Affiliation:
1. UPMC Children's Hospital of Pittsburgh Division of Genetic and Genomic Medicine University of Pittsburgh Pittsburgh Pennsylvania USA
2. Department of Pediatrics, Cincinnati Children's Hospital Medical Center Division of Human Genetics University of Cincinnati College of Medicine Cincinnati Ohio USA
3. Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research St. Jude Children's Research Hospital Memphis Tennessee USA
Abstract
AbstractIntroduction: Joubert syndrome (JS) arises from defects of primary cilia resulting in potential malformations of the brain, kidneys, eyes, liver, and limbs. Several of the 35+ genes associated with JS have recognized genotype/phenotype correlations, but most genes have not had enough reported individuals to draw meaningful conclusions.Methods: A PubMed literature review identified 688 individuals with JS across 32 genes and 112 publications to bolster known genotype/phenotype relationships and identify new correlations.All included patients had the “molar tooth sign” and a confirmed genetic diagnosis. Individuals were categorized by age, ethnicity, sex and the presence of developmental disability/intellectual disability, hypotonia, abnormal eye movements, ataxia, visual impairment, renal impairment, polydactyly, and liver abnormalities.Results: Most genes demonstrated unique phenotypic profiles. Grouping proteins based on physiologic interactions established stronger phenotypic relationships that reflect known ciliary pathophysiology. Age‐stratified data demonstrated that end‐organ disease is progressive in JS. Most genes demonstrated a significant skew towards having variants with either residual protein function or no residual protein function.Conclusion: This cohort demonstrates that clinically meaningful genotype/phenotype relationships exist within most JS‐related genes and can be referenced to allow for more personalized clinical care.
Subject
Genetics (clinical),Genetics