title: High frequency of CRB1 mutations as cause of Early-Onset Retinal Dystrophies in the Spanish population.
abstract: BACKGROUND
  CRB1 mutations are reported as cause of severe congenital and early-onset retinal dystrophies (EORD) with different phenotypic manifestations, including Leber congenital amaurosis (LCA), retinitis pigmentosa (RP) and cone-rod dystrophies. Comprehensive mutational scanning of the whole gene has been only performed in few cohorts, mainly in LCA patients. Here, we aimed investigating the real prevalence of CRB1 mutations in the Spanish population by extensive screening of CRB1 mutations in a large cohort of LCA and EORP cases.
  
  
  METHODS
  This report integrates data from previous studies on CRB1 defects in our Spanish cohort of LCA and early-onset RP (EORP) with new findings from a comprehensive mutational screening of the whole gene. The molecular tools used include mutation genotyping arrays, whole-genome homozygosity mapping, an optimized high-resolution melting (HRM) analysis and Sanger sequencing.
  
  
  RESULTS
  A large clinically well-characterized cohort of 404 Spanish cases was studied, 114 of which suffered from LCA and 290 from EORP. This study reveals that 11% of Spanish patients carried mutations in CRB1, ranging from 9% of EORP to 14% of LCA cases. More than three quarters of the mutations identified herein have been first described in this Spanish cohort, 13 of them are unreported new variants and 13 had been previously reported in our previous studies.
  
  
  CONCLUSIONS
  This work provides a wide spectrum of CRB1 mutations in the Spanish EORD patients and evidences the major role of CRB1 as causal gene in the Spanish EORP patients. It is noteworthy that a high rate of private mutations only described in our cohort has been found so far. To our knowledge, this study represents the most complete mutational screening of CRB1 in a Spanish LCA and EORP cohort, allowing us to establish gene-specific frequencies and to provide a wide spectrum of CRB1 mutations in the Spanish population.
authors: Department of Genetics, IIS - Fundación Jiménez Díaz, Madrid, Spain.
authors: Marta
authors: M
authors: Corton
authors: Sorina D
authors: SD
authors: Tatu
authors: Almudena
authors: A
authors: Avila-Fernandez
authors: Elena
authors: E
authors: Vallespín
authors: Ignacio
authors: I
authors: Tapias
authors: Diego
authors: D
authors: Cantalapiedra
authors: Fiona
authors: F
authors: Blanco-Kelly
authors: Rosa
authors: R
authors: Riveiro-Alvarez
authors: Sara
authors: S
authors: Bernal
authors: Blanca
authors: B
authors: García-Sandoval
authors: Montserrat
authors: M
authors: Baiget
authors: Carmen
authors: C
authors: Ayuso
mesh_terms: D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011159:Population Surveillance; D058499:Retinal Dystrophies / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D013030:Spain / Q000453:epidemiology
chemical_list: C448939:CRB1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins
references: Am J Hum Genet. 2001 Jul;69(1):198-203
references: 11389483
references: Bioinformatics. 2004 May 22;20(8):1233-40
references: 14871870
references: Hum Genet. 2007 Apr;121(2):287-8
references: 17598198
references: Hum Mutat. 2012 Feb;33(2):306-15
references: 22065545
references: Ophthalmic Genet. 2001 Sep;22(3):163-9
references: 11559858
references: Br J Ophthalmol. 2011 Jun;95(6):811-7
references: 20956273
references: J Cell Sci. 2004 Aug 15;117(Pt 18):4169-77
references: 15316081
references: Hum Mutat. 2004 Apr;23(4):306-17
references: 15024725
references: Invest Ophthalmol Vis Sci. 2010 May;51(5):2615-9
references: 19959634
references: Prog Retin Eye Res. 2008 Jul;27(4):391-419
references: 18632300
references: Mech Dev. 2002 Jan;110(1-2):203-7
references: 11744384
references: Hum Mutat. 2004 Nov;24(5):355-69
references: 15459956
references: Nat Genet. 1999 Oct;23(2):217-21
references: 10508521
references: Hum Genet. 2010 Jan;127(1):119
references: 20108431
references: Hum Genet. 2006 Feb;118(6):777
references: 17297689
references: J Med Genet. 2003 Jul;40(7):e89
references: 12843338
references: J Cell Sci. 2009 Aug 1;122(Pt 15):2587-96
references: 19625503
references: Hum Mutat. 2009 Jun;30(6):860-6
references: 19418555
references: Hum Genet. 2006 Feb;118(6):774
references: 17297678
references: PLoS Comput Biol. 2006 May;2(5):e41
references: 16699594
references: Arch Ophthalmol. 2001 Mar;119(3):415-20
references: 11231775
references: Hum Mutat. 2010 Oct;31(10):E1709-66
references: 20683928
references: Invest Ophthalmol Vis Sci. 2007 Sep;48(9):4284-90
references: 17724218
references: Nature. 2002 Mar 14;416(6877):143-9
references: 11850625
references: Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5653-61
references: 18055816
references: Hum Mol Genet. 2001 Nov 15;10(24):2767-73
references: 11734541
references: Hum Mutat. 2009 Jun;30(6):857-9
references: 19479960
references: Mol Vis. 2010 Dec 03;16:2550-8
references: 21151602