title: Identity-by-descent-guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy.
abstract: OBJECTIVE
  Autosomal recessive retinal dystrophies are clinically and genetically heterogeneous, which hampers molecular diagnosis. We evaluated identity-by-descent-guided Sanger sequencing or whole-exome sequencing in 26 families with nonsyndromic (19) or syndromic (7) autosomal recessive retinal dystrophies to identify disease-causing mutations.
  
  
  METHODS
  Patients underwent genome-wide identity-by-descent mapping followed by Sanger sequencing (16) or whole-exome sequencing (10). Whole-exome sequencing data were filtered against identity-by-descent regions and known retinal dystrophy genes. The medical history was reviewed in mutation-positive families.
  
  
  RESULTS
  We identified mutations in 14 known retinal dystrophy genes in 20/26 (77%) families: ABCA4, CERKL, CLN3, CNNM4, C2orf71, IQCB1, LRAT, MERTK, NMNAT1, PCDH15, PDE6B, RDH12, RPGRIP1, and USH2A. Whole-exome sequencing in single individuals revealed mutations in either the largest or smaller identity-by-descent regions, and a compound heterozygous genotype in NMNAT1. Moreover, a novel deletion was found in PCDH15. In addition, we identified mutations in CLN3, CNNM4, and IQCB1 in patients initially diagnosed with nonsyndromic retinal dystrophies.
  
  
  CONCLUSIONS
  Our study emphasized that identity-by-descent-guided mutation analysis and/or whole-exome sequencing are powerful tools for the molecular diagnosis of retinal dystrophy. Our approach uncovered unusual molecular findings and unmasked syndromic retinal dystrophies, guiding future medical management. Finally, elucidating ABCA4, LRAT, and MERTK mutations offers potential gene-specific therapeutic perspectives.
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors.forename: Frauke
authors.initials: F
authors.lastname: Coppieters
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Schil
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors.forename: Miriam
authors.initials: M
authors.lastname: Bauwens
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: Verdin
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: De Jaegher
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors.forename: Delfien
authors.initials: D
authors.lastname: Syx
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Sante
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors.forename: Steve
authors.initials: S
authors.lastname: Lefever
authors.affiliation: Department of Histology, Medical University of Sfax, Sfax, Tunisia.
authors.forename: Nouha Bouayed
authors.initials: NB
authors.lastname: Abdelmoula
authors.affiliation: Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
authors.forename: Fanny
authors.initials: F
authors.lastname: Depasse
authors.affiliation: Department of Ophthalmology, Leuven University Hospitals, Leuven, Belgium.
authors.forename: Ingele
authors.initials: I
authors.lastname: Casteels
authors.affiliation: Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium.
authors.forename: Thomy
authors.initials: T
authors.lastname: de Ravel
authors.affiliation: Department of Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Meire
authors.affiliation: 1] Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium [2] Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium [3] Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA [4] Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Center for Medical Genetics Ghent, Ghent University, Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
mesh_terms: D000293:Adolescent; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D019721:Ophthalmoscopes; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D058499:Retinal Dystrophies / Q000175:diagnosis* / Q000235:genetics*; D014070:Tooth / Q000473:pathology
chemical_list: C498835:CDHR15, human; D000070585:Cadherin Related Proteins; D015820:Cadherins