title: 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.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: CEINGE-Biotecnologie Avanzate s.c.a r.l., Via Gaetano Salvatore 486, I-80145, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Esposito
authors.affiliation: Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Second University of Naples, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Testa
authors.affiliation: Department of Nephrology, Second University of Naples, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Zacchia
authors.affiliation: CEINGE-Biotecnologie Avanzate s.c.a r.l., Via Gaetano Salvatore 486, I-80145, Naples, Italy.
authors.forename: Anna Alessia
authors.initials: AA
authors.lastname: Crispo
authors.affiliation: Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Second University of Naples, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Iorio
authors.affiliation: Department of Nephrology, Second University of Naples, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Capolongo
authors.affiliation: Department of Nephrology, Second University of Naples, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Rinaldi
authors.affiliation: CEINGE-Biotecnologie Avanzate s.c.a r.l., Via Gaetano Salvatore 486, I-80145, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: D'Antonio
authors.affiliation: IRCCS-Fondazione SDN Naples, Via Emanuele Gianturco 113, I-80143, Naples, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Fioretti
authors.affiliation: Area of Audiology, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Iadicicco
authors.affiliation: Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Second University of Naples, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Settimio
authors.initials: S
authors.lastname: Rossi
authors.affiliation: CEINGE-Biotecnologie Avanzate s.c.a r.l., Via Gaetano Salvatore 486, I-80145, Naples, Italy.|Area of Audiology, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Franzè
authors.affiliation: Area of Audiology, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Via Sergio Pansini 5, I-80131, Naples, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Marciano
authors.affiliation: Department of Nephrology, Second University of Naples, Via Sergio Pansini 5, I-80131, Naples, Italy. gb.capasso@unina2.it.
authors.forename: Giovanbattista
authors.initials: G
authors.lastname: Capasso
authors.affiliation: Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Second University of Naples, Via Sergio Pansini 5, I-80131, Naples, Italy. francesca.simonelli@unina2.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Simonelli
authors.affiliation: CEINGE-Biotecnologie Avanzate s.c.a r.l., Via Gaetano Salvatore 486, I-80145, Naples, Italy. salvator@unina.it.|IRCCS-Fondazione SDN Naples, Via Emanuele Gianturco 113, I-80143, Naples, Italy. salvator@unina.it.
authors.forename: Francesco
authors.identifier: http://orcid.org/0000-0002-2346-3564
authors.initials: F
authors.lastname: Salvatore
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001309:Auditory Threshold; D020788:Bardet-Biedl Syndrome / Q000235:genetics* / Q000473:pathology; D018833:Chaperonins; D002648:Child; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D004252:DNA Mutational Analysis; D005123:Eye / Q000000981:diagnostic imaging / Q000503:physiopathology*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D056385:Group II Chaperonins / Q000235:genetics; D006801:Humans; D007558:Italy; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics; D041623:Tomography, Optical Coherence; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: C512111:BBS10 protein, human; C464790:Bbs1 protein, human; C473309:Bbs2 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins; D004247:DNA; D018833:Chaperonins; D056385:Group II Chaperonins
keywords: BBS1, BBS2 and BBS10 gene variants; Bardet-Biedl syndrome; Ciliopathy; Renal, ocular and audiovestibular phenotype