Intellectual disability
Gene: KIF21B

KIF21B (kinesin family member 21B)
EnsemblGeneIds (GRCh38): ENSG00000116852
EnsemblGeneIds (GRCh37): ENSG00000116852
OMIM: 608322, Gene2Phenotype
KIF21B is in 2 panels

3 reviews

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.

Panel Version: 3.1510

Created: 9 Mar 2022, 3:40 p.m.
Last Modified: 9 Mar 2022, 3:40 p.m.
Panel version: 3.1510

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

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

32415109

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

Created: 13 Jul 2020, 7:25 p.m.

Panel version: 3.170

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Sources

Expert Review Green

Phenotypes

Global developmental delay
Intellectual disability
Abnormality of brain morphology
Microcephaly

Tags

gene-checked

OMIM

608322

Clinvar variants

Variants in KIF21B

Penetrance

unknown

Publications

32415109

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