gms | German Medical Science

Inherited retinal diseases (RD) show a high degree of clinical and genetic heterogeneity, and at the same time several genes are mutated in different subtypes of retinal diseases. In the last two decades more than 100 retinal disease genes were identified, mutations in which underlie between 50 and 75% of the cases. Candidate gene analysis, positional cloning studies, and animal models have facilitated the identification of the majority of RD genes. In the last two years, a new high-throughput sequencing technology coined ‘next generation sequencing’ (NGS) has revolutionarized the entire field of biology, and in particular human genetics. The genetic basis of intellectual disability, autism, and several developmental diseases have recently been elucidated. We have employed NGS in two different ways. First, we combined different types of positional information of the RD associated gene defect(s) with NGS. In families with autosomal dominant familial vitreoretinopathy (FEVR) we combined whole genome genetic linkage information with whole genome exon NGS and identified two novel FEVR genes, among which TSPAN12. Second, by homozygosity mapping in nonconsanguineous autosomal recessive cone-rod dystrophy (arCRD), and targeted NGS of the homozygous regions, we identified a novel arCRD gene. Second, we developed a NGS-based diagnostic screening platform for all inherited RDs by enriching the exon sequences of all known 111 inherited RD genes and subsequent NGS analysis. In this way, we were able to identify causative mutations in 50–60% of patients with autosomal recessive or isolated retinitis pigmentosa. The interpretation of sequence variants however remains challenging, in particular for (combinations of) missense mutations. The abovementioned studies and techniques are expected to identify more than 90% of the underlying defects in inherited RDs in the next 5 years. We are thus facing a new challenge, i.e. how to make maximal use of this knowledge for genetic counseling, disease prevention, and therapy. For ~75% of nonsyndromic recessive RDs, mouse models have been found or created, and more than 25% have already have been successfully used for proof-of-concept gene therapy studies. These studies include genes implicated in achromatopsia, arCRD, arRP, and Leber congenital amaurosis. The development of gene therapy trials in humans is gene-specific and thereby costly and time consuming. The question is whether there are sufficient financial resources to develop these therapies for the rare forms of RDs, many of which affect less than 1 in a million individuals.