Cardiomyopathy-hypotonia-lactic acidosis syndrome

Summary

Cardiomyopathy-hypotonia-lactic acidosis syndrome (MONDO:0012557) is a disease caused by SLC25A3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC25A3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 39
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001639	Hypertrophic cardiomyopathy	Very frequent (80-99%)
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0002151	Increased circulating lactate concentration	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0012103	Abnormality of the mitochondrion	Very frequent (80-99%)
HP:0000961	Cyanosis	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0009805	Low-output congestive heart failure	Frequent (30-79%)
HP:0002098	Respiratory distress	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiomyopathy-hypotonia-lactic acidosis syndrome
Mondo ID	MONDO:0012557
MeSH	C563665
OMIM	610773
Orphanet	91130
SNOMED CT	718713000
UMLS	C1835845
MedGen	324373
GARD	0016795
Is cancer (heuristic)	no

Also known as: hypertrophic cardiomyopathy with hypotonia and lactic acidosis syndrome

Data availability: 39 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › cardiomyopathy-hypotonia-lactic acidosis syndrome

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

39 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 5 benign, 5 conflicting classifications of pathogenicity, 3 pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
215165	NM_002635.4(SLC25A3):c.158-303A>G	SLC25A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9149	NM_005888.4(SLC25A3):c.215G>A (p.Gly72Glu)	SLC25A3	Pathogenic	no assertion criteria provided
977463	NM_002635.4(SLC25A3):c.883_895delinsCAGATAC (p.Gly295_Ser299delinsGlnIlePro)	SLC25A3	Pathogenic	no assertion criteria provided
977465	NM_002635.4(SLC25A3):c.596T>G (p.Leu199Trp)	SLC25A3	Pathogenic	no assertion criteria provided
310803	NM_002635.4(SLC25A3):c.858G>T (p.Val286=)	SLC25A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
508848	NM_002635.4(SLC25A3):c.147C>A (p.Ala49=)	SLC25A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880645	NM_002635.4(SLC25A3):c.61C>T (p.Leu21=)	SLC25A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880646	NM_002635.4(SLC25A3):c.75T>C (p.Gly25=)	SLC25A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
880647	NM_002635.4(SLC25A3):c.312C>T (p.Asn104=)	SLC25A3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2435997	NM_002635.4(SLC25A3):c.544A>G (p.Met182Val)	SLC25A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
310790	NM_005888.3(SLC25A3):c.-120G>C	SLC25A3	Uncertain significance	criteria provided, single submitter
310794	NM_005888.3(SLC25A3):c.-61G>T	SLC25A3	Uncertain significance	criteria provided, single submitter
310795	NM_002635.4(SLC25A3):c.-38C>T	SLC25A3	Uncertain significance	criteria provided, single submitter
310796	NM_002635.4(SLC25A3):c.-4-7C>T	SLC25A3	Uncertain significance	criteria provided, single submitter
310797	NM_002635.4(SLC25A3):c.4T>C (p.Phe2Leu)	SLC25A3	Uncertain significance	criteria provided, single submitter
310799	NM_002635.4(SLC25A3):c.715C>T (p.Arg239Cys)	SLC25A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
310800	NM_002635.4(SLC25A3):c.814+4C>T	SLC25A3	Uncertain significance	criteria provided, single submitter
310801	NM_002635.4(SLC25A3):c.814+5G>T	SLC25A3	Uncertain significance	criteria provided, multiple submitters, no conflicts
310804	NM_002635.4(SLC25A3):c.*94T>C	SLC25A3	Uncertain significance	criteria provided, single submitter
310808	NM_002635.4(SLC25A3):c.*255T>G	SLC25A3	Uncertain significance	criteria provided, single submitter
310810	NM_002635.4(SLC25A3):c.*411T>C	SLC25A3	Uncertain significance	criteria provided, single submitter
3892455	NM_002635.4(SLC25A3):c.34A>C (p.Asn12His)	SLC25A3	Uncertain significance	criteria provided, single submitter
882065	NM_002635.4(SLC25A3):c.648C>T (p.Tyr216=)	SLC25A3	Uncertain significance	criteria provided, single submitter
882066	NM_002635.4(SLC25A3):c.666C>G (p.Leu222=)	SLC25A3	Uncertain significance	criteria provided, single submitter
883212	NM_002635.4(SLC25A3):c.1020A>G (p.Arg340=)	SLC25A3	Uncertain significance	criteria provided, single submitter
883213	NM_002635.4(SLC25A3):c.*254A>G	SLC25A3	Uncertain significance	criteria provided, single submitter
883214	NM_002635.4(SLC25A3):c.*296G>T	SLC25A3	Uncertain significance	criteria provided, single submitter
883934	NM_005888.3(SLC25A3):c.-69G>A	SLC25A3	Uncertain significance	criteria provided, single submitter
884003	NM_002635.4(SLC25A3):c.*316A>G	SLC25A3	Uncertain significance	criteria provided, single submitter
884004	NM_002635.4(SLC25A3):c.*429C>G	SLC25A3	Uncertain significance	criteria provided, single submitter

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
SLC25A3	Strong	Autosomal recessive	cardiomyopathy-hypotonia-lactic acidosis syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A3	Orphanet:91130	Cardiomyopathy-hypotonia-lactic acidosis syndrome

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
SLC25A3	HGNC:10989	ENSG00000075415	Q00325	Solute carrier family 25 member 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A3	Solute carrier family 25 member 3	Inorganic ion transporter that transports phosphate or copper ions across the mitochondrial inner membrane into the matrix compartment.

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)
SLC25A3	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, SLC25A3/Pic2/Mir1-like

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
apex of heart	1
left ventricle myocardium	1
myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A3	306	ubiquitous	marker	left ventricle myocardium, apex of heart, myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A3	3,844

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A3	Q00325	80.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
mitochondrial phosphate ion transmembrane transport	1	16852.0×	1e-04	SLC25A3
phosphate ion transmembrane transport	1	1203.7×	8e-04	SLC25A3

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
SLC25A3	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
SLC25A3	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	SLC25A3

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)
SLC25A3	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.