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Incremental yield for Genome Sequencing in individuals with inherited retinal diseases

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction:
Inherited retinal diseases (IRDs) comprises a group of disorders with high clinical and genetic heterogeneity, variable age of onset, rate of disease progression, and prognosis.  Understanding the molecular etiology of IRDs is critical for management, prognosis, familial cascade testing, and most importantly treatment and surveillance for newly approved gene-specific therapeutics.  Molecular testing for diagnosis of suspected IRDs is variable and includes several next generation sequencing modalities as well as gene specific approaches.  Here we retrospectively assessed genome sequencing (GS) results in a cohort of patients with IRD to determine the overall yield of diagnostic results and compare incremental yield of this testing modality in patients with previous molecular testing.

Methods:
Patients with suspected IRDs (n=104) were evaluated at the Edward S. Harkness Eye Institute at Columbia University Irving Medical Center (CUIMC) between February 2018 and January 2023 and specimen for clinical GS sent to the New York Genome Center (NYGC).  Male-to-female ratio was 1.5:1 in the cohort with a median of 41.5  years and age range of 3-84 years.  Of the 104 individuals submitted for GS, 55 probands (52.9%) had undergone previous genetic testing considered non-informative.  Previous testing in these individuals included one or more retinal disease gene panels, exome sequencing, and one patient for whom chromosomal microarray was performed. A case was considered positive if GS detected Pathogenic (P) or Likely Pathogenic (LP) variant(s) that were consistent with the phenotype reported in the proband and were consistent with the inheritance pattern of the associated disease.  Cases were considered potentially positive if two or more variants with unknown phase were found in a gene with an autosomal recessive inheritance pattern if the disease association of that gene was consistent with the patient phenotype and at least one of the variants was classified as P/LP. 

Results:


GS resulted in a positive or potentially positive finding in 29.8% (31/104) of all patients. In total, there were 43 variants reported in positive and potentially positive cases including nonsense (n=11), missense (n=10), frameshift (n=7), copy number variants (n=6), intronic (n=3), Alu insertion (n=2), canonical splice (n=1), in-frame indel (n=1), noncoding (n=1), and synonymous (n=1) variants.  Mode of inheritance was autosomal dominant in 35.5% of cases, compound heterozygous in 29.0% of cases, homozygous in 25.8% of cases, hemizygous in 3.2% of cases, and two variants in the same gene, phase unknown in the two (6.5%) potentially positive cases. 

14 of the 31 cases solved by GS had previously uninformative diagnostic testing including 5 cases with previous panel only testing, 7 cases with previous exome sequencing, and 2 cases with previous panel and exome testing.  In total, 45.2% of positive cases (14/31) including 25.4% (14/55) of all cases with previous testing, received a positive result with GS.  This suggests an incremental yield of approximately 25% for GS compared to other testing modalities in our cohort.  Of the cases solved by GS with previously non-informative genetic testing, the most common variant types reported in GS positive cases with previous negative testing were copy number variants (n=4) and intronic variants outside of the +/-10bp splice region (n=3). 





Conclusion:
The results of this study do indicate that GS leads to an incremental diagnostic yield in individuals with IRD compared to other commonly utilized testing modalities.  This supports GS as a first-tier molecular test for individuals with IRDs.

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