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

Genes

Johannes Birtel¹  Kristina Hess¹  Martin Gliem¹  TheresaH. Birtel¹  FrankG. Holz¹  Philipp Herrmann¹  Ulrich Zechner²  HannoJ. Bolz² 

[1] Department of Ophthalmology, University of Bonn, 53113 Bonn, Germany;Senckenberg Centre for Human Genetics, 60314 Frankfurt, Germany;

关键词: molecular testing;    genotype;    phenotype;    dystrophy;    retina;    ngs;    retinitis pigmentosa;    stargardt disease;    waardenburg syndrome;    congenital stationary night blindness;   

DOI  :  10.3390/genes11020137

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown