Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

Summary

Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome (MONDO:0014869) is a disease caused by LARS2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LARS2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Identifiers

Disease identifiers

Field	Value
Canonical name	hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
Mondo ID	MONDO:0014869
OMIM	617021
Orphanet	528091
UMLS	C4310761
MedGen	934728
GARD	0017966
Is cancer (heuristic)	no

Also known as: HLASA · hydrops, lactic acidosis, and sideroblastic anaemia · hydrops, lactic acidosis, and sideroblastic anemia

Data availability: 25 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

25 retrieved; paginated sample, class counts are floors:

8 likely pathogenic, 6 benign, 4 uncertain significance, 4 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
191173	NM_015340.4(LARS2):c.457A>C (p.Asn153His)	LARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
245613	NM_015340.4(LARS2):c.1289C>T (p.Ala430Val)	LARS2	Pathogenic	no assertion criteria provided
55871	NM_015340.4(LARS2):c.1565C>A (p.Thr522Asn)	LARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1252055	NM_015340.4(LARS2):c.2134C>T (p.Pro712Ser)	LARS2	Likely pathogenic	no assertion criteria provided
3382175	NM_015340.4(LARS2):c.620G>A (p.Trp207Ter)	LARS2	Likely pathogenic	criteria provided, single submitter
691519	NM_015340.4(LARS2):c.683G>A (p.Arg228His)	LARS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
691520	NM_015340.4(LARS2):c.1313A>G (p.Asp438Gly)	LARS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
691521	NM_015340.4(LARS2):c.388G>A (p.Ala130Thr)	LARS2	Likely pathogenic	criteria provided, single submitter
691522	NM_015340.4(LARS2):c.2099C>T (p.Thr700Ile)	LARS2	Likely pathogenic	criteria provided, single submitter
691523	NM_015340.4(LARS2):c.440A>C (p.Gln147Pro)	LARS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
691524	NM_015340.4(LARS2):c.1607C>T (p.Pro536Leu)	LARS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1031906	NM_015340.4(LARS2):c.944C>T (p.Ser315Leu)	LARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
505168	NM_015340.4(LARS2):c.2572C>A (p.Gln858Lys)	LARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
667121	NM_015340.4(LARS2):c.1178C>A (p.Ala393Asp)	LARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
869196	NM_015340.4(LARS2):c.1237G>A (p.Glu413Lys)	LARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031905	NM_015340.4(LARS2):c.317C>T (p.Thr106Ile)	LARS2	Uncertain significance	criteria provided, single submitter
1384523	NM_015340.4(LARS2):c.2540A>G (p.Asn847Ser)	LARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2054175	NM_015340.4(LARS2):c.1922G>A (p.Ser641Asn)	LARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
504796	NM_015340.4(LARS2):c.1814G>A (p.Arg605His)	LARS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
226691	NM_015340.4(LARS2):c.1053T>C (p.Leu351=)	LARS2	Benign	criteria provided, multiple submitters, no conflicts
226697	NM_015340.4(LARS2):c.1760+12T>C	LARS2	Benign	criteria provided, multiple submitters, no conflicts
226698	NM_015340.4(LARS2):c.1983G>A (p.Thr661=)	LARS2	Benign	criteria provided, multiple submitters, no conflicts
226700	NM_015340.4(LARS2):c.2169T>C (p.Ala723=)	LARS2	Benign	criteria provided, multiple submitters, no conflicts
226704	NM_015340.4(LARS2):c.2358A>G (p.Val786=)	LARS2	Benign	criteria provided, multiple submitters, no conflicts
226693	NM_015340.4(LARS2):c.1455G>A (p.Ala485=)	LARS2-AS1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
LARS2	Strong	Autosomal recessive	hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LARS2	Orphanet:528091	Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome
LARS2	Orphanet:642945	Perrault syndrome type 1
LARS2	Orphanet:642976	Perrault syndrome type 2

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LARS2	HGNC:17095	ENSG00000011376	Q15031	Leucine–tRNA ligase, mitochondrial	gencc,clinvar
LARS2-AS1	HGNC:40796	ENSG00000232455		LARS2 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LARS2	Leucine–tRNA ligase, mitochondrial	Catalyzes the attachment of leucine to its cognate tRNA.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LARS2	Enzyme (other)	yes	6.1.1.4	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Leu-tRNA-ligase
LARS2-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

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
adrenal tissue	1
oocyte	1
ventricular zone	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LARS2	285	ubiquitous	yes	ventricular zone, oocyte, adrenal tissue
LARS2-AS1	108	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LARS2	3,406
LARS2-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LARS2	Q15031	90.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Mitochondrial tRNA aminoacylation	1	519.1×	0.007	LARS2
tRNA Aminoacylation	1	285.5×	0.007	LARS2
Translation	1	62.1×	0.021	LARS2
Metabolism of proteins	1	12.4×	0.081	LARS2

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
leucyl-tRNA aminoacylation	1	8426.0×	4e-04	LARS2
tRNA aminoacylation for protein translation	1	842.6×	0.002	LARS2
mitochondrial translation	1	173.7×	0.006	LARS2

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
LARS2	0	0
LARS2-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LARS2	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LARS2	6.1.1.4	leucine-tRNA ligase

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	1	LARS2
E	Difficult family or no structure, no drug	1	LARS2-AS1

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)
LARS2	1	—
LARS2-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.