Genetic Testing in Inherited Retinal Diseases

Educational Objectives

The goal of this program is to improve use of genetic testing for inherited retinal diseases in clinical practice. After hearing and assimilating this program, the clinician will be better able to:

1. Identify benefits and limitations of genetic testing for inherited retinal diseases.

Summary

Genetic counseling (GC): in addition to facilitating genetic testing for patients, GC involves review of medical and family history, patient and family education, addressing psychosocial aspects, and pretest and posttest counseling

Challenges in diagnosis of inherited retinal dystrophies (IRDs): nonspecific symptoms and phenotype — diagnosis relies heavily on electroretinography and other imaging techniques; genotype and phenotype overlap between many genes; variants within the same gene can cause different retinal disorders (eg, ABCA4 gene is associated with Stargardt disease, cone dystrophy, and cone-rod dystrophy); different syndromic disorders may be associated with a gene; many genes are often associated with a disorder (eg, retinitis pigmentosa); many phenocopies are present (eg, paraneoplastic syndrome, diabetic retinopathy); lack of family history — family history is often unavailable to indicate inheritance pattern; reduced penetrance and variable expressivity complicate the picture; noncoding variants — many are missed by gene panels

Genetic testing options: single gene tests — appropriate for diseases caused by mutations in a single gene (eg, CHM gene in choroideremia, repeat expansion within the SCA7 gene in spinocerebellar ataxia type 7); targeted tests may be used for known mutations in the family; multigene panels — cover certain variants (eg, ORF15 region in RPGR gene that is linked to X-linked retinitis pigmentosa, noncoding variants, deep intronic variants of ABCA4); some diseases require specific attention (eg, blue cone monochromacy, North Carolina macular dystrophy); clinical exome or genome sequencing — expensive and may not be covered by insurance

Detection rates in IRDs: depend on factors including coverage depth and inclusion of relevant noncoding regions; Gonzalez-Duarte et al (2019) reported a detection rate of ≈85% using targeted gene panels and ≈75% using exome sequencing; in general, detection rate for targeted panels is 60% to 70%; inclusion of additional genes may not increase diagnostic yield

Variation in detection rates: gene curation — laboratories include different number of genes and noncoding variants; variant classification — laboratories classify variants differently; variant classification recommended by the American College of Medical Genetics and Genomics (ACMG) is complicated and includes pathogenic, likely pathogenic, variants of unknown significance (VUS), benign, and likely benign

Types of genetic variants: single nucleotide variants — include nonsense, missense, and silent mutations; structural or copy number variants (CNV) — include insertion, deletion, and translocation

Benefits of a genetic diagnosis: guides medical management (eg, vitamin A is contraindicated in ABCA4 mutations) and referral to specialists; allows for inclusion in clinical trials of gene therapy; inheritance pattern can identify at-risk relatives and inform recurrence risk and family planning; may be helpful with prognosis and offer psychosocial benefits

Presymptomatic genetic tests: consider treatability of the condition; interpretation of risk differs among individuals; may affect family relationships and marriage; one may feel guilty with negative results or transmission to the next generation; the Genetic Information Nondiscrimination Act provides protection against discrimination by employers and in health insurance (does not cover other types of insurance) for presymptomatic individuals; minors — not recommended unless medical benefit is clear or testing affects medical management; carrier testing is also not recommended before reproductive age

Limitations of multigene panels: variants are reclassified over time (eg, VUS); covers only specific regions; new genes are discovered

Exome sequencing (ES): only exons (coding regions) are sequenced; does not capture noncoding variants and trinucleotide repeats; may not identify break points in CNV; polymorphisms are excluded; detection rate is 20% to 50% (higher with trio) and is much lower if performed after gene panels; ES is useful in multiple phenotypes, with multiple indications, and when gene panels are not available; ES can be less expensive; AMCG recommends reporting secondary findings (73 genes), which are identified in 2% to 5% of patients; ES is less likely to identify VUS; ES can identify consanguinity, nonpaternity, and nonmaternity; interpretation is evolving

Readings

Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370(25):2418-2425. doi:10.1056/NEJMra1312543; Gonzàlez-Duarte R, de Castro-Miró M, Tuson M, et al. Scaling new heights in the genetic diagnosis of inherited retinal dystrophies. Adv Exp Med Biol. 2019;1185:215-219. doi:10.1007/978-3-030-27378-1_35; Mustafi D, Hisama FM, Huey J, et al. The current state of genetic testing platforms for inherited retinal diseases. Ophthalmol Retina. 2022;6(8):702-710. doi:10.1016/j.oret.2022.03.011; Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Smith was recorded at Johns Hopkins Retinal Degeneration and Visual Electrophysiology Conference 2023, held September 15-16, 2023, in Baltimore, MD, and presented by Johns Hopkins University School of Medicine and The Wilmer Eye Institute. For more information about upcoming CME activities from this presenter, please visit https://hopkinscme.cloud-cme.com. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.50 CE contact hours.

Lecture ID:

OP621403

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.