A single-centre re-evaluation strategy increased reported diagnostic yield
A report in Ophthalmology Times Europe describes how systematic reanalysis and additional genetic testing changed the molecular diagnostic rate in a Portuguese inherited retinal dystrophy (IRD) cohort. João Pedro Marques, MD, PhD, discussed findings from a single-centre study presented at the American Society of Retina Specialists’ 44th Annual Scientific Meeting.
According to Marques, the initial testing approach identified a genetic explanation in 59.4% of families. After re-evaluating prior results and using targeted follow-up approaches, the reported solved rate reached 70.1%—an increase involving 86 families. The article characterizes variant reclassification as the main contributor to those additional diagnoses.
Why an initial negative or uncertain result may not be final
IRDs are genetically diverse conditions, and a negative, incomplete, or uncertain result does not necessarily rule out a genetic cause. Marques noted that standard exome sequencing and some gene panels may have technical limitations. Examples cited include difficult-to-sequence repetitive or GC-rich regions, such as the ORF15 region of RPGR, as well as deep intronic variants, including a disease-associated CEP290 variant.
The interview also highlighted structural changes in DNA, such as deletions and duplications, which may require copy-number testing rather than routine sequencing alone. In addition, a result may remain uncertain when family testing is unavailable or when laboratories cannot determine whether two variants are located on the same or different copies of a chromosome.
Scientific interpretation can also change over time. New gene–disease links are reported, and previously identified variants may be reclassified as additional evidence becomes available. The article gave an example involving a hypomorphic ABCA4 variant that had initially been considered too common to explain disease on its own but was later considered relevant in combination with another variant.
What the re-evaluation involved
Rather than simply repeating the same test, the study team reportedly revisited existing exome data and used updated gene panels. The strategy also included targeted testing for known blind spots, such as RPGR ORF15 and a CEP290 intronic variant, plus multiplex ligation-dependent probe amplification (MLPA) testing for deletions.
Family segregation studies were used to help clarify inheritance and the phase of variants. Variants of uncertain significance were reassessed using current scientific literature, ClinVar, gnomAD, and computational tools including REVEL and VarSome, according to the interview.
Why this may matter for the IRD community
A confirmed molecular diagnosis can be relevant when a therapy, research study, or clinical trial has gene-specific eligibility criteria. Marques noted that treatments may be directed at a particular gene or even a particular variant. The article referenced RPE65 as an example of a gene with an approved therapy, while emphasizing that an incomplete or uncertain genetic finding may affect whether a person can document eligibility.
The reported experience also underscores that genetic results may need periodic review as testing methods and variant knowledge evolve. For families, updated results may potentially clarify the underlying diagnosis and inheritance pattern. However, the publisher’s article does not provide enough detail to determine how often retesting should occur for every person with an IRD.
Important limitations
These findings come from a single referral centre and were described in a Q&A about a conference presentation. The publisher text does not provide the full study methods, participant characteristics, follow-up duration, statistical analyses, or a peer-reviewed publication. Therefore, the reported increase in diagnostic yield should not be assumed to apply equally across all testing laboratories, populations, or IRD types.
The article also does not establish that reanalysis or targeted testing leads to treatment access or improved vision outcomes. It reports a diagnostic strategy and its stated effect on the number of families receiving a molecular explanation.
Publisher source
Ophthalmology Times: When to retest for inherited retinal dystrophies