title: Exploring genotype-phenotype relationships in Bardet-Biedl syndrome families.
abstract: BACKGROUND
  Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy that displays retinal dystrophy, obesity, polydactyly, cognitive impairment, urogenital anomalies and renal abnormalities as primary clinical features. To date, 19 causative genes (BBS1-19) have been involved, whose mutations would explain over 80% of patients. The overlapping phenotypes among ciliopathies, in addition to the high intrafamilial and interfamilial variability in clinical presentation, further complicate the diagnosis of this syndrome. Thus, the main purpose of this study was to elucidate some genotype-phenotype trends that could be helpful to focus the molecular diagnosis of patients with BBS.
  
  
  METHODS
  Thirty-seven families (52 cases) with mutations in BBS1 or chaperonin-like BBS genes (BBS6, BBS10, BBS12) from our Spanish cohort were enrolled. Systemic and ocular features were documented as comprehensively as possible.
  
  
  RESULTS
  Comparing BBS1 versus chaperonin-like genes phenotypes we found more severe clinical features in the second group, since they displayed higher prevalence of all primary features, remarkable being the frequency of cognitive impairment (75%) in BBS12 and urogenital anomalies (83%) in patients with BBS10. With regards to p.(Met390Arg) cases, homozygotes showed a relatively more severe ocular phenotype than compound heterozygotes, since more severe fundus alterations and higher frequency of cataracts and dyschromatopsia (not previously described) were documented in the first group. The phenotypes observed frequently overlapped with Alström syndrome and, in the case of chaperonin-like genes, McKusick-Kauffman syndrome overlapping was detected.
  
  
  CONCLUSIONS
  We provide the first evidence of BBS12 mutations related to severe phenotypes as previously described for patients with BBS10, while BBS1 ocular phenotype should not be considered as mild as generally reported when compared with other BBS phenotypes.
authors.affiliation: Departamento de Bioquímica, Genética e Inmunología, Facultad de Biología, Universidad de Vigo, Vigo, Spain Instituto de Investigación Biomédica Ourense-Pontevedra-Vigo (IBI), Vigo, Spain.
authors.forename: Sheila
authors.initials: S
authors.lastname: Castro-Sánchez
authors.affiliation: Departamento de Bioquímica, Genética e Inmunología, Facultad de Biología, Universidad de Vigo, Vigo, Spain Instituto de Investigación Biomédica Ourense-Pontevedra-Vigo (IBI), Vigo, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Álvarez-Satta
authors.affiliation: Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cortón
authors.affiliation: Medical Genetics Unit, Pediatrics Service, Virgen de la Arrixaca University Hospital, Murcia, Spain.
authors.forename: Encarna
authors.initials: E
authors.lastname: Guillén
authors.affiliation: Department of Genetics, IIS-Fundación Jiménez Díaz, CIBERER, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.affiliation: Departamento de Bioquímica, Genética e Inmunología, Facultad de Biología, Universidad de Vigo, Vigo, Spain Instituto de Investigación Biomédica Ourense-Pontevedra-Vigo (IBI), Vigo, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Valverde
mesh_terms: D000328:Adult; D020788:Bardet-Biedl Syndrome / Q000235:genetics* / Q000473:pathology; D018833:Chaperonins; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D056385:Group II Chaperonins / Q000235:genetics*; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008875:Middle Aged; D009154:Mutation
chemical_list: C512111:BBS10 protein, human; C517002:BBS12 protein, human; C464790:Bbs1 protein, human; C414726:MKKS protein, human; D008869:Microtubule-Associated Proteins; D018833:Chaperonins; D056385:Group II Chaperonins
keywords: BBS genes; Bardet-Biedl Syndrome; Ciliopathies; genotype-phenotype