LIAS

protein-coding

lipoic acid synthetase, the group of Radical S-adenosylmethionine domain containing

Gene summary

The protein encoded by this gene belongs to the biotin and lipoic acid synthetases family. Localized in the mitochondrion, this iron-sulfur enzyme catalyzes the final step in the de novo pathway for the biosynthesis of lipoic acid, a potent antioxidant. The deficient expression of this enzyme has been linked to conditions such as diabetes, atherosclerosis and neonatal-onset epilepsy. Alternative splicing occurs at this locus, and several transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Aug 2020]

MANE transcript

NM_006859.4

Inheritance

ClinVar variants

P:36U:181B:78

Top phenotype

Hyperglycinemia, lactic acidosis, and seizures

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr4:39,459,004-39,485,109

External References & Databases

Ensembl (ENSG00000121897)

Transcript & Mutation Effects

hg38 • Region Span ~26.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *LIAS* and *LIAS*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 29, 2024. The *LIAS* gene encodes lipoic acid synthase, an enzyme important for the synthesis of lipoic acid, which is a cofactor of the pyruvate dehydrogenase complex (PDC) and other mitochondrial enzyme complexes [α-ketoglutarate dehydrogenase complex (KGDH), branched-chain α-keto acid dehydrogenase complex (BCDH), 2-oxoadipate dehydrogenase, and the glycine cleavage system (GCS)]. PDC catalyzes conversion of pyruvate into acetyl-CoA, thus is the link between glycolysis and the citric acid cycle. PDC deficiency leads to impaired energy metabolism. The *LIAS* gene was first reported in relation to autosomal recessive *LIAS*-related primary mitochondrial disease in 2011 (PMID: 22152680). *LIAS* has been associated with a single disease entity to date; hyperglycinemia, lactic acidosis, and seizures [OMIM# 614462]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *LIAS*-related primary mitochondrial disease. Of note, *LIAS* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on September 21, 2020 (SOP v7), with a final classification of Limited. This current curation for the association with *LIAS*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included nine unique variants (seven missense, one nonsense, one intronic variant impacting splicing) identified in six unrelated cases from five publications (PMIDs: 22152680, 24334290, 26108146, 28817111, 36680912). Onset is typically early in life and clinical features include LSS, seizures, myoclonic movements, cardiomyopathy, lactic acidosis, and non-ketotic hyperglycinemia. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), rescue studies in patient cells (PMID: 24334290), and an embryonic lethal mouse knockout model (PMID: 16135825). In summary, there is moderate evidence to support the relationship between *LIAS* and autosomal recessive *LIAS*-related primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 29, 2024 (SOP Version 10).

lipoic acid synthetase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013762

Submitter: Orphanet

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between LIAS and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of September 21, 2020. The LIAS gene encodes lipoic acid synthase, an enzyme important for the synthesis of lipoic acid, which is a cofactor of the pyruvate dehydrogenase complex (PDC). PDC catalyzes conversion of pyruvate into acetyl-CoA, thus is the link between glycolysis and the citric acid cycle. PDC deficiency leads to impaired energy metabolism. The LIAS gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2014 (PMID: 24334290). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four variants identified in three cases from three publications (PMID: 24334290, 28817111, 26108146). Of note, of five cases reported to date, three had features consistent with Leigh syndrome spectrum. No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, and animal models (PMIDs: 11389890, 25613900, 16135825). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 21, 2020 (SOP Version 7).

lipoic acid synthetase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013762

Submitter: Labcorp Genetics (formerly Invitae)

lipoic acid synthetase deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013762

Submitter: Ambry Genetics

lipoic acid synthetase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013762

Submitter: Genomics England PanelApp

lipoic acid synthetase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013762

Submitter: G2P

lipoic acid synthetase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013762

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hyperglycinemia, lactic acidosis, and seizuresAR

Manifestation: Biochemical; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22152680; 24334290; 36680912

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LIAS variants in ClinVar

6 Conditions Cataloged

Lipoic acid synthetase deficiencyTotal: 358

not providedTotal: 73

Inborn genetic diseasesTotal: 36

not specifiedTotal: 18

LIAS-related disorderTotal: 8

LIAS-related disordersTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006859.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	73 clinvar		74
missense	1 clinvar	6 clinvar	172 clinvar	4 clinvar		183
nonsense	5 clinvar	3 clinvar	2 clinvar			10
start loss			1 clinvar			1
frameshift	13 clinvar	3 clinvar	1 clinvar	1 clinvar		18
splice donor/acceptor (+/-2bp)		5 clinvar	4 clinvar			9
Total	19	17	181	78	0	295

Highest pathogenic variant AF is 0.000021189398

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006859.4	RefSeq	NP_006850.2	11	MANE Select
ENST00000640888.2	Ensembl	ENSP00000492260.1	11	MANE Select
NM_001278590.2	RefSeq	NP_001265519.1	10	Standard
NM_001278591.2	RefSeq	NP_001265520.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lipoic acid metabolism - Homo sapiens (human)
Metabolism of amino acids and derivatives
Metabolism
Glyoxylate metabolism and glycine degradation
lipoate biosynthesis and incorporation

Biological Process

neural tube closure
inflammatory response
response to oxidative stress
lipoate biosynthetic process
protein lipoylation

Molecular Function

lipoate synthase activity
metal ion binding
4 iron, 4 sulfur cluster binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261434
Coding exons: 11
Length: 18654
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125745
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.25	153	203	0.753	0.0000106	2406
Missense (PolyPhen)		33	68.225	0.48369		767
Synonymous	0.618	64	70.6	0.906	0.00000353	716
Loss of Function	2.11	11	21.6	0.510	0.00000108	277

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00037	0.00033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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 derivatives. {ECO:0000255|HAMAP-Rule:MF_03123}.;
Disease: DISEASE: Hyperglycinemia, lactic acidosis, and seizures (HGCLAS) [MIM:614462]: An enzymatic defect resulting in an autosomal recessive disorder of mitochondrial metabolism. It is characterized by early-onset lactic acidosis, severe encephalomyopathy, and a pyruvate oxidation defect. Affected individuals have neonatal-onset epilepsy, poor growth, psychomotor retardation, muscular hypotonia, lactic acidosis, and elevated glycine concentration in plasma and urine. {ECO:0000269|PubMed:22152680}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.358

Intolerance Scores

LoFtool: 0.576
RVIS EVS: -0.38
RVIS percentile EVS: 27.69

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.983

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium