1. Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants
- Author
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Annamaria Franzè, Anna Crispo, Luca Rinaldi, Miriam Zacchia, Francesco Salvatore, Valentina Di Iorio, Marcella D’Antonio, Giovanna Capolongo, Pasquale Iadicicco, Francesca Simonelli, Giovanbattista Capasso, Tiziana Fioretti, Francesco Testa, Elio Marciano, Gabriella Esposito, Settimio Rossi, Esposito, Gabriella, Testa, Francesco, Zacchia, Miriam, Crispo, Anna Alessia, Di Iorio, Valentina, Capolongo, Giovanna, Rinaldi, Luca, D'Antonio, Marcella, Fioretti, Tiziana, Iadicicco, Pasquale, Rossi, Settimio, Franzè, Annamaria, Marciano, Elio, Capasso, Giovambattista, Simonelli, Francesca, Salvatore, Francesco, Franze', Annamaria, and Capasso, Giovanbattista
- Subjects
Male ,0301 basic medicine ,BBS2 ,Chaperonins ,BBS1 ,DNA Mutational Analysis ,Group II Chaperonins ,BBS10 ,Eye ,Kidney ,Bioinformatics ,0302 clinical medicine ,Bardet-Biedl syndrome ,Genetics(clinical) ,Child ,Genetics (clinical) ,Genetics ,Polydactyly ,Genetic disorder ,Middle Aged ,Phenotype ,Italy ,Female ,BBS1, BBS2 and BBS10 gene variants ,Microtubule-Associated Proteins ,Tomography, Optical Coherence ,Research Article ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Genotype ,Ciliopathy ,Renal, ocular and audiovestibular phenotype ,Biology ,White People ,Young Adult ,03 medical and health sciences ,Bardet–Biedl syndrome ,Retinitis pigmentosa ,medicine ,Humans ,Genetic Association Studies ,Aged ,Polymorphism, Genetic ,Proteins ,Auditory Threshold ,DNA ,medicine.disease ,030104 developmental biology ,030221 ophthalmology & optometry ,BBS1, BBS2 and BBS10 gene variant - Abstract
Background: Bardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS. Methods: We analyzed three common BBS genes, BBS1, BBS10 and BBS2, in 25 Italian patients fulfilling the clinical criteria of BBS. In 12 patients, we identified gene-specific biallelic variants and thus correlated genotype to the ophthalmic, renal and audio-vestibular phenotypes. Results: At least one sequence variant was found in 60% of patients. The most common mutated gene was BBS1 followed by BBS10. Of the 17 sequence variants we found, 11 have not previously been associated with BBS. In 12 patients, we identified biallelic pathogenic variants; they had retinitis pigmentosa with early onset of visual impairment. However, retinal dystrophy was less severe in patients with BBS1 than in those with BBS10 variants. Overall, we found a high prevalence of renal dysmorphism and dysfunction. Notably, patients with BBS10 variants had the most severe renal impairment, which resulted in a critical decline in renal function. All the patients who underwent audio-vestibular evaluation had dysfunction of the cochlear outer hair cells, thus confirming the presence of hearing defects. Conclusion:BBS1, BBS2 and BBS10 are major causative genes in Italian BBS patients. BBS10 was associated with the worse outcome in terms of the renal, ocular and audiovestibular phenotypes. Cochlear dysfunction should be included among the hallmarks of BBS. Background: Bardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS.Methods: We analyzed three common BBS genes, BBS1, BBS10 and BBS2, in 25 Italian patients fulfilling the clinical criteria of BBS. In 12 patients, we identified gene-specific biallelic variants and thus correlated genotype to the ophthalmic, renal and audio-vestibular phenotypes.Results: At least one sequence variant was found in 60% of patients. The most common mutated gene was BBS1 followed by BBS10. Of the 17 sequence variants we found, 11 have not previously been associated with BBS. In 12 patients, we identified biallelic pathogenic variants; they had retinitis pigmentosa with early onset of visual impairment. However, retinal dystrophy was less severe in patients with BBS1 than in those with BBS10 variants. Overall, we found a high prevalence of renal dysmorphism and dysfunction. Notably, patients with BBS10 variants had the most severe renal impairment, which resulted in a critical decline in renal function. All the patients who underwent audio-vestibular evaluation had dysfunction of the cochlear outer hair cells, thus confirming the presence of hearing defects.Conclusion: BBS1, BBS2 and BBS10 are major causative genes in Italian BBS patients. BBS10 was associated with the worse outcome in terms of the renal, ocular and audiovestibular phenotypes. Cochlear dysfunction should be included among the hallmarks of BBS.
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