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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

Schematic showing the proposed allelic hierarchy of USH2A mutations: the presence of at least one retinal disease-specific (‘retina-specific') USH2A allele in a patient with USH2A-related disease results in normal hearing at least in childhood.
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fig5: Schematic showing the proposed allelic hierarchy of USH2A mutations: the presence of at least one retinal disease-specific (‘retina-specific') USH2A allele in a patient with USH2A-related disease results in normal hearing at least in childhood.

Mentions: In the present study, we confirm that recessive variants affecting USH2A function are a common cause of retinitis pigmentosa with disease-causing variants being spread throughout the gene. When allelic heterogeneity was studied and compared with that reported in Usher syndrome, the concept of ‘retinal disease-specific' USH2A alleles (ie, alleles associated with retinal degeneration and no hearing complaint in childhood) became apparent. The presence of at least one such allele in a patient with USH2A-related retinal degeneration results in relative preservation of hearing (Figure 5). Five likely ‘retinal disease-specific' variants (c.2802T>G; c.10073G>A; c.11156G>A; c.12295-3T>A and c.12575G>A) that are novel to this study were identified in addition to c.2276G>T, a relatively common sequence alteration previously associated with retinitis pigmentosa without hearing impairment.9, 10


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)

Schematic showing the proposed allelic hierarchy of USH2A mutations: the presence of at least one retinal disease-specific (‘retina-specific') USH2A allele in a patient with USH2A-related disease results in normal hearing at least in childhood.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Schematic showing the proposed allelic hierarchy of USH2A mutations: the presence of at least one retinal disease-specific (‘retina-specific') USH2A allele in a patient with USH2A-related disease results in normal hearing at least in childhood.
Mentions: In the present study, we confirm that recessive variants affecting USH2A function are a common cause of retinitis pigmentosa with disease-causing variants being spread throughout the gene. When allelic heterogeneity was studied and compared with that reported in Usher syndrome, the concept of ‘retinal disease-specific' USH2A alleles (ie, alleles associated with retinal degeneration and no hearing complaint in childhood) became apparent. The presence of at least one such allele in a patient with USH2A-related retinal degeneration results in relative preservation of hearing (Figure 5). Five likely ‘retinal disease-specific' variants (c.2802T>G; c.10073G>A; c.11156G>A; c.12295-3T>A and c.12575G>A) that are novel to this study were identified in addition to c.2276G>T, a relatively common sequence alteration previously associated with retinitis pigmentosa without hearing impairment.9, 10

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