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

TY - JOUR

T1 - Comprehensive Geno- and Phenotyping in a Complex Pedigree Including Four Different Inherited Retinal Dystrophies

AU - Birtel, Johannes

AU - Gliem, Martin

AU - Hess, Kristina

AU - Birtel, Theresa H

AU - Holz, Frank G

AU - Zechner, Ulrich

AU - Bolz, Hanno J

AU - Herrmann, Philipp

PY - 2020/1/28

Y1 - 2020/1/28

N2 - 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.

AB - 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.

KW - ATP-Binding Cassette Transporters/genetics

KW - Adolescent

KW - Albinism, Ocular/diagnosis

KW - Calcium Channels, L-Type/genetics

KW - Child

KW - Cone-Rod Dystrophies/diagnosis

KW - Eye Diseases, Hereditary/diagnosis

KW - Female

KW - Fluorescein Angiography

KW - Genetic Diseases, X-Linked/diagnosis

KW - Genetic Testing

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Male

KW - Microphthalmia-Associated Transcription Factor/genetics

KW - Middle Aged

KW - Mutation

KW - Myopia/diagnosis

KW - Night Blindness/diagnosis

KW - Parents

KW - Pedigree

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Sequence Analysis, DNA

U2 - 10.3390/genes11020137

DO - 10.3390/genes11020137

M3 - SCORING: Journal article

C2 - 32013026

VL - 11

JO - GENES-BASEL

JF - GENES-BASEL

SN - 2073-4425

IS - 2

ER -