Human Gene Module / Chromosome 16 / BCKDK

BCKDKBranched chain ketoacid dehydrogenase kinase

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
0 / 3
Rare Variants / Common Variants
5 / 0
Aliases
BCKDK, BCKDKD,  BDK
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
16p11.2
Associated Disorders
DD/NDD, EPS, ID, ASD
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.

Reports related to BCKDK (3 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 pediatri... Garca-Cazorla A , et al. (2014) No DD
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.[466C>T];[466C>T] p.[Arg156Ter];[Arg156Ter] stop_gained Familial Both parents Multiplex 22956686 Novarino G , et al. (2012)
c.[222delG];[222delG] p.[Met74fsTer];[Met74fsTer] frameshift_variant Familial Both parents Multiplex 22956686 Novarino G , et al. (2012)
c.[671G>C];[671G>C] p.[Arg224Pro];[Arg224Pro] missense_variant Familial Both parents Multiplex 22956686 Novarino G , et al. (2012)
c.520C>G; 512_543del p.[Arg174GlyfsTer1];[Arg174GlyfsTer1] splice_site_variant Familial Both parents Simplex 24449431 Garca-Cazorla A , et al. (2014)
c.[1166T>C];[1166T>C] p.[Leu389Pro];[Leu389Pro] missense_variant Familial Both parents Simplex 24449431 Garca-Cazorla A , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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).

2

Strong Candidate

See all Category 2 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.

04-01-2017
2

Initial score established: 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).

CNVs associated with BCKDK(1 CNVs)
16p11.2 88 Deletion-Duplication 147  /  1462
Animal Models associated with BCKDK(3 Models)
BCKDK_1_KO_HM Genetic
BCKDK_1_KO_HM_BCAAd RESCUE-Dietary
BCKDK_1_KO_HM_PROTH RESCUE-Dietary
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
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