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Impact Case Study

Unlocking the origin of a severe neurological disorder

Gene sequencing brings the origin of a fatal neurological genetic disease to light.

26 February 2019

Rare genetic diseases are set to become easier to diagnose and treat thanks to Saudi Human Genome Programteam. The researchers have developed a high-throughput method that identifies the aberrant gene responsible for an inherited neurological disorder called Alkuraya–Kučinskas syndrome. 

Genomic sequencing, in which disease-causing gene mutations are assessed by determining the order of nucleotides in DNA molecules, has emerged as the go-to approach to describe inherited genetic disorders. Despite tremendous advances, half the diseases linked to intellectual disability and developmental delay remain unsolved, especially those related to brain malformation.  

Clinicians first diagnosed Alkuraya–Kučinskas syndrome in two siblings from Lithuania. While the parents were healthy, the children showed pronounced brain malformations, such as underdeveloped cerebral functional tissue and abnormally large fluid-filled ventricles. These defects were associated with clubfeet and arthrogryposis — a rare condition involving stiffness at multiple joints and muscle weakness at birth.  This suggested that the syndrome is autosomal recessive, or inherited from two copies of an aberrant gene. However, the extreme rarity of the syndrome prevented the clinicians from being able to define the root of these symptoms.  

To tackle this issue, KACST-affiliated geneticist Fowzan Alkuraya and

Vaidutis Kučinskas of Vilnus University in Lithuania, together with collaborators from the University of Lausanne, came up with an approach that ascertains the genetic mutations responsible for this unusual combination of brain malformation and arthrogryposis.  

The researchers isolated and sequenced all the protein-coding genes—the exome—of the Lithuanian siblings and their parents to identify the mutations that induce the Alkuraya–Kučinskas syndrome. Their analysis singled out mutations in the gene KIAA1109 as potentially causing the observed symptoms, prompting a worldwide search for other patients presenting the same genetic variations. The team found 17 additional individuals from ten unrelated families in the United Kingdom, Singapore, the United States, Saudi Arabia and other countries, and confirmed the contribution of the KIAA1109 mutations to the syndrome by additional sequencing. Most patients affected with the disorder died in utero or shortly after birth, indicating the seriousness of the disease. The few survivors exhibited severe neurodevelopmental delay as well as speech and motor impairment.  

To further confirm these findings, the researchers fully or partly suppressed the activity of the KIAA1109 equivalents in mice, fruit flies, and zebrafish and investigated how these alterations impact the animals. While gene silencing resulted in death or acute neurological defects, reduced activity led to embryos with similar symptoms to humans.


  1. Gueneau, L., Fish, R. J., Shamseldin, H. E., Voisin, N., Mau-Them, F. T., Egle Preiksaitiene, E. et al.KIAA1109 variants are associated with a severe disorder of brain development and arthrogryposis. The American Journal of Human Genetics 102, 116–132 (2018).| article