Genes in panel
Regions in panel
Prev Next

Intellectual disability

Gene: KIF21B

Amber List (moderate evidence)

KIF21B (kinesin family member 21B)
EnsemblGeneIds (GRCh38): ENSG00000116852
EnsemblGeneIds (GRCh37): ENSG00000116852
OMIM: 608322, Gene2Phenotype
KIF21B is in 1 panel

2 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Rating Amber, but should be promoted to Green at the next GMS panel update (added 'for-review' tag)
Created: 26 Oct 2020, 12:39 p.m. | Last Modified: 26 Oct 2020, 12:39 p.m.
Panel Version: 3.485
New gene added by Konstantinos Varvagiannis. Four unrelated individuals reported in PMID:32415109 with variable degrees of ID - one severe (only microcephalic case) and one mild-moderate case (others borderline/mild). Developmental delay and learning difficulties were consistent. Includes supportive functional data.
Created: 26 Oct 2020, 12:37 p.m. | Last Modified: 26 Oct 2020, 12:37 p.m.
Panel Version: 3.484

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Asselin et al (2020 - PMID: 32415109) report on 4 individuals with KIF21B pathogenic variants. DD/ID (borderline intellectual functioning to severe ID) was a feature in all. Variable other findings included brain malformations (CCA) and microcephaly. 3 missense variants and a 4-bp insertion were identified, in 3 cases as de novo events while in a single subject the variant was inherited from the father who was also affected. The authors provide evidence for a role of KIF21B in the regulation of processes involved in cortical development and deleterious effect of the missense variants impeding neuronal migration and kinesin autoinhibition. Phenotypes specific to variants (e.g. CCA or microcephaly) were recapitulated in animal models. Missense variants are thought to exert a gain-of-function effect. As commented on, the 4-bp duplication (/frameshift) variant might not be pathogenic. In blood sample from the respective individual, RT-qPCR analysis suggested that haploinsufficiency (NMD) applies. Although Kif21b haploinsufficiency in mice was shown to lead to impaired neuronal positioning, the gene might partially tolerate LoF variants as also suggested by 28 such variants in gnomAD. Homozygous Kif21b ko mice display severe morphological abnormalities, partial loss of commissural fibers, cognitive deficits and altered synaptic transmission (several refs to previous studies provided by the authors).
Sources: Literature
Created: 13 Jul 2020, 7:25 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Abnormality of brain morphology
  • Microcephaly
Tags
for-review
OMIM
608322
Clinvar variants
Variants in KIF21B
Penetrance
unknown
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

26 Oct 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: kif21b has been classified as Amber List (Moderate Evidence).

26 Oct 2020, Gel status: 0

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag for-review tag was added to gene: KIF21B.

13 Jul 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Konstantinos Varvagiannis (Other)

gene: KIF21B was added gene: KIF21B was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: KIF21B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KIF21B were set to 32415109 Phenotypes for gene: KIF21B were set to Global developmental delay; Intellectual disability; Abnormality of brain morphology; Microcephaly Penetrance for gene: KIF21B were set to unknown Mode of pathogenicity for gene: KIF21B was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: KIF21B was set to GREEN