Progress and prospects of next-generation sequencing testing for inherited retinal dystrophy

Abstract

Next-generation sequencing, also known as massively paralleled sequencing, offers an unprecedented opportunity to study disease mechanisms of inherited retinal dystrophies: a dramatic change from a few years ago. The specific involvement of the retina and the manageable number of genes to sequence make inherited retinal dystrophies an attractive model to study genotype–phenotype correlations. Costs are reducing rapidly and the current overall mutation detection rate of approximately 60% offers real potential for personalized medicine and treatments. This report addresses the challenges ahead, which include: better understanding of the mutation mechanisms of syndromic genes in apparent non-syndromic patients; finding mutations in patients who have tested negative or inconclusive; better variant calling, especially for intronic and synonymous variants; more precise genotype–phenotype correlations and making genetic testing more broadly accessible.

Keywords:

• genes
• genetic testing
• genotyping
• inherited retinal dystrophy
• LCA
• molecular diagnosis
• NGS
• retina
• retinitis pigmentosa
• Stargardt disease

Acknowledgements

The Australian Inherited Retinal Disease Register and DNA Bank is financially supported by Retina Australia. The support of the Department of Medical Technology and Physics, Sir Charles Gairdner Hospital is gratefully acknowledged.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Inherited retinal dystrophies (IRDs), complicated genetic conditions with specific clinical presentations and continually enlarging number of genes identified, are coming to the center stage as a model to showcase the potential of personalized medicine.

• The molecular diagnosis of IRDs has come a long way, especially with the rapid progress experienced after the arrival of next-generation sequencing, which is becoming a key tool for the clinical diagnosis of IRDs.

• The non-hypothesis-driven approach, by sequencing all known genes implicated in IRDs simultaneously, offers the best opportunity for genotype–phenotype correlation studies.

• The finding of multiple mutations in different IRD-associated genes is not uncommon, which challenges the simple concept of single-gene diseases in IRDs.

• Multigenic and multiallelic inheritance patterns and genetic modifiers will become the new frontiers in the study of disease mechanisms of IRDs.

• Deep intronic mutations and mutations outside the typically sequenced regions may account for some of the missing, second mutations in autosomal recessive conditions.

• Most of the common IRD-associated genes have likely already been identified and syndromic genes, which have never been sequenced before in non-syndromic patients, may harbor many of the missing mutations.

• A true US$1000 genome is still many years away but the US$1000 IRD genome (at least the coding regions of all the known IRD-associated genes) is within reach.

• The value of molecular diagnosis as a first-line diagnostic tool for IRDs has significant potential in less-developed countries, where clinical services may be limited.

• Even in developed countries, the benefits of more timely and definitive answers will make molecular diagnosis a standard medical diagnostic tool for IRDs.