Phenotypic variability in Joubert syndrome is partially explained by ciliary pathophysiology

Area of Science:

• Genetics
• Developmental Biology
• Medical Research

Background:

• Joubert syndrome (JS) is a genetic disorder caused by primary ciliary defects, leading to malformations in multiple organs.
• While some JS-associated genes have known genotype/phenotype correlations, many lack sufficient data for robust conclusions.

Purpose of the Study:

• To expand genotype/phenotype correlations in Joubert syndrome by analyzing a large patient cohort.
• To identify new correlations and refine existing ones for improved clinical management.

Main Methods:

• A PubMed literature review identified 688 individuals with JS across 32 genes and 112 publications.
• Patients were included if they presented with the "molar tooth sign" and had a confirmed genetic diagnosis.
• Data on age, ethnicity, sex, and specific clinical features were collected and analyzed.

Main Results:

• Most JS-associated genes exhibited distinct phenotypic profiles.
• Grouping proteins by physiologic interactions strengthened phenotypic relationships, aligning with ciliary pathophysiology.
• Age-stratified analysis revealed progressive end-organ disease in JS patients.
• Genetic variants often skewed towards either residual or absent protein function.

Conclusions:

• Clinically significant genotype/phenotype relationships are evident for most JS-related genes.
• This comprehensive cohort data can inform more personalized clinical care strategies for individuals with Joubert syndrome.