p.Pro4Gln)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1518015	NM_170707.4(LMNA):c.244G>C (p.Glu82Gln)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161291	NM_170707.4(LMNA):c.1931G>A (p.Arg644His)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163878	NM_170707.4(LMNA):c.1634G>A (p.Arg545His)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · Orphanet: 21 · 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
LMNA	Definitive	Autosomal dominant	dilated cardiomyopathy 1A	40

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1

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
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.

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)
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf

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
mucosa of stomach	1
nipple	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMNA	P02545	28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Breakdown of the nuclear lamina	1	3806.7×	0.004	LMNA
Depolymerization of the Nuclear Lamina	1	761.3×	0.005	LMNA
Initiation of Nuclear Envelope (NE) Reformation	1	601.0×	0.005	LMNA
IRE1alpha activates chaperones	1	519.1×	0.005	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	519.1×	0.005	LMNA
Nuclear Envelope Breakdown	1	456.8×	0.005	LMNA
Unfolded Protein Response (UPR)	1	356.9×	0.006	LMNA
Oncogenic MAPK signaling	1	248.3×	0.008	LMNA
XBP1(S) activates chaperone genes	1	215.5×	0.008	LMNA
Signaling by BRAF and RAF1 fusions	1	170.4×	0.009	LMNA
Meiotic synapsis	1	141.0×	0.010	LMNA
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	LMNA
Cellular responses to stress	1	36.8×	0.031	LMNA
Cellular responses to stimuli	1	31.5×	0.034	LMNA
Disease	1	13.1×	0.076	LMNA

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
DNA double-strand break attachment to nuclear envelope	1	5617.3×	0.002	LMNA
establishment or maintenance of microtubule cytoskeleton polarity	1	4213.0×	0.002	LMNA
nuclear pore localization	1	3370.4×	0.002	LMNA
negative regulation of mesenchymal cell proliferation	1	2808.7×	0.002	LMNA
protein localization to nuclear envelope	1	2106.5×	0.002	LMNA
regulation of protein localization to nucleus	1	2106.5×	0.002	LMNA
negative regulation of cardiac muscle hypertrophy in response to stress	1	1872.4×	0.002	LMNA
ventricular cardiac muscle cell development	1	1532.0×	0.002	LMNA
nuclear envelope organization	1	991.3×	0.003	LMNA
regulation of telomere maintenance	1	842.6×	0.003	LMNA
negative regulation of release of cytochrome c from mitochondria	1	802.5×	0.003	LMNA
nuclear migration	1	732.7×	0.003	LMNA
double-strand break repair via nonhomologous end joining	1	421.3×	0.004	LMNA
negative regulation of extrinsic apoptotic signaling pathway	1	421.3×	0.004	LMNA
protein localization to nucleus	1	351.1×	0.005	LMNA
cellular senescence	1	295.6×	0.005	LMNA
heterochromatin formation	1	255.3×	0.006	LMNA
muscle organ development	1	166.8×	0.008	LMNA
regulation of cell migration	1	157.5×	0.008	LMNA
protein import into nucleus	1	144.0×	0.009	LMNA
regulation of protein stability	1	125.8×	0.009	LMNA
cellular response to hypoxia	1	121.2×	0.009	LMNA
intracellular protein localization	1	104.7×	0.010	LMNA
negative regulation of cell population proliferation	1	42.1×	0.025	LMNA
positive regulation of gene expression	1	38.7×	0.026	LMNA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LMNA	12	Binding:9, Functional:3

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

30 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)
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LMNA
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: 0.