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Nicola Gloeckle, Susanne Kohl, Julia Mohr, Kathrin Bengesser, Tim Scheurenbrand, Andrea Sprecher, Konstanze Hoertnagel, Bernd Wissinger, Saskia Biskup, ; Unusual genetic findings in 900 patients clinically diagnosed with hereditary retinal dystrophies. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1244.
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Genetic heterogeneity and variable expressivity are well known features in hereditary retinal dystrophies (RD). It can be challenging for physicians to determine an accurate diagnosis based solely on clinical examinations, especially without a wide set of diagnostic tools (e.g. ERG). Our aim was to show the divergence between clinical and molecular diagnosis in the field of RD and related syndromes.
More than 150 genes associated with RD were selected from literature or databases. A custom target-in-solution-enrichment was applied, followed by sequencing on either SOLiD 5500xl or Illumina HiSeq 2500 platforms. Different databases were used to annotate variants. Genes known to be associated with the suspected diagnosis and most likely mode of inheritance of each patient were first evaluated. If the patient declaration of consent included consent to inform the patient about incidental findings, we extended evaluation of variants to all RD-related genes that are enriched on this panel.
We analyzed 900 patients diagnosed with different forms of RD. We could solve 52% of these cases. Interestingly, in 6.8% of solved cases we identified pathogenic or likely pathogenic mutations in genes that had not been previously linked to the respective phenotypes. This indicates that it is not simple to clinically differentiate the different types of RD.<br /> In close collaboration with attending physicians, we could confirm that some patients have a syndromic form of RD not initially suspected. We identified mutations in ALMS1, BBS4, BBS7, CLN3, IQCB1 and VPS13B in patients initially diagnosed with different forms of non-syndromic RD.<br /> In addition, in 1.5% of solved cases of sporadic Retinitis Pigmentosa we identified mutations in genes known to follow an autosomal dominant mode of inheritance, which suggests a de novo mutation or reduced penetrance of the corresponding genes. The mode of inheritance is first assumed to be recessive in these cases.
Our results exemplify the advantage of using broad NGS panel-based diagnostic genetic testing with the possibility of sequencing all genes related to the different forms of RD. Extending and applying genetic panel testing to all known RD genes might improve diagnostic sensitivity and extend the genes and mutations linked to certain phenotypes and vice versa.
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