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Fetal anomalies

Gene: GPKOW

Green List (high evidence)

GPKOW (G-patch domain and KOW motifs)
EnsemblGeneIds (GRCh38): ENSG00000068394
EnsemblGeneIds (GRCh37): ENSG00000068394
OMIM: 301003, Gene2Phenotype
GPKOW is in 3 panels

2 reviews

Chirag Patel (Genetic Health Queensland)

Green List (high evidence)

GPKOW, a gene on the X-chromosome, encodes a nuclear RNA-binding protein important in mRNA processing as a spliceosome subunit. It has been shown in numerous model organisms and in human cells to be essential for survival.

PMID: 40221893
2 unrelated families with 3 affected males (deceased) presenting with IUGR, microcephaly, congenital ichthyosis, eye anomalies (microphthalmia, coloboma, ON hypoplasia), brain anomalies (absent septum pellucidum, ventriculomegaly), and skeletal anomalies (platyspondyly, brachydactyly). Trio WES/WGS testing identified 2 hemizygous frameshift variants affecting the last exon of GPKOW [p.(Arg441SerfsTer30) and p.(Ser444GlufsTer28)]. Some heterozygote females presented with short stature, microcephaly, and vision problems. Sequencing of fibroblasts' mRNA showed that GPKOW mRNA escapes nonsense-mediated decay but protein expression is reduced, suggesting protein instability. Studies in Drosophila showed that Gpkow is broadly expressed and is enriched in neurons and glia in eyes and head of developing and adult flies. Knockdown and overexpression of Gpkow in the fly eye cause eyeless/headless phenotype suggesting that the gene is dosage sensitive. Overexpression of the p.(Ser444GlufsTer28) variant caused milder defects than the reference allele, indicating that the truncated protein behaves as a partial loss-of-function allele.

PMID: 28612833
1 family with 5 affected males (stillbirth/TOP) with severe microcephaly and intrauterine growth restriction. X-exome sequencing in an obligate carrier identified a potential splice variant in the GPKOW gene (c.331+5G>A). The variant segregated in 9 additional family members, including one affected male fetus. GPKOW transcripts, in lymphoblastoid cell lines of 3 carrier females, showed that the variant disrupts normal splicing of its pre-mRNAs. A clonal culture expressing only the c.331+5G>A allele isolated from one carrier female LCL, showed an 80% reduction in wild type GPKOW mRNA, 70% reduction in the full length GPKOW protein and the presence of a truncated GPKOW protein with possible dominant negative effect.
Created: 1 May 2025, 9:18 p.m. | Last Modified: 1 May 2025, 9:18 p.m.
Panel Version: 1.328

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
microcephaly MONDO:0001149; fetal growth restriction MONDO:0005030

Publications

Ain Roesley (Victorian Clinical Genetics Services)

Red List (low evidence)

- multi-generational family with 5 deceased males (only 1 genotyped)
- X-exome sequencing identified NM_015698.4:c.331+5G>A, which segregated through the obligate carriers
- RNA from female carriers confirmed splicing defects, which leads to NMD

no additional reports since
Created: 3 Jan 2022, 10:30 p.m. | Last Modified: 3 Jan 2022, 10:30 p.m.
Panel Version: 0.1753

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
male-lethal microcephaly with intrauterine growth restriction

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Genomics England PanelApp
Phenotypes
  • syndromic disease, MONDO:0002254, GPKOW-related
OMIM
301003
Clinvar variants
Variants in GPKOW
Penetrance
None
Publications
Panels with this gene

History Filter Activity

2 May 2025, Gel status: 3

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: GPKOW were set to 28612833

2 May 2025, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: GPKOW were changed from male-lethal microcephaly with intrauterine growth restriction to syndromic disease, MONDO:0002254, GPKOW-related

1 May 2025, Gel status: 3

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

Gene: gpkow has been classified as Green List (High Evidence).

4 Jan 2022, Gel status: 1

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: gpkow has been classified as Red List (Low Evidence).

4 Jan 2022, Gel status: 1

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: gpkow has been classified as Red List (Low Evidence).

24 Oct 2021, Gel status: 2

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

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: GPKOW was added gene: GPKOW was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp Mode of inheritance for gene: GPKOW was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: GPKOW were set to 28612833 Phenotypes for gene: GPKOW were set to male-lethal microcephaly with intrauterine growth restriction