Limits...
A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.

Lenassi E, Vincent A, Li Z, Saihan Z, Coffey AJ, Steele-Stallard HB, Moore AT, Steel KP, Luxon LM, Héon E, Bitner-Glindzicz M, Webster AR - Eur. J. Hum. Genet. (2015)

Bottom Line: Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A.Some of these variants were predominantly associated with nonsyndromic retinal degeneration ('retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His).The following model is proposed: the presence of at least one 'retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing.

View Article: PubMed Central - PubMed

Affiliation: UCL Institute of Ophthalmology and Moorfields Eye Hospital, University College of London, London, UK.

ABSTRACT
Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration ('retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one 'retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype-phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.

No MeSH data available.


Related in: MedlinePlus

Fundus autofluorescence (FAF) imaging and foveal OCT scans of three patients with USH2A retinopathy. Three patterns were observed: (i) a hyperautofluorescent ring on FAF and preserved photoreceptor inner segment ellipsoid line in the area within the hyperautofluorescent ring on OCT (subject D8a; top row); (ii) central hyperautofluorescence on FAF and absent photoreceptor inner segment ellipsoid line on OCT (subject D17; middle row), and (iii) severely decreased autofluorescence on FAF and absent outer retina layers with thinning of the retinal pigment epithelium/Bruch's membrane complex band (subject D19; bottom row). Y.o., years old.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4592079&req=5

fig3: Fundus autofluorescence (FAF) imaging and foveal OCT scans of three patients with USH2A retinopathy. Three patterns were observed: (i) a hyperautofluorescent ring on FAF and preserved photoreceptor inner segment ellipsoid line in the area within the hyperautofluorescent ring on OCT (subject D8a; top row); (ii) central hyperautofluorescence on FAF and absent photoreceptor inner segment ellipsoid line on OCT (subject D17; middle row), and (iii) severely decreased autofluorescence on FAF and absent outer retina layers with thinning of the retinal pigment epithelium/Bruch's membrane complex band (subject D19; bottom row). Y.o., years old.

Mentions: From the fundus autofluorescence images of 24 patients (48 eyes) three patterns were observed (Figure 3). Most patients (n=39 eye; 81.3%) showed preserved central autofluorescence surrounded by a variable diameter ring of high density (‘hyperautofluorescent ring' Figure 3, top row). Five (10.4%) eyes had an abnormally increased signal in the fovea with no obvious hyperautofluorescent ring (‘central hyperautofluorescence' Figure 3, middle row). Four (8.3%) eyes were characterised by widespread hypoautofluorescence corresponding to retinal pigment epithelial atrophy (‘severely decreased autofluorescence' Figure 3, bottom row). The findings were concordant between the eyes in all but two patients. Overlaying of fundus autofluorescence and OCT images suggested that the hyperautofluorescent ring represents a border between relatively preserved and diseased retinal tissue (Figure 3), and future structure–function correlation studies are expected to provide important insights into the clinical utility of this imaging modality


A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.

Lenassi E, Vincent A, Li Z, Saihan Z, Coffey AJ, Steele-Stallard HB, Moore AT, Steel KP, Luxon LM, Héon E, Bitner-Glindzicz M, Webster AR - Eur. J. Hum. Genet. (2015)

Fundus autofluorescence (FAF) imaging and foveal OCT scans of three patients with USH2A retinopathy. Three patterns were observed: (i) a hyperautofluorescent ring on FAF and preserved photoreceptor inner segment ellipsoid line in the area within the hyperautofluorescent ring on OCT (subject D8a; top row); (ii) central hyperautofluorescence on FAF and absent photoreceptor inner segment ellipsoid line on OCT (subject D17; middle row), and (iii) severely decreased autofluorescence on FAF and absent outer retina layers with thinning of the retinal pigment epithelium/Bruch's membrane complex band (subject D19; bottom row). Y.o., years old.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592079&req=5

fig3: Fundus autofluorescence (FAF) imaging and foveal OCT scans of three patients with USH2A retinopathy. Three patterns were observed: (i) a hyperautofluorescent ring on FAF and preserved photoreceptor inner segment ellipsoid line in the area within the hyperautofluorescent ring on OCT (subject D8a; top row); (ii) central hyperautofluorescence on FAF and absent photoreceptor inner segment ellipsoid line on OCT (subject D17; middle row), and (iii) severely decreased autofluorescence on FAF and absent outer retina layers with thinning of the retinal pigment epithelium/Bruch's membrane complex band (subject D19; bottom row). Y.o., years old.
Mentions: From the fundus autofluorescence images of 24 patients (48 eyes) three patterns were observed (Figure 3). Most patients (n=39 eye; 81.3%) showed preserved central autofluorescence surrounded by a variable diameter ring of high density (‘hyperautofluorescent ring' Figure 3, top row). Five (10.4%) eyes had an abnormally increased signal in the fovea with no obvious hyperautofluorescent ring (‘central hyperautofluorescence' Figure 3, middle row). Four (8.3%) eyes were characterised by widespread hypoautofluorescence corresponding to retinal pigment epithelial atrophy (‘severely decreased autofluorescence' Figure 3, bottom row). The findings were concordant between the eyes in all but two patients. Overlaying of fundus autofluorescence and OCT images suggested that the hyperautofluorescent ring represents a border between relatively preserved and diseased retinal tissue (Figure 3), and future structure–function correlation studies are expected to provide important insights into the clinical utility of this imaging modality

Bottom Line: Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A.Some of these variants were predominantly associated with nonsyndromic retinal degeneration ('retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His).The following model is proposed: the presence of at least one 'retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing.

View Article: PubMed Central - PubMed

Affiliation: UCL Institute of Ophthalmology and Moorfields Eye Hospital, University College of London, London, UK.

ABSTRACT
Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration ('retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one 'retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype-phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.

No MeSH data available.


Related in: MedlinePlus