Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies

Glöckle, Nicola; Kohl, Susanne; Mohr, Julia; Scheurenbrand, Tim; Sprecher, Andrea; Weisschuh, Nicole; Bernd, Antje; Rudolph, Günther; Schubach, Max; Poloschek, Charlotte M.; Zrenner, Eberhart; Biskup, Saskia; Berger, Wolfgang; Wissinger, Bernd; Neidhardt, John

doi:10.1038/ejhg.2013.72

Cited by 223 publications

(186 citation statements)

References 29 publications

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“…4 Panel-based sequencing of 105 retinal degenerationassociated genes and whole-genome sequencing, respectively, were performed as described before. 5,6 In-house automated data analysis pipeline and variant interpretation tools were used for variant calling.…”

Section: Methodsmentioning

confidence: 99%

Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone–rod dystrophy by pseudoexon activation

et al. 2015

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Several genes have been implicated in the autosomal recessive form of cone-rod dystrophy (CRD), but the majority of cases remain unsolved. We identified a homozygous interval comprising two known genes associated with the autosomal recessive form of CRD, namely RAB28 and PROM1, in a consanguineous family with clinical evidence of CRD. Both genes proved to be mutation negative upon sequencing of exons and canonical splice sites but whole-genome sequencing revealed a private variant located deep in intron 18 of PROM1. In silico and functional analyses of this variant using minigenes as splicing reporters revealed the integration of a pseudoexon in the mutant transcript, thereby leading to a premature termination codon and presumably resulting in a functional null allele. This is the first report of a deep intronic variant that acts as a splicing mutation in PROM1. The detection of such variants escapes the exon-focused techniques typically used in genetic analyses. Sequencing the entire genomic regions of known disease genes might identify more causal mutations in the autosomal recessive form of CRD.

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Section: Methodsmentioning

confidence: 99%

Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone–rod dystrophy by pseudoexon activation

et al. 2015

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“…It is usually stated that the analysis of known BBS genes detects biallelic mutations in ∼ 80% of BBS patients Forsythe and Beales, 2013;Glöckle et al, 2014]. There are a number of limitations related to this issue.…”

Section: Bbs Genesmentioning

confidence: 99%

Bardet-Biedl Syndrome

Suspitsin

Imyanitov²

2016

Mol Syndromol

109

122

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Bardet-Biedl syndrome (BBS) is a rare autosomal recessive genetic disorder. It is characterized by heterogeneous clinical manifestations including primary features of the disease (rod-cone dystrophy, polydactyly, obesity, genital abnormalities, renal defects, and learning difficulties) and secondary BBS characteristics (developmental delay, speech deficit, brachydactyly or syndactyly, dental defects, ataxia or poor coordination, olfactory deficit, diabetes mellitus, congenital heart disease, etc.); most of these symptoms may not be present at birth but appear and progressively worsen during the first and second decades of life. At least 20 BBS genes have already been identified, and all of them are involved in primary cilia functioning. Genetic diagnosis of BBS is complicated due to lack of gene-specific disease symptoms; however, it is gradually becoming more accessible with the invention of multigene sequencing technologies. Clinical management of BBS is largely limited to a symptomatic treatment. Mouse experiments demonstrate that the most debilitating complication of BBS, blindness, can be rescued by topical gene therapy. There is a published case report describing the delay of BBS symptoms by nutritional compensation of the disease-related biochemical deficiencies. Progress in DNA testing technologies is likely to rapidly resolve all limitations in BBS diagnosis; however, much slower improvement is expected with regard to BBS treatment.

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“…This mutation, together with the known splice-site mutation c.3317-2A>G, has been described in a sporadic ARRP patient. 9 Interestingly, it is located in a homozygous region of only 1.5 Mb, in which the USH2A gene is only partially located (see Supplementary Figure S2 online).…”

Section: Combined Ibd Mapping and Wesmentioning

confidence: 99%

Identity-by-descent–guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy

Coppieters

Schil

Bauwens

et al. 2014

Genetics in Medicine

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Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies

Cited by 223 publications

References 29 publications

Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone–rod dystrophy by pseudoexon activation

Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone–rod dystrophy by pseudoexon activation

Bardet-Biedl Syndrome

Identity-by-descent–guided mutation analysis and exome sequencing in consanguineous families reveals unusual clinical and molecular findings in retinal dystrophy

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