Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies.
Inherited retinal dystrophies (IRD) comprise a wide group of clinically and genetically complex diseases that progressively affect the retina. Over recent years, the development of next-generation sequencing (NGS) methods has transformed our ability to diagnose heterogeneous diseases. In this work, we have evaluated the implementation of whole exome sequencing (WES) for the molecular diagnosis of IRD. Using Ion ProtonTMsystem, we simultaneously analyzed 212 genes that are responsible for more than 25 syndromic and non-syndromic IRD. This approach was used to evaluate 59 unrelated families, with the pathogenic variant(s) successfully identified in 71.18% of cases. Interestingly, the mutation detection rate varied substantially depending on the IRD subtype. Overall, we found 63 different mutations (21 novel) in 29 distinct genes, and performed in vivo functional studies to determine the deleterious impact of variants identified in MERTK, CDH23, and RPGRIP1. In addition, we provide evidences that support CDHR1 as a gene responsible for autosomal recessive retinitis pigmentosa with early macular affectation, and present data regarding the disease mechanism of this gene. Altogether, these results demonstrate that targeted WES of all IRD genes is a reliable, hypothesis-free approach, and a cost- and time-effective strategy for the routine genetic diagnosis of retinal dystrophies.
Departament de Genètica, Institut de Microcirurgia Ocular (IMO), Barcelona, Spain.
Marina
M
Riera
Departament de Retina, Institut de Microcirurgia Ocular (IMO), Barcelona, Spain.
Rafael
R
Navarro
Departament de Genètica, Institut de Microcirurgia Ocular (IMO), Barcelona, Spain.
Sheila
S
Ruiz-Nogales
Departament de Genètica, Institut de Microcirurgia Ocular (IMO), Barcelona, Spain.
Pilar
P
Méndez
Departament de Retina, Institut de Microcirurgia Ocular (IMO), Barcelona, Spain.
Anniken
A
Burés-Jelstrup
Departament de Retina, Institut de Microcirurgia Ocular (IMO), Barcelona, Spain.
Borja
B
Corcóstegui
Departament de Genètica, Institut de Microcirurgia Ocular (IMO), Barcelona, Spain.
Esther
E
Pomares
D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D003598:Cytoskeletal Proteins; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D050505:Mutant Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D058499:Retinal Dystrophies / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics; D000073359:Exome Sequencing / Q000379:methods*; D000076202:c-Mer Tyrosine Kinase / Q000235:genetics
C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D003598:Cytoskeletal Proteins; D050505:Mutant Proteins; D011506:Proteins; C415903:RPGRIP1 protein, human; C097072:MERTK protein, human; D000076202:c-Mer Tyrosine Kinase