Genotype-Phenotype correlations in Joubert Syndrome in the Era of Next Generation Sequencing

Abstract

Results Core JS diagnostic features (hypotonia, ataxia, cognitive dysfunction, oculo-motor apraxia) were present in >80% of individuals, while abnormal breathing pattern was reported in 60%. Frequently associated features included retinal dystrophy (31.4%), renal disease (20.9%), coloboma (17.7%), polydactyly (15.3%), liver fibrosis (15.2%) and encephalocele (8%). Liver fibrosis and coloboma were strongly associated with each other (Odds Ratio 7.0, 95% Confidence Interval = 3.0-13.2), while retinal dystrophy and renal disease were weakly associated (O.R. 2.2, 95%C. I. = 1.7-5.6). Additional clinical features included other brain abnormalities (n = 73), seizures (n = 49), cleft palate (n = 16), hearing loss (n = 14) and psychiatric problems (n = 45). The genetic cause was identified in 60% of families, with 5 genes accounting for the majority of patients (C5ORF42, CEP290, CC2D2A, AHI1, TMEM67). Bi-allelic causal mutations in B9D2 and C2CD3 were identified in 2 families each. Bi-allelic mutations in 2 different genes were identified in 4 families and heterozygous mutations (in addition to the causal mutation) were present in 62 individuals. Significant (p<0.0001) genotype-phenotype correlations were observed: CEP290 with renal disease and retinal dystrophy; TMEM67 with liver fibrosis and coloboma.