Lipoic acid synthetase deficiency

Summary

Lipoic acid synthetase deficiency (MONDO:0013762) is a disease caused by LIAS (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LIAS (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 368

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lipoic acid synthetase deficiency
Mondo ID	MONDO:0013762
OMIM	614462
Orphanet	401859
UMLS	C3280887
MedGen	482517
GARD	0012678
Is cancer (heuristic)	no

Also known as: HGCLAS · PDHLD · pyruvate dehydrogenase lipoic acid synthetase deficiency

Data availability: 368 ClinVar variants · 6 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 › inherited lipoic acid biosynthesis defect › lipoic acid synthetase deficiency

Related subtypes (5): pyruvate dehydrogenase E3 deficiency, lipoyl transferase 1 deficiency, spasticity-ataxia-gait anomalies syndrome, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, fatal multiple mitochondrial dysfunctions syndrome

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

368 retrieved; paginated sample, class counts are floors:

174 uncertain significance, 143 likely benign, 18 pathogenic, 11 conflicting classifications of pathogenicity, 9 likely pathogenic, 6 benign, 6 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073123	NM_006859.4(LIAS):c.649C>T (p.Arg217Ter)	LIAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1076367	NM_006859.4(LIAS):c.100A>T (p.Lys34Ter)	LIAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1424012	NM_006859.4(LIAS):c.520del (p.Tyr174fs)	LIAS	Pathogenic	criteria provided, single submitter
1451689	NM_006859.4(LIAS):c.999dup (p.Val334fs)	LIAS	Pathogenic	criteria provided, single submitter
2005335	NM_006859.4(LIAS):c.130del (p.Asp44fs)	LIAS	Pathogenic	criteria provided, single submitter
2165560	NM_006859.4(LIAS):c.107dup (p.Glu37fs)	LIAS	Pathogenic	criteria provided, multiple submitters, no conflicts
224601	NM_006859.4(LIAS):c.475_477delinsAAA (p.Glu159Lys)	LIAS	Pathogenic	no assertion criteria provided
2796701	NM_006859.4(LIAS):c.480del (p.Tyr161fs)	LIAS	Pathogenic	criteria provided, single submitter
2838766	NM_006859.4(LIAS):c.280A>T (p.Lys94Ter)	LIAS	Pathogenic	criteria provided, single submitter
2850745	NM_006859.4(LIAS):c.367_389dup (p.Leu132fs)	LIAS	Pathogenic	criteria provided, single submitter
3678499	NM_006859.4(LIAS):c.328C>T (p.Arg110Ter)	LIAS	Pathogenic	criteria provided, single submitter
4808299	NM_006859.4(LIAS):c.109G>T (p.Glu37Ter)	LIAS	Pathogenic	criteria provided, single submitter
523916	NM_006859.4(LIAS):c.277del (p.Lys92_Leu93insTer)	LIAS	Pathogenic	criteria provided, multiple submitters, no conflicts
540088	NM_006859.4(LIAS):c.64dup (p.Cys22fs)	LIAS	Pathogenic	criteria provided, single submitter
540089	NM_006859.4(LIAS):c.363del (p.Glu122fs)	LIAS	Pathogenic	criteria provided, single submitter
936919	NM_006859.4(LIAS):c.664_665delinsTA (p.Ala222Ter)	LIAS	Pathogenic	criteria provided, single submitter
937476	NM_006859.4(LIAS):c.440dup (p.Thr148fs)	LIAS	Pathogenic	criteria provided, multiple submitters, no conflicts
940068	NM_006859.4(LIAS):c.212del (p.Gly71fs)	LIAS	Pathogenic	criteria provided, single submitter
951412	NM_006859.4(LIAS):c.266dup (p.Asn89fs)	LIAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1524663	NM_006859.4(LIAS):c.884-1G>A	LIAS	Likely pathogenic	criteria provided, single submitter
2814833	NM_006859.4(LIAS):c.218+1G>A	LIAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
379693	NM_006859.4(LIAS):c.954+1G>A	LIAS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4813729	NM_006859.4(LIAS):c.236G>A (p.Trp79Ter)	LIAS	Likely pathogenic	criteria provided, single submitter
4845692	NM_006859.4(LIAS):c.313-38_367del	LIAS	Likely pathogenic	criteria provided, single submitter
572236	NM_006859.4(LIAS):c.737+1G>A	LIAS	Likely pathogenic	criteria provided, single submitter
930324	NM_006859.4(LIAS):c.643del (p.Asp215fs)	LIAS	Likely pathogenic	criteria provided, single submitter
978713	NM_006859.4(LIAS):c.587C>A (p.Thr196Asn)	LIAS	Likely pathogenic	no assertion criteria provided
978714	NM_006859.4(LIAS):c.1063G>C (p.Ala355Pro)	LIAS	Likely pathogenic	no assertion criteria provided
1030164	NM_006859.4(LIAS):c.76A>G (p.Arg26Gly)	LIAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1080298	NM_006859.4(LIAS):c.46-5T>C	LIAS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
LIAS	Strong	Autosomal recessive	lipoic acid synthetase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LIAS	Orphanet:401859	Lipoic acid synthetase deficiency

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
LIAS	HGNC:16429	ENSG00000121897	O43766	Lipoyl synthase, mitochondrial	gencc,clinvar
KLB	HGNC:15527	ENSG00000134962	Q86Z14	Beta-klotho	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LIAS	Lipoyl synthase, mitochondrial	Catalyzes the radical-mediated insertion of two sulfur atoms into the C-6 and C-8 positions of the octanoyl moiety bound to the lipoyl domains of lipoate-dependent enzymes, thereby converting the octanoylated domains into lipoylated deriva…
KLB	Beta-klotho	Contributes to the transcriptional repression of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis.

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)
LIAS	Other/Unknown	no		Lipoyl_synth, Elp3/MiaA/NifB-like_rSAM, rSAM
KLB	Other/Unknown	no		Glyco_hydro_1, GH_hydrolase_sf

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
hindlimb stylopod muscle	1
muscle of leg	1
primordial germ cell in gonad	1
buccal mucosa cell	1
liver	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LIAS	258	ubiquitous	marker	primordial germ cell in gonad, hindlimb stylopod muscle, muscle of leg
KLB	146	broad	marker	sperm, buccal mucosa cell, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LIAS	1,735
KLB	1,139

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LIAS	O43766	5
KLB	Q86Z14	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 33. 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
betaKlotho-mediated ligand binding	1	1903.3×	0.008	KLB
Downstream signaling of activated FGFR4	1	1903.3×	0.008	KLB
IGF1R signaling cascade	1	713.8×	0.008	KLB
IRS-mediated signalling	1	519.1×	0.008	KLB
IRS-related events triggered by IGF1R	1	519.1×	0.008	KLB
Signaling by FGFR4	1	519.1×	0.008	KLB
Protein lipoylation	1	519.1×	0.008	LIAS
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	475.8×	0.008	KLB
Signaling by Insulin receptor	1	439.2×	0.008	KLB
FGFR4 ligand binding and activation	1	407.9×	0.008	KLB
Phospholipase C-mediated cascade; FGFR4	1	380.7×	0.008	KLB
Insulin receptor signalling cascade	1	335.9×	0.008	KLB
PI-3K cascade:FGFR4	1	285.5×	0.009	KLB
SHC-mediated cascade:FGFR4	1	271.9×	0.009	KLB
FRS-mediated FGFR4 signaling	1	248.3×	0.009	KLB
Negative regulation of FGFR4 signaling	1	203.9×	0.010	KLB
PI3K/AKT Signaling in Cancer	1	184.2×	0.011	KLB
Signaling by FGFR	1	173.0×	0.011	KLB
Negative regulation of the PI3K/AKT network	1	139.3×	0.012	KLB
PI3K Cascade	1	135.9×	0.012	KLB
MAPK1/MAPK3 signaling	1	65.6×	0.024	KLB
Constitutive Signaling by Aberrant PI3K in Cancer	1	63.4×	0.024	KLB
MAPK family signaling cascades	1	51.4×	0.028	KLB
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	48.4×	0.028	KLB
Intracellular signaling by second messengers	1	45.7×	0.029	KLB
PIP3 activates AKT signaling	1	33.4×	0.038	KLB
RAF/MAP kinase cascade	1	30.5×	0.040	KLB
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.041	KLB
Signaling by Receptor Tyrosine Kinases	1	25.8×	0.044	KLB
Post-translational protein modification	1	9.6×	0.112	LIAS

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
lipoate biosynthetic process	1	8426.0×	0.001	LIAS
positive regulation of MAPKKK cascade by fibroblast growth factor receptor signaling pathway	1	1404.3×	0.002	KLB
protein lipoylation	1	1203.7×	0.002	LIAS
neural tube closure	1	93.6×	0.021	LIAS
carbohydrate metabolic process	1	68.0×	0.021	KLB
response to oxidative stress	1	65.3×	0.021	LIAS
response to lipopolysaccharide	1	62.4×	0.021	LIAS
inflammatory response	1	18.9×	0.059	LIAS
positive regulation of cell population proliferation	1	16.8×	0.059	KLB

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
LIAS	0	0
KLB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	LIAS, KLB

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)
LIAS	0	—
KLB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.