KIF4A

protein-coding

kinesin family member 4A, the group of Kinesins

Gene summary

This gene encodes a member of the kinesin 4 subfamily of kinesin related proteins. The encoded protein is an ATP dependent microtubule-based motor protein that is involved in the intracellular transport of membranous organelles. This protein also associates with condensed chromosome arms and may be involved in maintaining chromosome integrity during mitosis. This protein may also be involved in the organization of the central spindle prior to cytokinesis. A pseudogene of this gene is found on chromosome X.[provided by RefSeq, Mar 2010]

MANE transcript

NM_012310.5

Inheritance

ClinVar variants

P:7U:279B:40

Top phenotype

Intellectual developmental disorder, X-linked 100; Taurodontism, microdontia, and dens invaginatus

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chrX:70,290,104-70,420,886

External References & Databases

Ensembl (ENSG00000090889)

Transcript & Mutation Effects

hg38 • Region Span ~130.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 100MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010488

Submitter: Illumina

intellectual developmental disorder, X-linked 100LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010488

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, X-linked 100STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010488

Submitter: PanelApp Australia

taurodontism, microdontia, and dens invaginatusSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010740

Submitter: PanelApp Australia

complex neurodevelopmental disorder with or without congenital anomaliesLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0100465

Submitter: ClinGen

*KIF4A* was first reported in relation to X-linked recessive complex neurodevelopmental disorder with or without congenital anomalies in 2014 (Willemsen et al., PMID: 24812067). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we determined two distinct disease entities, as *KIF4A* was also reported in relation to the disease taurodontism, microdontia, and dens invaginatus. Kalantari et al. (2021, PMID: 34346154) reported two male siblings (Patients 7 & 8) with taurodontism, microdontia, and dens invaginatus. Neither manifested developmental delay or intellectual disability. While future evidence may elucidate a spectrum which includes probands with teeth abnormalities and without neurodevelopmental presentations, with our current understanding of the disease, they have not been included in this curation at this time. Therefore, the two disease entities have been split and this curation summarizes the gene-disease relationship between *KIF4A* and X-linked recessive complex neurodevelopmental disorder with or without congenital anomalies. Affected individuals present with a variety of clinical features, including developmental delay, intellectual disability, seizures, bilateral cystic dysplastic kidneys, brain anomalies, and other congenital anomalies. Specific brain anomalies include hydrocephalus and agenesis of the corpus callosum. Ten variants (missense and in-frame indel) that have been reported in 15 probands across 3 publications (PMIDs: 24812067, 30679815, 34346154) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence. *Kif4a* knockdown in rat hippocampal neurons using siRNA was shown to alter the balance between excitatory and inhibitory synaptic input (PMID: 24812067). Additionally, a significant reduction in *KIF4A* mRNA was observed in the brain tissue of an affected fetus with hydrocephalus (PMID: 30679815). In summary, there is limited evidence to support the relationship between *KIF4A* and complex neurodevelopmental disorder with or without congenital anomalies. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 11, 2024 (SOP Version 10).

intellectual developmental disorder, X-linked 100LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010488

Submitter: G2P

intellectual developmental disorder, X-linked 100LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010488

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 100; Taurodontism, microdontia, and dens invaginatusXL

Manifestation: Dental; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 24812067; 31616463

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KIF4A variants in ClinVar

20 Conditions Cataloged

not providedTotal: 134

not specifiedTotal: 120

Intellectual disability, X-linked 100Total: 25

KIF4A-related disorderTotal: 21

Taurodontism, microdontia, and dens invaginatusTotal: 2

Pes planusTotal: 1

ObesityTotal: 1

GynecomastiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012310.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			19 clinvar	19 clinvar	2 clinvar	40
missense	4 clinvar	1 clinvar	229 clinvar	17 clinvar	2 clinvar	253
nonsense			8 clinvar			8
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)	2 clinvar		22 clinvar			24
Total	6	1	279	36	4	326

Highest pathogenic variant AF is 0.0000028525055

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012310.5	RefSeq	NP_036442.3	30	MANE Select
ENST00000374403.4	Ensembl	ENSP00000363524.3	30	MANE Select
ENST00000859344.1	Ensembl	ENSP00000529403.1	31	Standard
ENST00000859344.2	Ensembl	ENSP00000529403.1	31	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Retinoblastoma (RB) in Cancer
Developmental Biology
Recycling pathway of L1
Vesicle-mediated transport
Membrane Trafficking

Biological Process

mitotic cytokinesis
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
organelle organization
microtubule-based movement
mitotic spindle organization

Molecular Function

DNA binding
microtubule motor activity
protein binding
ATP binding
microtubule binding

Cellular Component

nucleoplasm
chromosome
cytoplasm
cytosol
kinesin complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374403
Coding exons: 30
Length: 130804
Individuals with no LoFs: 125736
Homozygous LoFs: 1
Heterozygous LoFs: 7
Defined: 125744
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.56	300	453	0.662	0.0000353	8131
Missense (PolyPhen)		51	122.98	0.41469		2353
Synonymous	0.740	150	162	0.926	0.0000121	2268
Loss of Function	6.08	5	52.5	0.0952	0.00000422	871

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00013	0.000099	rare
East Asian	0.000072	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000074	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Motor protein that translocates PRC1 to the plus ends of interdigitating spindle microtubules during the metaphase to anaphase transition, an essential step for the formation of an organized central spindle midzone and midbody and for successful cytokinesis. May play a role in mitotic chromosomal positioning and bipolar spindle stabilization. {ECO:0000269|PubMed:15297875, ECO:0000269|PubMed:15625105}.;

Recessive Scores

pRec: 0.119

Intolerance Scores

LoFtool: 0.241
RVIS EVS: -0.75
RVIS percentile EVS: 13.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.737

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium