Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa

McGee, Terri L.; Seyedahmadi, B. Jian; Sweeney, Meredith O.; Dryja, Thaddeus P.; Berson, Eliot L.

doi:10.1136/jmg.2009.075143

Cited by 125 publications

(94 citation statements)

References 39 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A grade, varying from C0 to C65, is given to estimate the probability that a certain variant is pathogenic. We interpreted C0 as "probably benign," C15, C25, and C35 as "possibly pathogenic" and C45, C55, and C65 as "probably pathogenic" in agreement with McGee et al [McGee et al, 2010].…”

Section: Align-gvgdsupporting

confidence: 52%

“…Therefore, we included PolyPhen-2 and Align-GVGD in our classification system, but did not include SIFT ( Table 2). The output of PolyPhen-2 and Align-GVGD was scored as 0 (benign), +0.5 (possibly pathogenic), or +1 (probably pathogenic) and was then summed as previously suggested by McGee et al [McGee et al, 2010].…”

Section: Development Of Our Classification Systemmentioning

confidence: 99%

“…Each algorithm has its unique strengths and weaknesses. Therefore, it is worthwhile to combine different algorithms to increase the accuracy of the prediction [Frederic et al, 2009;McGee et al, 2010]. In addition, structural models, when available, can help in predicting the effect of a certain variant on the structural and binding properties of the protein [Alibes et al, 2010;Kim et al, 2008;Pey et al, 2007;Rakoczy et al, 2011;van der Sloot et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

et al. 2012

View full text Add to dashboard Cite

CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo-and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5 and 3 regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations.

show abstract

Section: Align-gvgdsupporting

confidence: 52%

Section: Development Of Our Classification Systemmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

et al. 2012

View full text Add to dashboard Cite

show abstract

“…En un estudio de población francesa, que se llevó a cabo con una metodología muy similar, se reportó la presencia de mutaciones en 39 % de la población con síndrome de Usher, tipo 2 (25), una frecuencia muy cercana a la reportada en este estudio, pero con una mayor heterogeneidad de mutaciones identificadas. Estudios similares, pero realizados mediante secuenciación, han revelado la presencia de alguna mutación patológica en 87 % de la población en países del norte de Europa (22) y en 57 % de la de Estados Unidos (27), frecuencias más altas que la reportada en este estudio (38 %) debido tal vez a la técnica utilizada, ya que el análisis de secuenciación resulta ser más acertado aunque más costoso que el análisis de SSCP (28). Además, uno de los estudios reporta una frecuencia alélica de 39 % de la mutación 2299delG (22), una frecuencia mayor que la reportada en éste y en otros estudios en población europea.…”

Section: Figuraunclassified

“…Un análisis posterior de la isoforma larga del gen permitirá conocer nuevas mutaciones en estos individuos y genotipificar a una mayor proporción de la población, ya que se ha reportado que esta isoforma puede albergar incluso más mutaciones que la isoforma corta (26,27,30,31). Se ha propuesto la técnica de microarrays como un método de genotipificación rápido y efectivo (32), pero, para poder llevarlo a cabo, es necesario tener una mejor idea de las mutaciones propias de población colombiana.…”

Section: Figuraunclassified

Frecuencia de mutaciones en el gen de la usherina (USH2A) en 26 individuos colombianos con síndrome de Usher, tipo II

2011

View full text Add to dashboard Cite

Introducción. El síndrome de Usher se caracteriza por hipoacusia neurosensorial congénita, retinitis pigmentaria y disfunción vestibular. Es la causa más frecuente de sordo-ceguera en el mundo. Se divide en tres tipos clínicos y doce subtipos genéticos. El tipo II es la forma más común y cerca de 80 % de los casos corresponden al subtipo 2 del síndrome de Usher. Objetivo. Establecer la frecuencia de mutaciones en la isoforma corta del gen USH2A en individuos colombianos con síndrome de Usher, tipo II. Materiales y métodos. Se estudiaron 26 individuos colombianos con diagnóstico clínico de síndrome de Usher, tipo II. Se hizo análisis de SSCP para los 20 exones que codifican para la isoforma corta y se secuenciaron los patrones anormales. Además, se secuenció el exón 13 en todos los individuos, ya que allí se encuentra la mutación más frecuente de este gen. Resultados. La mutación más frecuente es la c.2299delG, correspondiente al 27 % de la población. La segunda mutación identificada es la p.R334W, con una frecuencia de 15 %. Se identificó un nuevo cambio, el g.129G>T,en la región 5'UTR del gen, correspondiente al 4 % de la población. Se identificaron cuatro cambios polimórficos, uno de ellos es una deleción nueva identificada en el exón 20. Conclusiones. Se logró establecer que, al menos, 38 % de la población analizada con síndrome de Usher, tipo II, presenta alguna mutación en la isoforma corta del gen de la usherina. El diagnóstico molecular se logró establecer en el 23 %.Palabras clave: síndromes de Usher/genética, retinitis pigmentaria, pérdida auditiva neurosensorial; análisis de mutación de ADN, Colombia. Mutational frequencies in usherin (USH2A gene) in 26 Colombian individuals with Usher syndrome type IIIntroduction. Usher syndrome is a disorder characterized by progressive retinitis pigmentosa, prelingual sensory hearing loss and vestibular dysfunction. It is the most frequent cause of deaf-blindness in humans. Three clinical types and twelve genetic subtypes have been characterized. Type II is the most common, and among these cases, nearly 80% have mutations in the USH2A gene. Objective. The aim of the study was to establish the mutational frequencies for the short isoform of USH2A gene in Usher syndrome type II. Materials and methods. Twenty-six Colombian individuals with Usher syndrome type II were included. SSCP analysis for 20 exons of the short isoform was performed and abnormal patterns were sequenced. Sequencing of exon 13 of the USH2A gene was performed for all the individuals because the most frequent mutation is located in this exon. Results. The most frequent mutation was c.2299delG, identified in the 27% (n=8) of the sample. The second mutation, p.R334W, showed a frequency of 15%. A new variant identified in the 5'UTR region, g.129G>T, was present in 1 individual (4%). Four polymorphisms were identified; one of them is a new deletion in exon 20, first reported in this study. Conclusions. Mutations in the usherin short isoform were identified in 38% of a sample of 26 USH2 cases. Molecular di...

show abstract

Identification of a Novel Mutation in the CDHR1 Gene in a Family With Recessive Retinal Degeneration

Duncan¹,

Roorda²,

Navani³

et al. 2012

Arch Ophthalmol

View full text Add to dashboard Cite

Objectives To describe the clinical phenotype and identify the molecular basis of disease in a consanguineous family of Palestinian origin with autosomal recessive retinal degeneration. Methods Eight family members were evaluated with visual acuity and perimetry tests, color fundus photographs, full-field electroretinography, and optical coherence tomography. Cone photoreceptors surrounding the fovea were imaged in 2 members, using adaptive optics scanning laser ophthalmoscopy. Exome was captured using probes and sequenced. Readings were mapped to reference hg19. Variant calls and annotations were performed, using published protocols. Confirmation of variants and segregation analysis was performed using dideoxy sequencing. Results Analysis detected 24 037 single-nucleotide variants in one affected family member, of which 3622 were rare and potentially damaging to encoded proteins. Further analysis revealed a novel homozygous nonsense change, c.1381 C>T, p.Gln461X in exon 13 of the CDHR1 gene, which segregated with retinal degeneration in this family. Affected members had night blindness beginning during adolescence with progressive visual acuity and field loss and unmeasurable electroretinographic responses, as well as macular outer retinal loss, although residual cones with increased cone spacing were observed in the youngest individual. Conclusions Exome analysis revealed a novel CDHR1 nonsense mutation segregating with progressive retinal degeneration causing severe central vision loss by the fourth decade of life. High-resolution retinal imaging revealed outer retinal changes suggesting that CDHR1 is important for normal photoreceptor structure and survival. Clinical Relevance Exome sequencing is a powerful technique that may identify causative genetic variants in families with autosomal recessive retinal degeneration.

show abstract

Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa

Cited by 125 publications

References 39 publications

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

A novel classification system to predict the pathogenic effects of CHD7 missense variants in CHARGE syndrome

Frecuencia de mutaciones en el gen de la usherina (USH2A) en 26 individuos colombianos con síndrome de Usher, tipo II

Identification of a Novel Mutation in the CDHR1 Gene in a Family With Recessive Retinal Degeneration

Contact Info

Product

Resources

About