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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 of the usherin protein and localisation of the likely disease-causing variants detected in the discovery cohort of patients (n=186); mutations previously reported in individuals with Usher syndrome type II are shown below the schematic. Presumed ‘retinal disease disease-specific' alleles are shown in red.
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fig1: Schematic of the usherin protein and localisation of the likely disease-causing variants detected in the discovery cohort of patients (n=186); mutations previously reported in individuals with Usher syndrome type II are shown below the schematic. Presumed ‘retinal disease disease-specific' alleles are shown in red.

Mentions: We define as ‘retinal disease-specific' variants or alleles that (i) were present in more than one patient with nonsyndromic retinal degeneration (in our discovery cohort and/or the literature) and (ii) have not been clearly associated with Usher syndrome type II to date (Table 3). On this basis, the following variants were categorised as likely ‘retinal disease-specific': c.2802 T>G, p.(Cys934Trp); c.10073 G>A; c.11156 G>A; c.12295-3 T>A; and c.12575 G>A. The c.2276 G>T variant that has been previously associated mainly with disease confined to the eye9, 10 was also included in this group. Notably, the most prevalent c.2276 G>T and c.10073 G>A variants were statistically significantly enriched in nonsyndromic cases compared with Usher syndrome type II cases (P=0.0060 and P=0.047, respectively (Fisher's exact test); the data on Usher syndrome type II were obtained from the UK National Collaborative Usher Study8). All ‘retinal disease-specific' variants were located in laminin-type EGF-like domains or fibronectin type 3 domains (Figure 1).


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 of the usherin protein and localisation of the likely disease-causing variants detected in the discovery cohort of patients (n=186); mutations previously reported in individuals with Usher syndrome type II are shown below the schematic. Presumed ‘retinal disease disease-specific' alleles are shown in red.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Schematic of the usherin protein and localisation of the likely disease-causing variants detected in the discovery cohort of patients (n=186); mutations previously reported in individuals with Usher syndrome type II are shown below the schematic. Presumed ‘retinal disease disease-specific' alleles are shown in red.
Mentions: We define as ‘retinal disease-specific' variants or alleles that (i) were present in more than one patient with nonsyndromic retinal degeneration (in our discovery cohort and/or the literature) and (ii) have not been clearly associated with Usher syndrome type II to date (Table 3). On this basis, the following variants were categorised as likely ‘retinal disease-specific': c.2802 T>G, p.(Cys934Trp); c.10073 G>A; c.11156 G>A; c.12295-3 T>A; and c.12575 G>A. The c.2276 G>T variant that has been previously associated mainly with disease confined to the eye9, 10 was also included in this group. Notably, the most prevalent c.2276 G>T and c.10073 G>A variants were statistically significantly enriched in nonsyndromic cases compared with Usher syndrome type II cases (P=0.0060 and P=0.047, respectively (Fisher's exact test); the data on Usher syndrome type II were obtained from the UK National Collaborative Usher Study8). All ‘retinal disease-specific' variants were located in laminin-type EGF-like domains or fibronectin type 3 domains (Figure 1).

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