KIAA0586 is Mutated in Joubert Syndrome

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Ciliopathies

Background:

• Joubert syndrome (JS) is a rare, recessive neurodevelopmental disorder.
• It is characterized by mid-hindbrain malformation and is classified as a ciliopathy due to primary cilium dysfunction.
• Genetic causes are identified in only 62% of JS cases, highlighting the need for novel gene discovery.

Purpose of the Study:

• To identify novel genetic causes of Joubert syndrome.
• To investigate the role of KIAA0586 in the pathophysiology of JS.

Main Methods:

• Whole exome sequencing was performed on 35 individuals with JS.
• Targeted next-generation sequencing was used in a larger cohort to validate findings.
• Analysis focused on identifying biallelic rare deleterious variants (RDVs).

Main Results:

• Biallelic RDVs in KIAA0586 were identified in one individual through whole exome sequencing.
• KIAA0586, encoding a centrosomal protein crucial for ciliogenesis, was found to be a novel JS gene.
• An additional eight families with biallelic RDVs in KIAA0586 were identified, accounting for an estimated 2.5% prevalence.
• Affected individuals presented with milder JS phenotypes.

Conclusions:

• KIAA0586 is a newly identified gene associated with Joubert syndrome.
• Mutations in KIAA0586 contribute to a subset of JS cases, particularly milder forms.
• This discovery expands the genetic landscape of JS and ciliopathies.