ABSTRACT
BACKGROUND: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. METHODS: We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off. RESULTS: We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a 'pure JS' phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes. CONCLUSIONS: This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.
Subject(s)
Cerebellum/abnormalities , Genetic Heterogeneity , Retina/abnormalities , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Cerebellum/pathology , Cohort Studies , DNA Mutational Analysis , Eye Abnormalities/genetics , Eye Abnormalities/pathology , Genetic Association Studies , Humans , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/pathology , Models, Theoretical , Pedigree , Retina/pathology , Sequence Analysis, DNAABSTRACT
This study investigated third molar removal as a risk factor for temporomandibular disorder (TMD) in all age groups. We compared 2217 Kaiser Permanente Northwest health plan enrollees with a history of third molar extraction with 2217 age-and gender-matched enrollees with radiographic confirmation of no lifetime third molar removal. Common Dental Terminology codes were used to identify information on third molar removal, and International Classification of Disease codes were used to identify TMD. Relative risks were calculated overall, and by each decade of life, in univariate and multivariate analyses. The incidence of TMD in subjects with and without third molar removal were 7 and 5 per thousand person-years, respectively. Third molar removal among subjects of all ages resulted in a statistically insignificant increased relative risk for TMD (1.4, 95% confidence interval (CI): 0.9-2.2). The relative risk was slightly higher in those under 21, but was also not statistically significant (1.6, CI: 0.8-3.1).
