Practical guide to genetic screening for inherited eye diseases.

Cécile Méjécase,Gavin Arno,Amy Slater,Samantha Malka,Zeyu Guan,Mariya Moosajee

doi:10.1177/2515841420954592

Abstract

Genetic eye diseases affect around one in 1000 people worldwide for which the molecular aetiology remains unknown in the majority. The identification of disease-causing gene variant(s) allows a better understanding of the disorder and its inheritance. There is now an approved retinal gene therapy for autosomal recessive RPE65-retinopathy, and numerous ocular gene/mutation-targeted clinical trials underway, highlighting the importance of establishing a genetic diagnosis so patients can fully access the latest research developments and treatment options. In this review, we will provide a practical guide to managing patients with these conditions including an overview of inheritance patterns, required pre- and post-test genetic counselling, different types of cytogenetic and genetic testing available, with a focus on next generation sequencing using targeted gene panels, whole exome and genome sequencing. We will expand on the pros and cons of each modality, variant interpretation and options for family planning for the patient and their family. With the advent of genomic medicine, genetic screening will soon become mainstream within all ophthalmology subspecialties for prevention of disease and provision of precision therapeutics.

Highlights

Worldwide, approximately one in 1000 people are affected with genetic eye disease.[1]
We provide guidance on current and future practices for genetic testing of Mendelian eye disorders, how to interpret results and guide genetic counselling
Vaclavik and colleagues reported one consanguineous family where the father and two of his three children were affected with enhanced S-cone syndrome, the pedigree appeared autosomal dominant but genetic analyses identified a homozygous variant in NR2E3 which cosegregated with the phenotype, revealing a pseudo-dominant inheritance.[50]

Summary

Introduction

Approximately one in 1000 people are affected with genetic eye disease.[1]. Incomplete or reduced penetrance means that a pathogenic variant does not always result in the patient being affected with the disease.[48] For example, PRPF31, which causes autosomal dominant RP, has been shown to exhibit variable expressivity and reduced penetrance, severity of symptoms can vary significantly in affected relatives within the same family with some carriers being totally asymptomatic (Figure 5).[49]. Pseudo-dominance is more likely to occur in families with consanguinity or in recessive disorders where there may be a high carrier frequency of mutations (perhaps enriched in an isolated community or ethnicity).[50] Vaclavik and colleagues reported one consanguineous family where the father and two of his three children were affected with enhanced S-cone syndrome, the pedigree appeared autosomal dominant but genetic analyses identified a homozygous variant in NR2E3 which cosegregated with the phenotype, revealing a pseudo-dominant inheritance.[50]. Counselling a patient on inheritance and family risks prior to genetic testing can be challenging, as many Mendelian hereditary eye disorders can be inherited by more than one

Aim

Variant calling

Variant annotation

Optional

Findings

Conclusion