A Novel Splice-Site Variant in CACNA1F Causes a Phenotype Synonymous with Åland Island Eye Disease and Incomplete Congenital Stationary Night Blindness

Background: CACNA1F-related disorders encompass progressive and non-progressive disorders, including Åland island eye disease and incomplete congenital stationary night blindness. These two X-linked disorders are characterized by nystagmus, color vision defect, myopia, and electroretinography (ERG) abnormalities. Ocular hypopigmentation and iris transillumination are reported only in patients with Åland island eye disease. Around 260 variants were reported to be associated with these two non-progressive disorders, with 19 specific to Åland island eye disease and 14 associated with both Åland island eye disease and incomplete congenital stationary night blindness. CACNA1F variants spread on the gene and further analysis are needed to reveal phenotype-genotype correlation. Case Report: A complete ocular exam and genetic testing were performed on a 13-year-old boy. A novel splice-site variant, c.4294-11C>G in intron 36 in CACNA1F, was identified at hemizygous state in the patient and at heterozygous state in his asymptomatic mother and explained the phenotype synonymous with Åland island eye disease and incomplete congenital stationary night blindness observed in the patient. Conclusion: We present a novel variant in the CACNA1F gene causing phenotypic and electrophysiologic findings indistinguishable from those of AIED/CSNB2A disease. This finding further expands the mutational spectrum and our knowledge of CACNA1F-related disease.

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

Genes ◽

10.3390/genes11020137 ◽

2020 ◽

Vol 11 (2) ◽

pp. 137

Author(s):

Johannes Birtel ◽

Martin Gliem ◽

Kristina Hess ◽

Theresa H. Birtel ◽

Frank G. Holz ◽

...

Keyword(s):

Genetic Testing ◽

Night Blindness ◽

Molecular Genetic ◽

Cone Dystrophy ◽

Molecular Testing ◽

Congenital Stationary Night Blindness ◽

Molecular Genetic Testing ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies ◽

Novel Variant

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.

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Clinical Characteristics, Mutation Spectrum, and Prevalence of Åland Eye Disease/Incomplete Congenital Stationary Night Blindness in Denmark

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.16-19445 ◽

2016 ◽

Vol 57 (15) ◽

pp. 6861 ◽

Cited By ~ 13

Author(s):

Marianne N. Hove ◽

Kevser Z. Kilic-Biyik ◽

Alana Trotter ◽

Karen Grønskov ◽

Birgit Sander ◽

...

Keyword(s):

Clinical Characteristics ◽

Night Blindness ◽

Mutation Spectrum ◽

Eye Disease ◽

Congenital Stationary Night Blindness

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A Novel Heterozygous Missense Mutation in GNAT1 Leads to Autosomal Dominant Riggs Type of Congenital Stationary Night Blindness

BioMed Research International ◽

10.1155/2018/7694801 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Christina Zeitz ◽

Cécile Méjécase ◽

Mathilde Stévenard ◽

Christelle Michiels ◽

Isabelle Audo ◽

...

Keyword(s):

Binding Site ◽

Night Blindness ◽

Autosomal Dominant ◽

Protein Localization ◽

Cone Dystrophy ◽

Congenital Stationary Night Blindness ◽

Gtp Binding ◽

Novel Variant ◽

Localization Signal ◽

Phototransduction Cascade

Autosomal dominant congenital stationary night blindness (adCSNB) is rare and results from altered phototransduction giving a Riggs type of electroretinogram (ERG) with loss of the rod a-wave and small b-waves. These patients usually have normal vision in light. Only few mutations in genes coding for proteins of the phototransduction cascade lead to this condition; most of these gene defects cause progressive rod-cone dystrophy. Mutation analysis of an adCSNB family with a Riggs-type ERG revealed a novel variant (c.155T>A p.Ile52Asn) in GNAT1 coding for the α-subunit of transducin, cosegregating with the phenotype. Domain predictions and 3D-modelling suggest that the variant does not affect the GTP-binding site as other GNAT1 adCSNB mutations do. It affects a predicted nuclear localization signal and a part of the first α-helix, which is distant from the GTP-binding site. The subcellular protein localization of this and other mutant GNAT1 proteins implicated in CSNB are unaltered in mammalian GNAT1 overexpressing cells. Our findings add a third GNAT1 mutation causing adCSNB and suggest that different pathogenic mechanisms may cause this condition.

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Faculty Opinions recommendation of Congenital stationary night blindness type 2 mutations S229P, G369D, L1068P, and W1440X alter channel gating or functional expression of Ca(v)1.4 L-type Ca2+ channels.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1024014.285837 ◽

2005 ◽

Author(s):

Gerald Zamponi

Keyword(s):

Night Blindness ◽

Channel Gating ◽

Functional Expression ◽

Congenital Stationary Night Blindness ◽

Ca2 Channels

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Substantial restoration of night vision in adult mice with congenital stationary night blindness

Molecular Therapy — Methods & Clinical Development ◽

10.1016/j.omtm.2021.05.008 ◽

2021 ◽

Author(s):

Juliette Varin ◽

Nassima Bouzidi ◽

Gregory Gauvain ◽

Corentin Joffrois ◽

Melissa Desrosiers ◽

...

Keyword(s):

Night Blindness ◽

Night Vision ◽

Congenital Stationary Night Blindness ◽

Adult Mice

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A rare large duplication of MLH1 identified in Lynch syndrome

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-021-00167-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Abhishek Kumar ◽

Nagarajan Paramasivam ◽

Obul Reddy Bandapalli ◽

Matthias Schlesner ◽

Tianhui Chen ◽

...

Keyword(s):

Amino Acid ◽

Lynch Syndrome ◽

Splice Site ◽

Stop Codon ◽

Premature Stop Codon ◽

Splice Donor Site ◽

Laboratory Diagnostics ◽

Mmr Genes ◽

Base Pair Deletion ◽

Splice Site Variant

Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.

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