Identity-by-descent–guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy

• DOI: 10.1038/gim.2014.24
• Publication Date: 2014-03-13T16:27:00Z
• Authors: Frauke Coppieters; Kristof Van Schil; Miriam Bauwens; Hannah Verdin; Annelies De Jaegher; Delfien Syx; Tom Sante; Steve Lefever; Nouha Bouayed Abd...; Fanny Depasse; Ingele Casteels; Thomy de Ravel; Françoise Meire; Bart P. Leroy; Elfride De Baere
• Keywords: Male; Génétique clinique; identity-by-descent mapping; Child, preschool; Adolescent; DNA Mutational Analysis; Mutation, Missense; variant filtering; Cadherin Related Proteins; Genes, Recessive; Polymorphism, Single Nucleotide; Consanguinity; 03 medical and health sciences; Humans; Exome; whole-exome sequencing; retinal dystrophy; Child; 0303 health sciences; Cadherins/genetics; Retinal Dystrophies/diagnosis; Ophthalmoscopes; Tooth/pathology; Homozygote; Cadherins; Pedigree; 3. Good health; Phenotype; Child, Preschool; Mutation; Female; mutation; copy-number variation analysis; exome; Genome-Wide Association Study

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.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.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.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.