BTD

Summary

BTD (biotinidase, HGNC:1122) is a protein-coding gene on chromosome 3p25.1, encoding Biotinidase (P43251). Catalytic release of biotin from biocytin, the product of biotin-dependent carboxylases degradation.

The protein encoded by this gene functions to recycle protein-bound biotin by cleaving biocytin (biotin-epsilon-lysine), a normal product of carboxylase degradation, resulting in regeneration of free biotin. The encoded protein has also been shown to have biotinyl transferase activity. Mutations in this gene are associated with biotinidase deficiency. Multiple transcript variants encoding different isoforms have been described.

Source: NCBI Gene 686 — RefSeq curated summary.

At a glance

• Gene–disease (curated): biotinidase deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 807 total — 97 pathogenic, 97 likely-pathogenic
• Phenotypes (HPO): 52
• Druggable target: yes
• MANE Select transcript: NM_001370658

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1122
Approved symbol	BTD
Name	biotinidase
Location	3p25.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000169814
Ensembl biotype	protein_coding
OMIM	609019
Entrez	686

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 44 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000303498, ENST00000417015, ENST00000427382, ENST00000436193, ENST00000437172, ENST00000449107, ENST00000467027, ENST00000471964, ENST00000480711, ENST00000482824, ENST00000642517, ENST00000643237, ENST00000646371, ENST00000671928, ENST00000672141, ENST00000672336, ENST00000672427, ENST00000672760, ENST00000672892, ENST00000672968, ENST00000673467, ENST00000673620, ENST00000713693, ENST00000713694, ENST00000713695, ENST00000900224, ENST00000900225, ENST00000900226, ENST00000900227, ENST00000900228, ENST00000900229, ENST00000900230, ENST00000900231, ENST00000900232, ENST00000900233, ENST00000900234, ENST00000900235, ENST00000900236, ENST00000900237, ENST00000900238, ENST00000900239, ENST00000900240, ENST00000900241, ENST00000936763, ENST00000936764, ENST00000936765, ENST00000950873, ENST00000950874, ENST00000950875, ENST00000950876

RefSeq mRNA: 41 — MANE Select: NM_001370658 NM_001281723, NM_001281724, NM_001281725, NM_001281726, NM_001323582, NM_001370658, NM_001370752, NM_001370753, NM_001407364, NM_001407365, NM_001407366, NM_001407367, NM_001407368, NM_001407369, NM_001407370, NM_001407371, NM_001407372, NM_001407373, NM_001407374, NM_001407375, NM_001407376, NM_001407377, NM_001407378, NM_001407379, NM_001407380, NM_001407381, NM_001407382, NM_001407383, NM_001407384, NM_001407386, NM_001407388, NM_001407390, NM_001407392, NM_001407394, NM_001407395, NM_001407396, NM_001407397, NM_001407398, NM_001407399, NM_001407400, NM_001407401

CCDS: CCDS63565, CCDS87052, CCDS93220, CCDS93221

Canonical transcript exons

ENST00000643237 — 4 exons

Exon	Start	End
ENSE00001149075	15641908	15642057
ENSE00003673314	15635424	15635688
ENSE00003827559	15644316	15653714
ENSE00003828310	15601745	15601894

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 91.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.1278 / max 135.2094, expressed in 1794 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35522	15.4126	1789
35523	1.4200	685
35521	0.2952	113

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	91.18	gold quality
right lobe of liver	UBERON:0001114	90.75	gold quality
liver	UBERON:0002107	90.07	gold quality
duodenum	UBERON:0002114	89.87	gold quality
jejunal mucosa	UBERON:0000399	89.45	gold quality
gall bladder	UBERON:0002110	89.16	gold quality
stromal cell of endometrium	CL:0002255	88.97	gold quality
body of pancreas	UBERON:0001150	88.92	gold quality
right adrenal gland	UBERON:0001233	88.84	gold quality
pancreas	UBERON:0001264	88.56	gold quality
left adrenal gland	UBERON:0001234	88.46	gold quality
right adrenal gland cortex	UBERON:0035827	88.44	gold quality
left adrenal gland cortex	UBERON:0035825	88.20	gold quality
adrenal cortex	UBERON:0001235	87.57	gold quality
adrenal tissue	UBERON:0018303	87.46	gold quality
adrenal gland	UBERON:0002369	87.42	gold quality
left ovary	UBERON:0002119	86.82	gold quality
right ovary	UBERON:0002118	86.75	gold quality
rectum	UBERON:0001052	86.72	gold quality
body of stomach	UBERON:0001161	86.49	gold quality
corpus epididymis	UBERON:0004359	86.36	gold quality
colonic epithelium	UBERON:0000397	85.94	gold quality
calcaneal tendon	UBERON:0003701	85.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.88	gold quality
stomach	UBERON:0000945	85.70	gold quality
bone marrow cell	CL:0002092	85.42	gold quality
omental fat pad	UBERON:0010414	85.33	gold quality
peritoneum	UBERON:0002358	85.30	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.18	gold quality
small intestine	UBERON:0002108	85.13	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	15.34
E-ANND-3	yes	6.82

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

32 targeting BTD, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-4752	98.71	68.04	833
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-3691-5P	98.62	65.88	552
HSA-MIR-4726-3P	98.49	63.89	1385
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-3085-5P	97.72	65.43	544
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-938	97.41	68.28	656
HSA-MIR-1227-3P	97.36	66.94	834
HSA-MIR-6866-5P	96.64	68.06	624
HSA-MIR-877-5P	94.62	66.30	710

Literature-anchored findings (GeneRIF, showing 30)

• review of mutations causing biotinidase deficiency (PMID:11668630)
• report of 17 novel mutations that cause profound biotinidase deficiency. Six of the mutations are due to deletions, whereas the remaining 11 mutations are missense mutations located throughout the gene (PMID:12359137)
• analysis of mutations in biotinidase deficiency (PMID:15776412)
• 21 different mutations were identified in 49 patients, including four novel mutations. Ten mutations proved to be unique to the Hungarian population. (PMID:17185019)
• Posttranslational modification of histones by biotinylation can be catalyzed by biotinidase; role of this function is ambiguous. (PMID:18479898)
• This case indicates that biotinidase deficiency should be included in the differential diagnosis of subacute myelopathy and emphasizes the importance of a prompt diagnosis to prevent irreversible neurological damage. (PMID:18645204)
• Six different mutations in the biotinidase gene are identified in biotinidase in four Chinese patients; determination of biotinidase activities are performed for selective screening of biotinidase deficiency (PMID:19728141)
• Four Somali patients have the P497S mutation, with one of the four being homozygous for the mutation (PMID:19757147)
• 12 patients with multiple carboxylase deficiency, six mutations were found in the BT gene and 4 in the HLCS gene, including 5 novel mutations. (PMID:19806568)
• Report incidence of profound biotinase deficiency in Swedish newborns and adoptive immigrant children. (PMID:20224900)
• Plasma BTD activity increases in hepatic glycogen storage disease patients. (PMID:20532819)
• Mutations in biotinidase is associated with biotinidase deficiency. (PMID:20539236)
• High frequencies of biotinidase mutations may explain the high incidence of biotinidase deficiency in Hungary. (PMID:20549359)
• 140 known mutations in the biotinidase gene (BTD) that cause biotinidase deficiency, are reported. (PMID:20556795)
• loss of overall biotinidase expression is a novel marker for thyroid cancer aggressiveness. (PMID:22911723)
• Mutation analysis revealed three novel mutations, c.del631C and c.1557T>G within exon 4 and c.324-325insTA in exon 3 in Biotinidase deficiency patients and families. (PMID:23481307)
• Three novel pathogenic variants in BTD gene were identified in a cohort of Brazilian patients with biotinidase deficiency and control suggesting an allelic heteregeneity of the condition. (PMID:25174816)
• Summary of the demographic features of patients identified as biotinidase deficient from August of 2012 through August of 2013 and mutation analysis results for 20 cases in the southeast region of Turkey. (PMID:25423671)
• The common biotinidase gene mutations (p.R157H, p.D444H, c.98-104del7ins3, p.T532M) cumulatively accounted for 72.3% of all the mutant alleles in the Turkish population. (PMID:25754625)
• The history and genetic basis of biotinidase deficiency has been presented. (Review) (PMID:26456103)
• Biotinidase deficiency is reviewed. (PMID:26577040)
• 48 novel alterations in the biotinidase gene have been identified; correlating the individual’s serum enzymatic activity with genotype, were able to determine the effect of the novel alteration on enzyme activity and, thereby, determine its likelihood of being pathogenic in 44 of these individuals (PMID:26810761)
• Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). (PMID:27378695)
• BTD mutation is associated with biotinidase deficiency. (PMID:29995633)
• In patients with biotinidase deficiency, the p.Leu40Pro, p.Cys160Tyr and p.Leu446Pro variants are deleterious; the p.Asn489Ser is probably related to a mild biochemical phenotype; and p.Asp222Asn variant is probably not deleterious. The p.Asp444His variant seems to code for a protein with variable activity. (PMID:31337602)
• BTD Gene Mutations in Biotinidase Deficiency: Genotype-Phenotype Correlation. (PMID:34271776)
• Biotinidase deficiency: What have we learned in forty years? (PMID:37027963)
• Evaluation of 700 patients referred with a preliminary diagnosis of biotinidase deficiency by the national newborn metabolic screening program: a single-center experience. (PMID:37119528)
• Sequence variants in the BTD underlying biotinidase deficiency in families of Pakistani origin. (PMID:37751899)
• Biotinidase biochemical and molecular analyses: Experience at a large reference laboratory. (PMID:38299772)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	btd	ENSDARG00000099596
mus_musculus	Btd	ENSMUSG00000021900
rattus_norvegicus	Btd	ENSRNOG00000019656
drosophila_melanogaster	Btnd	FBGN0029848
drosophila_melanogaster	vanin-like	FBGN0040069
drosophila_melanogaster	CG32750	FBGN0052750
drosophila_melanogaster	CG32751	FBGN0052751

Paralogs (2): VNN1 (ENSG00000112299), VNN2 (ENSG00000112303)

Protein

Protein identifiers

Biotinidase — P43251 (reviewed: P43251)

All UniProt accessions (11): P43251, A0A2R8Y5J9, A0A5F9ZH15, A0A5F9ZH57, A0A5F9ZH80, A0A5F9ZH97, A0A5F9ZHE9, A0A5F9ZHF5, A0A5F9ZHR1, A0AAQ5BGS3, C9JSN9

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic release of biotin from biocytin, the product of biotin-dependent carboxylases degradation.

Subcellular location. Secreted. Extracellular space.

Disease relevance. Biotinidase deficiency (BTD deficiency) [MIM:253260] A juvenile form of multiple carboxylase deficiency, an autosomal recessive disorder of biotin metabolism, characterized by ketoacidosis, hyperammonemia, excretion of abnormal organic acid metabolites, and dermatitis. Biotinidase deficiency is characterized by seizures, hypotonia, skin rash, alopecia, ataxia, hearing loss, and optic atrophy. If untreated, symptoms usually become progressively worse, and coma and death may occur. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the carbon-nitrogen hydrolase superfamily. BTD/VNN family.

Isoforms (4)

UniProt ID	Names	Canonical?
P43251-4	4	yes
P43251-1	1
P43251-2	2
P43251-3	3

RefSeq proteins (41): NP_001268652, NP_001268653, NP_001268654, NP_001268655, NP_001310511, NP_001357587, NP_001357681, NP_001357682, NP_001394293, NP_001394294, NP_001394295, NP_001394296, NP_001394297, NP_001394298, NP_001394299, NP_001394300, NP_001394301, NP_001394302, NP_001394303, NP_001394304, NP_001394305, NP_001394306, NP_001394307, NP_001394308, NP_001394309, NP_001394310, NP_001394311, NP_001394312, NP_001394313, NP_001394315, NP_001394317, NP_001394319, NP_001394321, NP_001394323, NP_001394324, NP_001394325, NP_001394326, NP_001394327, NP_001394328, NP_001394329, NP_001394330 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003010	C-N_Hydrolase	Domain
IPR012101	Biotinidase-like_euk	Family
IPR036526	C-N_Hydrolase_sf	Homologous_superfamily
IPR040154	Biotinidase/VNN	Family
IPR043957	Vanin_C	Domain

Pfam: PF00795, PF19018

Enzyme classification (BRENDA):

• EC 3.5.1.12 — biotinidase (BRENDA: 12 organisms, 61 substrates, 32 inhibitors, 107 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BIOTINYL-6-AMINOQUINOLINE	0.0038–24.1	50
EPSILON-N-BIOTINYL-L-LYSINE	0.0005–0.016	20
P-(N-BIOTINYLAMINO)BENZOIC ACID	0.0042–0.05	15
BIOTINYL-4-AMINOBENZOIC ACID	0.01–0.055	3
BIOTINYL-DI-IODOTYRAMINE	0.0259–0.027	2
LIPOYL-4-AMINOBENZOIC ACID +	0.69–1.3	2
M-(N-BIOTINYLAMINO)BENZOIC ACID	0.0905–0.1002	2
N-DL-DESTHIOBIOTINYL-P-AMINOBENZOIC ACID	0.0685–0.0714	2
1’-N-METHOXYCARBONYL-BIOCYTIN	5	1
BIOTINYL-MONOIODOTYRAMINE	0.0158	1
DYNORPHIN A (1-6)	0.167	1
DYNORPHIN A (1-7)	0.132	1
LEU-ENKEPHALIN AMIDE	0.119	1
LIPOYLLYSINE	1.3	1
MET-ENKEPHALIN	0.303	1

Catalyzed reactions (Rhea), 2 shown:

• biotin amide + H2O = biotin + NH4(+) (RHEA:13081)
• biocytin + H2O = biotin + L-lysine (RHEA:77171)

UniProt features (26 total): sequence variant 10, glycosylation site 6, splice variant 3, active site 3, signal peptide 1, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43251-F1	86.77	0.79

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 92 (proton acceptor); 192 (proton donor); 225 (nucleophile)

Glycosylation sites (6): 382, 469, 99, 130, 183, 329

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-196780	Biotin transport and metabolism
R-HSA-3371598	Defective BTD causes biotidinase deficiency
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-3296482	Defects in vitamin and cofactor metabolism
R-HSA-3323169	Defects in biotin (Btn) metabolism
R-HSA-5668914	Diseases of metabolism

MSigDB gene sets: 274 (showing top): BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, MORF_ATRX, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, MORF_PPP5C, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_AMIDE_METABOLIC_PROCESS, MORF_FANCG, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, SANSOM_APC_TARGETS_DN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, MORF_PML, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, MORF_MT4, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN

GO Biological Process (2): biotin metabolic process (GO:0006768), central nervous system development (GO:0007417)

GO Molecular Function (4): biotinidase activity (GO:0047708), protein binding (GO:0005515), hydrolase activity (GO:0016787), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides (GO:0016811)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), mitochondrial matrix (GO:0005759), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Defects in biotin (Btn) metabolism	1
Metabolism of vitamins and cofactors	1
Metabolism	1
Diseases of metabolism	1
Defects in vitamin and cofactor metabolism	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sulfur compound metabolic process	1
monocarboxylic acid metabolic process	1
nervous system development	1
system development	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
binding	1
catalytic activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
cellular anatomical structure	1
mitochondrion	1
intracellular organelle lumen	1
extracellular vesicle	1

Protein interactions and networks

STRING

1246 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BTD	HLCS	P50747	968
BTD	PC	P11498	903
BTD	MCCC2	Q9HCC0	811
BTD	USHBP1	Q8N6Y0	810
BTD	PCCA	P05165	779
BTD	MCCC1	Q96RQ3	774
BTD	SLC19A3	Q9BZV2	726
BTD	ACACA	Q13085	616
BTD	SLC19A2	O60779	611
BTD	SLC5A6	Q9Y289	552
BTD	SLC19A1	P41440	497
BTD	ASB14	A6NK59	474
BTD	IZUMO1R	A6ND01	414
BTD	C7	P10643	409
BTD	FOLR3	P41439	405

IntAct

25 interactions, top by confidence:

A	B	Type	Score
SCGB1D1	MANBA	psi-mi:“MI:0914”(association)	0.640
BTD	MYO1D	psi-mi:“MI:0915”(physical association)	0.590
ERP44	MEX3A	psi-mi:“MI:0914”(association)	0.530
SERPINC1	BTD	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CDCA5	BDP1	psi-mi:“MI:0914”(association)	0.350
KIF21B		psi-mi:“MI:0914”(association)	0.350
SIKE1	STK24	psi-mi:“MI:0914”(association)	0.350
CCND1	REV3L	psi-mi:“MI:0914”(association)	0.350
	VPS37C	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
DHFR2	MANBA	psi-mi:“MI:0914”(association)	0.350
PTPRK	MANBA	psi-mi:“MI:0914”(association)	0.350
NMS	MANBA	psi-mi:“MI:0914”(association)	0.350
SPX	ERI3	psi-mi:“MI:0914”(association)	0.350
UCN3	PCDH7	psi-mi:“MI:0914”(association)	0.350
TAFA2	ERN1	psi-mi:“MI:0914”(association)	0.350
CST5	BCHE	psi-mi:“MI:0914”(association)	0.350
SERPINC1	HSPA5	psi-mi:“MI:0914”(association)	0.350
DHFR2	EGFR	psi-mi:“MI:0914”(association)	0.350

BioGRID (40): BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), MYO1D (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS), BTD (Affinity Capture-MS)

ESM2 similar proteins: A5PJN5, A6QQ07, B2RXS4, O08590, O15031, O35632, O95497, O95498, P09172, P14616, P15101, P19801, P26011, P36633, P43251, P83548, Q3SZL5, Q3V5L5, Q4R7M2, Q58CQ9, Q5FVF9, Q5R8R3, Q5XI31, Q64237, Q64716, Q6PD26, Q765H6, Q76HN1, Q8AV84, Q8BG22, Q8CIF4, Q8IRR1, Q8JZQ5, Q8NFI3, Q8SQG7, Q91ZJ9, Q9BDJ5, Q9DA79, Q9DBX3, Q9H3S1

Diamond homologs: A6QQ07, C6KYS2, O95497, O95498, P43251, Q58CQ9, Q5FVF9, Q8AV84, Q8CIF4, Q9BDJ5, Q9QZ25, Q9TSX8, Q9Z0K8, P83548, Q9UYV8, P49954

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

807 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	97
Likely pathogenic	97
Uncertain significance	228
Likely benign	220
Benign	17

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068552	NM_001370658.1(BTD):c.743dup (p.Tyr248Ter)	Pathogenic
1069218	NM_001370658.1(BTD):c.359G>A (p.Trp120Ter)	Pathogenic
1072526	NC_000003.11:g.(?15683405)(15687154_?)del	Pathogenic
1075658	NM_001370658.1(BTD):c.56_59dup (p.Gly21fs)	Pathogenic
1325380	NM_001370658.1(BTD):c.1103dup (p.Asn369fs)	Pathogenic
1343815	NM_001370658.1(BTD):c.424G>C (p.Ala142Pro)	Pathogenic
1351678	NC_000003.11:g.(?15643358)(15683584_?)del	Pathogenic
1408008	NC_000003.11:g.(?15643358)(15643421_?)del	Pathogenic
1409898	NM_001370658.1(BTD):c.588C>G (p.Tyr196Ter)	Pathogenic
1453530	NM_001370658.1(BTD):c.950del (p.Val317fs)	Pathogenic
1453804	NM_001370658.1(BTD):c.477_478delinsAA (p.Cys159_His160delinsTer)	Pathogenic
1459410	NM_001370658.1(BTD):c.805G>C (p.Ala269Pro)	Pathogenic
156005	NM_001370658.1(BTD):c.1312dup (p.Cys438fs)	Pathogenic
1704286	NM_001370658.1(BTD):c.550G>A (p.Gly184Arg)	Pathogenic
1711566	NM_001370658.1(BTD):c.249+2C>G	Pathogenic
188805	NM_001370658.1(BTD):c.1167_1181delinsTTCCAATGGCC (p.Trp389fs)	Pathogenic
189072	NM_001370658.1(BTD):c.142_145dup (p.Leu49fs)	Pathogenic
1895	NM_001370658.1(BTD):c.38_44delinsTCC (p.Cys13fs)	Pathogenic
1898	NM_001370658.1(BTD):c.1552C>T (p.Arg518Cys)	Pathogenic
1901	NM_001370658.1(BTD):c.695A>G (p.Asp232Gly)	Pathogenic
1903563	NM_001370658.1(BTD):c.346C>T (p.Gln116Ter)	Pathogenic
1998635	NM_001370658.1(BTD):c.901dup (p.Trp301fs)	Pathogenic
2012754	NM_001370658.1(BTD):c.1092dup (p.Lys365fs)	Pathogenic
2018405	NM_001370658.1(BTD):c.399+2T>G	Pathogenic
2047147	NM_001370658.1(BTD):c.686del (p.Leu229fs)	Pathogenic
2066797	NM_001370658.1(BTD):c.48C>G (p.Tyr16Ter)	Pathogenic
2122286	NM_001370658.1(BTD):c.1130_1155dup (p.Val386delinsArgTer)	Pathogenic
2203315	NM_001370658.1(BTD):c.524A>G (p.Asn175Ser)	Pathogenic
2203320	NM_001370658.1(BTD):c.1256C>A (p.Ala419Asp)	Pathogenic
2203322	NM_001370658.1(BTD):c.1309G>A (p.Val437Met)	Pathogenic

SpliceAI

3718 predictions. Top by Δscore:

Variant	Effect	Δscore
3:15601345:T:TA	donor_gain	1.0000
3:15601350:AGGAG:A	donor_gain	1.0000
3:15635478:C:CA	acceptor_gain	1.0000
3:15635665:C:T	donor_gain	1.0000
3:15642016:T:TA	donor_gain	1.0000
3:15642017:G:GA	donor_gain	1.0000
3:15642055:G:GT	donor_gain	1.0000
3:15642055:GAG:G	donor_gain	1.0000
3:15644312:CTAG:C	acceptor_loss	1.0000
3:15644313:TAG:T	acceptor_loss	1.0000
3:15644314:A:AG	acceptor_gain	1.0000
3:15644315:G:GG	acceptor_gain	1.0000
3:15675894:TTACC:T	donor_loss	1.0000
3:15675895:TAC:T	donor_loss	1.0000
3:15675896:A:AC	donor_gain	1.0000
3:15675896:AC:A	donor_gain	1.0000
3:15675897:C:CC	donor_gain	1.0000
3:15675897:C:G	donor_loss	1.0000
3:15675897:CC:C	donor_gain	1.0000
3:15675897:CCA:C	donor_gain	1.0000
3:15675897:CCATT:C	donor_gain	1.0000
3:15675986:AGGT:A	acceptor_gain	1.0000
3:15675987:GGT:G	acceptor_gain	1.0000
3:15675988:GT:G	acceptor_gain	1.0000
3:15675989:TCTAG:T	acceptor_loss	1.0000
3:15675990:C:CA	acceptor_loss	1.0000
3:15675990:C:CC	acceptor_gain	1.0000
3:15675991:T:C	acceptor_loss	1.0000
3:15676972:A:AC	donor_gain	1.0000
3:15676973:C:CA	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000012218 (3:15683696 T>C), RS1000055938 (3:15702435 T>C), RS1000075985 (3:15673221 G>A), RS1000092548 (3:15680677 A>G,T), RS1000121857 (3:15675260 G>C), RS1000148724 (3:15655184 C>T), RS1000149083 (3:15673500 G>C,T), RS1000152230 (3:15720743 G>A), RS1000195466 (3:15634079 T>C), RS1000206503 (3:15627883 G>A,T), RS1000207819 (3:15658061 G>A), RS1000210664 (3:15692892 A>C), RS1000230584 (3:15607139 C>T), RS1000233079 (3:15717087 G>T), RS1000332634 (3:15710747 T>C)

Disease associations

OMIM: gene MIM:609019 | disease phenotypes: MIM:253260, MIM:219050

GenCC curated gene-disease

Disease	Classification	Inheritance
biotinidase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Moderate	AR
biotinidase deficiency	Definitive	AR

Mondo (5): biotinidase deficiency (MONDO:0009665), optic nerve disorder (MONDO:0002135), intellectual disability (MONDO:0001071), cryptorchidism (MONDO:0009047), epilepsy (MONDO:0005027)

Orphanet (2): Biotinidase deficiency (Orphanet:79241), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000478	Abnormality of the eye
HP:0000509	Conjunctivitis
HP:0000572	Visual loss
HP:0000575	Scotoma
HP:0000648	Optic atrophy
HP:0000707	Abnormality of the nervous system
HP:0000964	Eczematoid dermatitis
HP:0000988	Skin rash
HP:0001051	Seborrheic dermatitis
HP:0001138	Optic neuropathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001263	Global developmental delay
HP:0001581	Recurrent skin infections
HP:0001596	Alopecia
HP:0001744	Splenomegaly
HP:0001987	Hyperammonemia
HP:0001992	Organic aciduria
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002069	Bilateral tonic-clonic seizure
HP:0002098	Respiratory distress
HP:0002104	Apnea
HP:0002123	Generalized myoclonic seizure

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002740_75	Inflammatory skin disease	6.000000e-08
GCST004967_1	Moderate or severe diarrhoea in darapladib-treated cardiovascular disease (time to event)	4.000000e-08
GCST006479_54	Diverticular disease	2.000000e-07
GCST006585_164	Blood protein levels	4.000000e-122
GCST009391_1907	Metabolite levels	5.000000e-06
GCST010244_84	Triglyceride levels	2.000000e-09
GCST010796_5234	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008395	response to darapladib
EFO:0009959	diverticular disease
EFO:0010463	asymmetric dimethylarginine measurement
EFO:0004530	triglyceride measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D028921	Biotinidase Deficiency	C16.320.565.100.620.100; C16.320.565.202.720.100; C18.452.648.100.620.100; C18.452.648.202.720.100
D003456	Cryptorchidism	C12.100.500.829.258; C12.200.294.829.258; C12.200.706.258; C12.800.258; C16.131.939.258; C19.391.829.258
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009901	Optic Nerve Diseases	C10.292.700; C11.640

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4802066 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

34 potent at pChembl≥5 of 41 total, top 34 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.45	IC50	35.5	nM	CHEMBL6171297
7.40	IC50	40	nM	CHEMBL5083289
7.27	IC50	53.4	nM	CHEMBL6168735
7.00	IC50	100	nM	CHEMBL6169674
6.95	IC50	112.4	nM	CHEMBL6169941
6.82	IC50	151	nM	CHEMBL6166267
6.79	IC50	163.9	nM	CHEMBL6169693
6.78	IC50	164.5	nM	CHEMBL6165507
6.77	IC50	171.5	nM	CHEMBL6175067
6.74	IC50	181.5	nM	CHEMBL6159999
6.66	IC50	217.1	nM	CHEMBL6171281
6.62	IC50	238.3	nM	CHEMBL6169437
6.59	IC50	254.8	nM	CHEMBL6166800
6.59	IC50	254.1	nM	CHEMBL6160100
6.59	IC50	255.7	nM	CHEMBL6161321
6.55	IC50	279.7	nM	CHEMBL6164946
6.50	IC50	316	nM	CHEMBL6142359
6.48	IC50	334.3	nM	CHEMBL6160100
6.48	IC50	334.3	nM	CHEMBL6166035
6.40	IC50	400	nM	CHEMBL6162242
6.14	IC50	729	nM	CHEMBL6170519
6.13	IC50	737.4	nM	CHEMBL6175174
6.12	IC50	758.1	nM	CHEMBL6163444
6.11	IC50	784.4	nM	CHEMBL6161761
6.06	IC50	877.7	nM	CHEMBL6164798
5.99	IC50	1020	nM	CHEMBL5087956
5.92	IC50	1200	nM	CHEMBL5072128
5.89	IC50	1300	nM	CHEMBL5092354
5.72	IC50	1900	nM	CHEMBL5082540
5.63	IC50	2363	nM	CHEMBL6161266
5.55	IC50	2800	nM	CHEMBL5088348
5.44	IC50	3600	nM	CHEMBL5085625
5.13	IC50	7400	nM	CHEMBL5092194
5.05	IC50	8900	nM	CHEMBL5084938

PubChem BioAssay actives

9 with measured affinity, of 26 total; 9 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
7-oxa-2-azaspiro[3.5]nonan-2-yl-[2-[[(1S)-1-pyrazin-2-ylethyl]amino]pyrimidin-5-yl]methanone	1824868: Inhibition of N-terminal FLAG/His6-tagged human biotinidase expressed in COS cells using biotinyl-7-amino-4-trifluoromethylcoumarin as substrate preincubated for 10 mins followed by substrate addition and measured after 90 mins	ic50	0.0400	uM
8-oxa-2-azaspiro[4.5]decan-2-yl-[2-[(1-pyrimidin-5-ylcyclopropyl)amino]pyrimidin-5-yl]methanone	1824868: Inhibition of N-terminal FLAG/His6-tagged human biotinidase expressed in COS cells using biotinyl-7-amino-4-trifluoromethylcoumarin as substrate preincubated for 10 mins followed by substrate addition and measured after 90 mins	ic50	1.0200	uM
7-oxa-2-azaspiro[3.5]nonan-2-yl-[2-(2-pyrazin-2-ylpropan-2-ylamino)pyrimidin-5-yl]methanone	1824868: Inhibition of N-terminal FLAG/His6-tagged human biotinidase expressed in COS cells using biotinyl-7-amino-4-trifluoromethylcoumarin as substrate preincubated for 10 mins followed by substrate addition and measured after 90 mins	ic50	1.2000	uM
8-oxa-2-azaspiro[4.5]decan-2-yl-[2-[(3-pyrimidin-5-yloxetan-3-yl)amino]pyrimidin-5-yl]methanone	1824868: Inhibition of N-terminal FLAG/His6-tagged human biotinidase expressed in COS cells using biotinyl-7-amino-4-trifluoromethylcoumarin as substrate preincubated for 10 mins followed by substrate addition and measured after 90 mins	ic50	1.3000	uM
8-oxa-2-azaspiro[4.5]decan-2-yl-[2-(2-pyrimidin-5-ylpropan-2-ylamino)pyrimidin-5-yl]methanone	1824868: Inhibition of N-terminal FLAG/His6-tagged human biotinidase expressed in COS cells using biotinyl-7-amino-4-trifluoromethylcoumarin as substrate preincubated for 10 mins followed by substrate addition and measured after 90 mins	ic50	1.9000	uM
8-oxa-2-azaspiro[4.5]decan-2-yl-[2-[[(1S)-1-pyrazin-2-ylethyl]amino]pyrimidin-5-yl]methanone	1824868: Inhibition of N-terminal FLAG/His6-tagged human biotinidase expressed in COS cells using biotinyl-7-amino-4-trifluoromethylcoumarin as substrate preincubated for 10 mins followed by substrate addition and measured after 90 mins	ic50	2.8000	uM
8-oxa-2-azaspiro[4.5]decan-2-yl-[2-(2-pyrazin-2-ylpropan-2-ylamino)pyrimidin-5-yl]methanone	1824868: Inhibition of N-terminal FLAG/His6-tagged human biotinidase expressed in COS cells using biotinyl-7-amino-4-trifluoromethylcoumarin as substrate preincubated for 10 mins followed by substrate addition and measured after 90 mins	ic50	3.6000	uM
7-oxa-2-azaspiro[3.5]nonan-2-yl-[2-(pyrazin-2-ylmethylamino)pyrimidin-5-yl]methanone	1824868: Inhibition of N-terminal FLAG/His6-tagged human biotinidase expressed in COS cells using biotinyl-7-amino-4-trifluoromethylcoumarin as substrate preincubated for 10 mins followed by substrate addition and measured after 90 mins	ic50	7.4000	uM
8-oxa-2-azaspiro[4.5]decan-2-yl-[2-[(1-pyrazin-2-ylcyclobutyl)amino]pyrimidin-5-yl]methanone	1824868: Inhibition of N-terminal FLAG/His6-tagged human biotinidase expressed in COS cells using biotinyl-7-amino-4-trifluoromethylcoumarin as substrate preincubated for 10 mins followed by substrate addition and measured after 90 mins	ic50	8.9000	uM

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, decreases methylation	3
sodium arsenite	decreases expression, increases abundance	2
chromium hexavalent ion	affects localization, decreases expression, decreases reaction	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Nickel	decreases expression	2
Valproic Acid	affects expression, decreases expression	2
testosterone enanthate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
trichostatin A	decreases expression, decreases reaction, increases expression	1
beta-lapachone	decreases expression	1
butyraldehyde	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Cannabidiol	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
1-Methyl-3-isobutylxanthine	increases expression, affects cotreatment	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4880315	Binding	Biotinidase assay	Data for DCP probe PFI-653

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SF90	HAP1 BTD (-) 1	Cancer cell line	Male
CVCL_XM13	HAP1 BTD (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

205 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03269045	PHASE1/PHASE2	COMPLETED	Study of ORL-1B in Patients With Biotinidase Deficiency
NCT00894920	Not specified	COMPLETED	Biotin Status in Pregnancy
NCT03268681	Not specified	COMPLETED	BIOtinidase Test In Optic-Neuropathy
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT06723925	Not specified	RECRUITING	Neonatal Screening of Biotinidase Deficiency: Genotype-phenotype Correlation and Clinical Follow-up
NCT02382627	Not specified	TERMINATED	Choroidal Thickness in Optic Neuropathy
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population