Holocarboxylase synthetase deficiency

Summary

Holocarboxylase synthetase deficiency (MONDO:0009666) is a disease caused by HLCS (GenCC Definitive), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: HLCS (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 967
• Phenotypes (HPO): 20
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.5	Europe	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000737	Irritability	Very frequent (80-99%)
HP:0001096	Keratoconjunctivitis	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001824	Weight loss	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002039	Anorexia	Very frequent (80-99%)
HP:0011127	Perioral eczema	Very frequent (80-99%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0001992	Organic aciduria	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001596	Alopecia	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0007549	Desquamation of skin soon after birth	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	holocarboxylase synthetase deficiency
Mondo ID	MONDO:0009666
MeSH	D028922
OMIM	253270
Orphanet	79242
DOID	DOID:859
NCIT	C98842
SNOMED CT	15307001, 360369003
UMLS	C0268581
MedGen	120653
GARD	0002721
Is cancer (heuristic)	no

Also known as: early-onset multiple carboxylase deficiency · holocarboxylase synthase deficiency · holocarboxylase synthetase deficiency · multiple carboxylase deficiency · neonatal multiple carboxylase deficiency

Data availability: 967 ClinVar variants · 5 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › multiple carboxylase deficiency › holocarboxylase synthetase deficiency

Related subtypes (1): biotinidase 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

600 retrieved; paginated sample, class counts are floors:

334 likely benign, 101 uncertain significance, 55 likely pathogenic, 43 pathogenic, 27 pathogenic/likely pathogenic, 16 conflicting classifications of pathogenicity, 15 benign, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069237	NM_001352514.2(HLCS):c.1869del (p.Thr624fs)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071012	NC_000021.8:g.(?38269140)(38269451_?)del	HLCS	Pathogenic	criteria provided, single submitter
1071507	NC_000021.8:g.(?38302541)(38311304_?)del	HLCS	Pathogenic	criteria provided, single submitter
1071508	NC_000021.8:g.(?38269140)(38311203_?)del	HLCS	Pathogenic	criteria provided, single submitter
1075159	NM_001352514.2(HLCS):c.1156C>T (p.Gln386Ter)	HLCS	Pathogenic	criteria provided, single submitter
1075784	NM_001352514.2(HLCS):c.1646G>A (p.Trp549Ter)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1389118	NM_001352514.2(HLCS):c.664_667del (p.Gln222fs)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1413934	NM_001352514.2(HLCS):c.2361_2362insT (p.Val788fs)	HLCS	Pathogenic	criteria provided, single submitter
1452545	NM_001352514.2(HLCS):c.1634del (p.Pro545fs)	HLCS	Pathogenic	criteria provided, single submitter
1452913	NM_001352514.2(HLCS):c.1627_1628del (p.Arg543fs)	HLCS	Pathogenic	criteria provided, single submitter
1453907	NM_001352514.2(HLCS):c.863del (p.Ser288fs)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454873	NM_001352514.2(HLCS):c.763G>T (p.Glu255Ter)	HLCS	Pathogenic	criteria provided, single submitter
1457493	NC_000021.8:g.(?38132018)(38362704_?)del	HLCS	Pathogenic	criteria provided, single submitter
1458476	NM_001352514.2(HLCS):c.1543del (p.Ile514_Leu515insTer)	HLCS	Pathogenic	criteria provided, multiple submitters, no conflicts
1460039	NM_001352514.2(HLCS):c.727del (p.Val243fs)	HLCS	Pathogenic	criteria provided, multiple submitters, no conflicts
1685876	NM_001352514.2(HLCS):c.2279T>C (p.Ile760Thr)	HLCS	Pathogenic	criteria provided, single submitter
1685877	NM_001352514.2(HLCS):c.2144G>A (p.Trp715Ter)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1724963	NM_001352514.2(HLCS):c.726dup (p.Val243fs)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1907	NM_001352514.2(HLCS):c.1151T>C (p.Leu384Pro)	HLCS	Pathogenic	criteria provided, multiple submitters, no conflicts
1908	NM_001352514.2(HLCS):c.2152G>A (p.Asp718Asn)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1909	NM_001352514.2(HLCS):c.1963C>T (p.Arg655Trp)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1910	NM_001352514.2(HLCS):c.2182G>A (p.Gly728Ser)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1911	NM_001352514.2(HLCS):c.2089G>A (p.Val697Met)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1912	NM_001352514.2(HLCS):c.1960+5G>A	HLCS	Pathogenic	criteria provided, multiple submitters, no conflicts
1913	NM_001352514.2(HLCS):c.1096dup (p.Ile366fs)	HLCS	Pathogenic	criteria provided, multiple submitters, no conflicts
1914	NM_001352514.2(HLCS):c.1088T>G (p.Leu363Arg)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1914425	NM_001352514.2(HLCS):c.1083T>A (p.Cys361Ter)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1962881	NM_001352514.2(HLCS):c.2458del (p.Gln820fs)	HLCS	Pathogenic	criteria provided, single submitter
1983627	NM_001352514.2(HLCS):c.1631del (p.Asp544fs)	HLCS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1996544	NM_001352514.2(HLCS):c.1444_1456delinsATAGTGCAAACTCCAACATAGTGCAAACT (p.Leu482_Pro486delinsIleValGlnThrProThrTer)	HLCS	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
HLCS	Definitive	Autosomal recessive	holocarboxylase synthetase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HLCS	Orphanet:79242	Holocarboxylase 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
HLCS	HGNC:4976	ENSG00000159267	P50747	Biotin–protein ligase	gencc,clinvar
CHAF1B	HGNC:1911	ENSG00000159259	Q13112	Chromatin assembly factor 1 subunit B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HLCS	Biotin–protein ligase	Biotin–protein ligase catalyzing the biotinylation of the 4 biotin-dependent carboxylases acetyl-CoA-carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase.
CHAF1B	Chromatin assembly factor 1 subunit B	Acts as a component of the histone chaperone complex chromatin assembly factor 1 (CAF-1), which assembles histone octamers onto DNA during replication and repair.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HLCS	Other/Unknown	no		BPL_C, BPL_LPL_catalytic, Biotin_CoA_COase_ligase
CHAF1B	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_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
frontal pole	1
middle frontal gyrus	1
paraflocculus	1
gastrocnemius	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HLCS	205	ubiquitous	marker	paraflocculus, frontal pole, middle frontal gyrus
CHAF1B	175	ubiquitous	marker	secondary oocyte, oocyte, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HLCS	2,554
CHAF1B	1,989

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHAF1B	Q13112	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HLCS	P50747	77.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Defects in biotin (Btn) metabolism	1	2284.0×	0.003	HLCS
Defective HLCS causes multiple carboxylase deficiency	1	1631.4×	0.003	HLCS
Biotin transport and metabolism	1	1038.2×	0.003	HLCS
Defects in vitamin and cofactor metabolism	1	601.0×	0.004	HLCS
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.010	HLCS
Metabolism of vitamins and cofactors	1	116.5×	0.013	HLCS
Diseases of metabolism	1	80.4×	0.016	HLCS
Disease	1	13.1×	0.086	HLCS
Metabolism	1	11.6×	0.086	HLCS

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
response to biotin	1	4213.0×	0.002	HLCS
biotin metabolic process	1	2106.5×	0.002	HLCS
DNA replication-dependent chromatin assembly	1	1053.2×	0.002	CHAF1B
post-translational protein modification	1	210.7×	0.008	HLCS
DNA replication	1	82.6×	0.017	CHAF1B
nucleosome assembly	1	70.2×	0.017	CHAF1B
DNA repair	1	31.9×	0.031	CHAF1B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
CHAF1B	1	2
HLCS	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	CHAF1B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HLCS	8	Binding:8
CHAF1B	6	Binding:6

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

1 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)
MOLIBRESIB	2	CHAF1B

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	1	CHAF1B
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HLCS

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)
HLCS	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening