Rare GPKOW Gene Variants Linked to Multisystemic X-Linked Developmental Disorder

Recent research published in Genetics in Medicine has identified a novel gene, GPKOW, playing a crucial role in human development, particularly affecting the brain, eyes, and other organ systems. The study, conducted by researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, highlights how rare variants in GPKOW, a gene located on the X chromosome, lead to a severe multisystem disorder. This syndrome is characterized by restricted fetal growth, microcephaly (small head size), and significant neurological and ocular abnormalities.

The investigation involved whole-exome sequencing of affected patients and their parents, revealing mutations in GPKOW that interfere with its normal function. GPKOW encodes a protein essential for mRNA processing, although its functions have not been extensively studied before. To better understand its role, researchers used Drosophila (fruit fly) models, demonstrating that the fly equivalent of GPKOW is vital for survival and proper development. Downregulation of this gene in specific tissues such as the eye and brain caused severe developmental issues, mirroring the human condition.

Further analysis showed that the identified variants are partial loss-of-function mutations, reducing the gene's activity without completely abolishing it. Since GPKOW is on the X chromosome, males with only one copy of the gene are more severely affected, often experiencing life-threatening symptoms early in life. Two male patients, maternal half-brothers, sadly passed away within their first year. Females with one normal GPKOW copy exhibited milder features like short stature, microcephaly, and vision problems.

Understanding the function of GPKOW and its associated spectrum of conditions can enhance diagnostic accuracy and inform targeted clinical management. The study's findings advance the knowledge of this rare genetic disorder and facilitate the identification of other affected individuals, potentially ending prolonged diagnostic journeys for many families.

For further details, see the publication: Jung-Wan Mok et al., "C-terminal frameshift variants in GPKOW are associated with a multisystemic X-linked disorder," Genetics in Medicine (2025). DOI: 10.1016/j.gim.2025.101429. Source: Medical Xpress.