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Genes (Basel). 2020 Jan 28;11(2). pii: E137. doi: 10.3390/genes11020137.

Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies.

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Department of Ophthalmology, University of Bonn, 53113 Bonn, Germany.
Center for Rare Diseases Bonn (ZSEB), University of Bonn, 53113 Bonn, Germany.
Roche Pharma Research and Early Development, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
Senckenberg Centre for Human Genetics, 60314 Frankfurt, Germany.
Institute of Human Genetics, University Medical Center Mainz, 55131 Mainz, Germany.
Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany.


Inherited retinal dystrophies (IRDs) are characterized by high clinical and genetic heterogeneity. A precise characterization is desirable for diagnosis and has impact on prognosis, patient counseling, and potential therapeutic options. Here, we demonstrate the effectiveness of the combination of in-depth retinal phenotyping and molecular genetic testing in complex pedigrees with different IRDs. Four affected Caucasians and two unaffected relatives were characterized including multimodal retinal imaging, functional testing, and targeted next-generation sequencing. A considerable intrafamilial phenotypic and genotypic heterogeneity was identified. While the parents of the index family presented with rod-cone dystrophy and ABCA4-related retinopathy, their two sons revealed characteristics in the spectrum of incomplete congenital stationary night blindness and ocular albinism, respectively. Molecular testing revealed previously described variants in RHO, ABCA4, and MITF as well as a novel variant in CACNA1F. Identified variants were verified by intrafamilial co-segregation, bioinformatic annotations, and in silico analysis. The coexistence of four independent IRDs caused by distinct mutations and inheritance modes in one pedigree is demonstrated. These findings highlight the complexity of IRDs and underscore the need for the combination of extensive molecular genetic testing and clinical characterization. In addition, a novel variant in the CACNA1F gene is reported associated with incomplete congenital stationary night blindness.


NGS; Stargardt disease; Waardenburg syndrome; congenital stationary night blindness; dystrophy; genotype; molecular testing; phenotype; retina; retinitis pigmentosa

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