Human Gene Module / Chromosome 16 / BCKDK

BCKDKBranched chain ketoacid dehydrogenase kinase

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
18 / 0
EAGLE Score
3.1
Limited Learn More
Aliases
BCKDK, BCKDKD,  BDK
Associated Syndromes
-
Chromosome Band
16p11.2
Associated Disorders
DD/NDD, ID, ASD, EPS
Genetic Category
Rare Single Gene Mutation
Relevance 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
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Rat
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
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
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We 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
2
icon
1

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
2
icon
2

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).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2016
3
icon
2

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
No data
icon
3

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
No data
icon
3

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]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.005804358040029

Ranking 10455/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.75515169420077

Ranking 1607/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 45

Ranking 40/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.66776662166556

Ranking 20215/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
CNVs associated with BCKDK(1 CNVs)
Sort By:
16p11.2 145 Deletion-Duplication 212  /  1657
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
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
Submit New Gene

Report an Error