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HOUSTON, TX – Researchers have identified a novel gene, , variants of which are linked to a severe multisystemic developmental disorder affecting the brain, eyes, and other organs, according to a new study published in Genetics in Medicine. The discovery, led by scientists at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, pinpoints rare variants on this X-chromosome gene as the cause of significant developmental abnormalities.
The study focused on patients presenting with restricted fetal growth, microcephaly (abnormally small head size), and severe abnormalities in the brain and eyes. Using whole-exome sequencing, researchers analyzed the protein-coding regions of the genomes of affected individuals and their parents. This analysis revealed rare genetic variants clustered in a specific area of the gene. This gene, previously not well-studied, encodes a protein believed to be important for processing messenger RNA (mRNA).
To confirm whether these variants were indeed disease-causing, functional studies were conducted using Drosophila (fruit fly) models at Baylor’s Center for Precision Medicine Models. “We found that the fly ortholog of is critically important to survival in the fly,” stated Dr. Jung-Wan Mok, first author of the study and a postdoctoral associate in Dr. Shinya Yamamoto’s lab at Baylor. “Downregulation of this gene in specific tissues like the eyes or brain that are affected in the patients causes severe phenotypes and problems in the developmental process in the fly model.”
The research demonstrated that the identified variants result in a partial loss-of-function, meaning the gene’s activity is reduced but not completely eliminated. Because is located on the X chromosome, the effects differ significantly between sexes. Males, having only one X chromosome, experience severe outcomes if they inherit the variant. Tragically, two male patients in the study, who were maternal half-brothers, died within their first year. Females, typically having two X chromosomes, possess one normal copy of the gene alongside the variant copy, leading to less severe symptoms, such as short stature, microcephaly, and vision problems.
The identification of as a disease-causing gene holds significant promise for clinical practice and research. “Characterization of this gene function and the spectrum of conditions that it may cause will help clinicians to provide targeted clinical management for the patients and will push research on this condition even further,” commented Dr. Keren Machol, co-corresponding author and assistant professor of molecular and human genetics at Baylor.
Dr. Shinya Yamamoto, co-corresponding author, associate professor at Baylor, and investigator at the Duncan NRI, added, “The documentation of as a human disease-causing gene will help identify other individuals affected by this understudied condition, ending diagnostic odysseys for many families and promoting further research.”
The findings are detailed in the paper titled “C-terminal frameshift variants in are associated with a multisystemic X-linked disorder” published in Genetics in Medicine.
Disclaimer: This news article is based on information from a scientific study published in Genetics in Medicine (DOI: 10.1016/j.gim.2025.101429). It is intended for informational purposes only and does not constitute medical advice. Individuals concerned about genetic disorders or the conditions mentioned should consult with a qualified healthcare professional or genetic counselor.
