BCKDKBranched chain ketoacid dehydrogenase kinase
Autism Reports / Total Reports
5 / 8Rare Variants / Common Variants
18 / 0Chromosome Band
16p11.2Associated Disorders
DD/NDD, ID, ASD, EPSGenetic Category
Rare Single Gene MutationRelevance to Autism
Three different homozygous variants (one nonsense, one frameshift, one missense) in the BCKDK gene that segregated with disease were identified in three consanguineous families presenting with autism and ID (Novarino et al., 2012).
Molecular Function
Catalyzes the phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, the key regulatory enzyme of the valine, leucine and isoleucine catabolic pathways. Key enzyme that regulate the activity state of the BCKD complex. Defects in this gene are associated with branched-chain ketoacid dehydrogenase kinase deficiency (BCKDKD) [MIM:614923], a metabolic disorder characterized by autism, epilepsy, intellectual disability, and reduced branched-chain amino acids.
External Links
SFARI Genomic Platforms
Reports related to BCKDK (8 Reports)
# | Type | Title | Author, Year | Autism Report | Associated Disorders |
---|---|---|---|---|---|
1 | Primary | Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy | Novarino G , et al. (2012) | No | ASD, ID, epilepsy |
2 | Recent Recommendation | Structure-based design and mechanisms of allosteric inhibitors for mitochondrial branched-chain ?-ketoacid dehydrogenase kinase | Tso SC , et al. (2013) | No | - |
3 | Recent Recommendation | Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients | Garca-Cazorla A , et al. (2014) | No | DD |
4 | Support | Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks | Ruzzo EK , et al. (2019) | Yes | - |
5 | Support | - | Zou D et al. (2021) | Yes | - |
6 | Support | - | Boemer F et al. (2022) | Yes | - |
7 | Support | - | Zhou X et al. (2022) | Yes | - |
8 | Recent Recommendation | - | Tangeraas T et al. (2023) | Yes | Epilepsy/seizures |
Rare Variants (18)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
c.256C>T | p.His86Tyr | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.716+1G>A | - | splice_site_variant | Familial | Paternal | - | 34145886 | Zou D et al. (2021) | |
c.433C>T | p.Gln145Ter | stop_gained | Unknown | - | Simplex | 36729635 | Tangeraas T et al. (2023) | |
c.1100G>A | p.Gly367Asp | missense_variant | Unknown | - | Simplex | 36729635 | Tangeraas T et al. (2023) | |
c.14C>A | p.Ser5Ter | stop_gained | Familial | Both parents | Simplex | 36729635 | Tangeraas T et al. (2023) | |
c.265-2A>G | - | splice_site_variant | Familial | Both parents | Simplex | 36729635 | Tangeraas T et al. (2023) | |
c.159_160dup | p.Tyr54PhefsTer18 | frameshift_variant | Familial | Maternal | - | 34145886 | Zou D et al. (2021) | |
c.1159C>T | p.Gln387Ter | stop_gained | Familial | Both parents | Simplex | 36729635 | Tangeraas T et al. (2023) | |
c.264+1G>C | - | splice_site_variant | Familial | Both parents | Multiplex | 36729635 | Tangeraas T et al. (2023) | |
c.466C>T | p.Arg156Ter | stop_gained | Familial | Both parents | Multiplex | 22956686 | Novarino G , et al. (2012) | |
c.466C>T | p.Arg156Ter | stop_gained | Familial | Both parents | Multiplex | 36729635 | Tangeraas T et al. (2023) | |
c.617A>C | p.His206Pro | missense_variant | Familial | Both parents | Simplex | 36729635 | Tangeraas T et al. (2023) | |
c.671G>C | p.Arg224Pro | missense_variant | Familial | Both parents | Multiplex | 22956686 | Novarino G , et al. (2012) | |
c.999_1001del | p.Thr335del | inframe_deletion | Familial | Both parents | Multiplex | 35216372 | Boemer F et al. (2022) | |
c.986dup | p.Met329IlefsTer9 | frameshift_variant | Familial | Maternal | Multiplex | 31398340 | Ruzzo EK , et al. (2019) | |
c.1166T>C | p.Leu389Pro | missense_variant | Familial | Both parents | Simplex | 24449431 | Garca-Cazorla A , et al. (2014) | |
c.520C>G | p.Arg174Gly | splice_site_variant | Familial | Both parents | Simplex | 24449431 | Garca-Cazorla A , et al. (2014) | |
c.222del | p.Met74IlefsTer15 | frameshift_variant | Familial | Both parents | Multiplex | 22956686 | Novarino G , et al. (2012) |
Common Variants
No common variants reported.
SFARI Gene score
High Confidence
Score Delta: Score remained at 1
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
10/1/2019
Decreased from 2 to 1
New Scoring Scheme
Description
Homozygous loss-of-function variants in the BCKDK gene were identified that segregated with ASD and intellectual disability in two consanguineous multiplex families (PMID 22956686). While these variants were not observed in ethnically-matched controls or publically available databases, there was no rigorous statistical comparison of variant frequency in controls. Homozygous missense variants in the BCKDK gene that resulted in reduced protein levels and other functional effects were recently identified in two unrelated patients with developmental delay, microcephaly, and neurobehavioral anomalies (PMID 24449431).
Reports Added
[New Scoring Scheme]7/1/2019
Decreased from 2 to 2
Description
Homozygous loss-of-function variants in the BCKDK gene were identified that segregated with ASD and intellectual disability in two consanguineous multiplex families (PMID 22956686). While these variants were not observed in ethnically-matched controls or publically available databases, there was no rigorous statistical comparison of variant frequency in controls. Homozygous missense variants in the BCKDK gene that resulted in reduced protein levels and other functional effects were recently identified in two unrelated patients with developmental delay, microcephaly, and neurobehavioral anomalies (PMID 24449431).
4/1/2016
Decreased from 3 to 2
Description
Homozygous loss-of-function variants in the BCKDK gene were identified that segregated with ASD and intellectual disability in two consanguineous multiplex families (PMID 22956686). While these variants were not observed in ethnically-matched controls or publically available databases, there was no rigorous statistical comparison of variant frequency in controls. Homozygous missense variants in the BCKDK gene that resulted in reduced protein levels and other functional effects were recently identified in two unrelated patients with developmental delay, microcephaly, and neurobehavioral anomalies (PMID 24449431).
7/1/2014
Increased from No data to 3
Description
Homozygous loss-of-function variants in the BCKDK gene were identified that segregated with ASD and intellectual disability in two consanguineous multiplex families (PMID 22956686). While these variants were not observed in ethnically-matched controls or publically available databases, there was no rigorous statistical comparison of variant frequency in controls. Homozygous missense variants in the BCKDK gene that resulted in reduced protein levels and other functional effects were recently identified in two unrelated patients with developmental delay, microcephaly, and neurobehavioral anomalies (PMID 24449431).
4/1/2014
Increased from No data to 3
Description
Homozygous loss-of-function variants in the BCKDK gene were identified that segregated with ASD and intellectual disability in two consanguineous multiplex families (PMID 22956686). While these variants were not observed in ethnically-matched controls or publically available databases, there was no rigorous statistical comparison of variant frequency in controls. Homozygous missense variants in the BCKDK gene that resulted in reduced protein levels and other functional effects were recently identified in two unrelated patients with developmental delay, microcephaly, and neurobehavioral anomalies (PMID 24449431).
Krishnan Probability Score
Score 0.49473584634897
Ranking 3453/25841 scored genes
[Show Scoring Methodology]
ExAC Score
Score 0.005804358040029
Ranking 10455/18225 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.75515169420077
Ranking 1607/18665 scored genes
[Show Scoring Methodology]
Larsen Cumulative Evidence Score
Score 45
Ranking 40/461 scored genes
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Zhang D Score
Score -0.66776662166556
Ranking 20215/20870 scored genes
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CNVs associated with BCKDK(1 CNVs)
Sort By:
16p11.2 | 145 | Deletion-Duplication | 212 / 1657 |
External PIN Data
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
---|---|---|---|---|---|
BCKDHA | branched chain keto acid dehydrogenase E1, alpha polypeptide | Human | Protein Binding | 593 | B4DP47 |
CAB39 | calcium binding protein 39 | Human | Protein Binding | 51719 | A8K8L7 |
CAB39L | calcium binding protein 39-like | Human | Protein Binding | 81617 | Q9H9S4 |
CETN1 | Centrin-1 | Human | Protein Binding | 1068 | Q12798 |
CETN2 | centrin, EF-hand protein, 2 | Human | Protein Binding | 1069 | P41208 |
CETN3 | centrin, EF-hand protein, 3 | Human | Protein Binding | 1070 | O15182 |
CHD2 | chromodomain helicase DNA binding protein 2 | Human | Protein Binding | 1106 | O14647 |
FAM98B | family with sequence similarity 98, member B | Human | Protein Binding | 283742 | Q52LJ0 |
GCNT3 | Beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase 3 | Human | Protein Binding | 9245 | O95395 |
ISLR | Immunoglobulin superfamily containing leucine-rich repeat protein | Human | Protein Binding | 3671 | O14498 |
LGALS3BP | lectin, galactoside-binding, soluble, 3 binding protein | Human | Protein Binding | 3959 | Q08380 |
METTL21C | Protein-lysine methyltransferase METTL21C | Human | Protein Binding | 196541 | Q5VZV1 |
NBEA | neurobeachin | Mouse | Protein Binding | 26422 | Q9EPN1 |
NIT1 | nitrilase 1 | Human | Protein Binding | NM_005600 | Q86X76 |
RNF219 | ring finger protein 219 | Human | Protein Binding | 79596 | Q5W0B1 |
RTCA | RNA 3'-terminal phosphate cyclase | Human | Protein Binding | 8634 | O00442 |
TERF2 | telomeric repeat binding factor 2 | Human | Protein Binding | 7014 | Q9NYB0 |
WDTC1 | WD and tetratricopeptide repeats 1 | Human | Protein Binding | 23038 | Q8N5D0 |