Limits...
Retinitis Pigmentosa with EYS Mutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations.

Arai Y, Maeda A, Hirami Y, Ishigami C, Kosugi S, Mandai M, Kurimoto Y, Takahashi M - J Ophthalmol (2015)

Bottom Line: We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%.This study found 43 novel sequence variants.EYS mutations are the most prevalent among Japanese patients with IRD.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan.

ABSTRACT
The aim of this study was to gain information about disease prevalence and to identify the responsible genes for inherited retinal dystrophies (IRD) in Japanese populations. Clinical and molecular evaluations were performed on 349 patients with IRD. For segregation analyses, 63 of their family members were employed. Bioinformatics data from 1,208 Japanese individuals were used as controls. Molecular diagnosis was obtained by direct sequencing in a stepwise fashion utilizing one or two panels of 15 and 27 genes for retinitis pigmentosa patients. If a specific clinical diagnosis was suspected, direct sequencing of disease-specific genes, that is, ABCA4 for Stargardt disease, was conducted. Limited availability of intrafamily information and decreasing family size hampered identifying inherited patterns. Differential disease profiles with lower prevalence of Stargardt disease from European and North American populations were obtained. We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%. This study found 43 novel sequence variants. In silico analysis suggests that 20 of 25 novel missense variants are pathogenic. EYS mutations had the highest prevalence at 23.5%. c.4957_4958insA and c.8868C>A were the two major EYS mutations identified in this cohort. EYS mutations are the most prevalent among Japanese patients with IRD.

No MeSH data available.


Related in: MedlinePlus

A pedigree of arRP with novel EYS mutations. A family carrying two novel EYS mutations, c.8439_8442dupTGCA (a) and c.5202_5203delGT (b), is presented. Affected II-2 and II-4 carried compound heterozygous mutations. I-1 carried a heterozygous c.8439_8442dupTGCA mutation and I-2 did another c.5202_5203delGT heterozygous mutation. Affected individuals are indicated as filled symbols, and an arrow indicates the proband in this family.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4487330&req=5

fig5: A pedigree of arRP with novel EYS mutations. A family carrying two novel EYS mutations, c.8439_8442dupTGCA (a) and c.5202_5203delGT (b), is presented. Affected II-2 and II-4 carried compound heterozygous mutations. I-1 carried a heterozygous c.8439_8442dupTGCA mutation and I-2 did another c.5202_5203delGT heterozygous mutation. Affected individuals are indicated as filled symbols, and an arrow indicates the proband in this family.

Mentions: This study revealed 43 novel sequence variants including 32 EYS mutations (Tables 3–5). A total of 11 novel sequence variants were identified in the following genes: ABCA4, CRX, PROM1, RDS/PRPH2, RHO, and RP11 (Table 3). The same novel alteration, c.613_615delTAC in RP11, was found in two unrelated families. As shown in Figure 3, segregation analyses revealed that this novel mutation contributed to adRP in this family with III-2 as a nonpenetrant. The same novel c.1738A>C alteration was detected in PROM1 in three unrelated families (this variant is described more in the section of “Association of EYS, CRB1, and PROM1 in retinal dystrophy”). This cohort also included a family with a novel RHO sequence variant, c.36delC (Figure 4). II-5 in this family carried the heterozygous mutation, and her clinical phenotype was relatively mild with late onset at the age of 62. III-2 showed only marginal clinical signs of RP when she had underwent clinical evaluations at the age of 44. A possible carrier of this mutation, I-1, died before the age when III-2 presented RP symptoms. This truncating variant is located in exon 1 and it is likely to contribute to adRP. A total of 13 novel truncating EYS sequence variants were found in 21 RP patients in 13 families (Table 4) and 19 missense changes in EYS were also recognized (Table 5). Two novel EYS mutations, c.8439_8442dupTGCA and c.5202_5203delGT, were found in a single family (Figure 5). Affected family members II-2 and II-4 carried the compound heterozygous mutations. In silico analysis suggests that 20 of 25 novel missense mutations identified here harbor potential deleterious effects (Table 5), and further segregation analyses are essential to conclude their pathogenesis.


Retinitis Pigmentosa with EYS Mutations Is the Most Prevalent Inherited Retinal Dystrophy in Japanese Populations.

Arai Y, Maeda A, Hirami Y, Ishigami C, Kosugi S, Mandai M, Kurimoto Y, Takahashi M - J Ophthalmol (2015)

A pedigree of arRP with novel EYS mutations. A family carrying two novel EYS mutations, c.8439_8442dupTGCA (a) and c.5202_5203delGT (b), is presented. Affected II-2 and II-4 carried compound heterozygous mutations. I-1 carried a heterozygous c.8439_8442dupTGCA mutation and I-2 did another c.5202_5203delGT heterozygous mutation. Affected individuals are indicated as filled symbols, and an arrow indicates the proband in this family.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4487330&req=5

fig5: A pedigree of arRP with novel EYS mutations. A family carrying two novel EYS mutations, c.8439_8442dupTGCA (a) and c.5202_5203delGT (b), is presented. Affected II-2 and II-4 carried compound heterozygous mutations. I-1 carried a heterozygous c.8439_8442dupTGCA mutation and I-2 did another c.5202_5203delGT heterozygous mutation. Affected individuals are indicated as filled symbols, and an arrow indicates the proband in this family.
Mentions: This study revealed 43 novel sequence variants including 32 EYS mutations (Tables 3–5). A total of 11 novel sequence variants were identified in the following genes: ABCA4, CRX, PROM1, RDS/PRPH2, RHO, and RP11 (Table 3). The same novel alteration, c.613_615delTAC in RP11, was found in two unrelated families. As shown in Figure 3, segregation analyses revealed that this novel mutation contributed to adRP in this family with III-2 as a nonpenetrant. The same novel c.1738A>C alteration was detected in PROM1 in three unrelated families (this variant is described more in the section of “Association of EYS, CRB1, and PROM1 in retinal dystrophy”). This cohort also included a family with a novel RHO sequence variant, c.36delC (Figure 4). II-5 in this family carried the heterozygous mutation, and her clinical phenotype was relatively mild with late onset at the age of 62. III-2 showed only marginal clinical signs of RP when she had underwent clinical evaluations at the age of 44. A possible carrier of this mutation, I-1, died before the age when III-2 presented RP symptoms. This truncating variant is located in exon 1 and it is likely to contribute to adRP. A total of 13 novel truncating EYS sequence variants were found in 21 RP patients in 13 families (Table 4) and 19 missense changes in EYS were also recognized (Table 5). Two novel EYS mutations, c.8439_8442dupTGCA and c.5202_5203delGT, were found in a single family (Figure 5). Affected family members II-2 and II-4 carried the compound heterozygous mutations. In silico analysis suggests that 20 of 25 novel missense mutations identified here harbor potential deleterious effects (Table 5), and further segregation analyses are essential to conclude their pathogenesis.

Bottom Line: We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%.This study found 43 novel sequence variants.EYS mutations are the most prevalent among Japanese patients with IRD.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan.

ABSTRACT
The aim of this study was to gain information about disease prevalence and to identify the responsible genes for inherited retinal dystrophies (IRD) in Japanese populations. Clinical and molecular evaluations were performed on 349 patients with IRD. For segregation analyses, 63 of their family members were employed. Bioinformatics data from 1,208 Japanese individuals were used as controls. Molecular diagnosis was obtained by direct sequencing in a stepwise fashion utilizing one or two panels of 15 and 27 genes for retinitis pigmentosa patients. If a specific clinical diagnosis was suspected, direct sequencing of disease-specific genes, that is, ABCA4 for Stargardt disease, was conducted. Limited availability of intrafamily information and decreasing family size hampered identifying inherited patterns. Differential disease profiles with lower prevalence of Stargardt disease from European and North American populations were obtained. We found 205 sequence variants in 159 of 349 probands with an identification rate of 45.6%. This study found 43 novel sequence variants. In silico analysis suggests that 20 of 25 novel missense variants are pathogenic. EYS mutations had the highest prevalence at 23.5%. c.4957_4958insA and c.8868C>A were the two major EYS mutations identified in this cohort. EYS mutations are the most prevalent among Japanese patients with IRD.

No MeSH data available.


Related in: MedlinePlus