Phenotypic variability in Joubert syndrome is partially explained by ciliary pathophysiology.

Autor: Owens JW; UPMC Children's Hospital of Pittsburgh Division of Genetic and Genomic Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Department of Pediatrics, Cincinnati Children's Hospital Medical Center Division of Human Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Hopkin RJ; Department of Pediatrics, Cincinnati Children's Hospital Medical Center Division of Human Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Martin LJ; Department of Pediatrics, Cincinnati Children's Hospital Medical Center Division of Human Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA., Kodani A; Department of Cell and Molecular Biology, Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, Tennessee, USA., Simpson BN; Department of Pediatrics, Cincinnati Children's Hospital Medical Center Division of Human Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Jazyk: angličtina
Zdroj: Annals of human genetics [Ann Hum Genet] 2024 Jan; Vol. 88 (1), pp. 86-100. Date of Electronic Publication: 2023 Nov 03.
DOI: 10.1111/ahg.12537
Abstrakt: Introduction: 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.
(© 2023 University College London (UCL) and John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz: