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

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.

Figure 1

A stepwise screening for patients with IRD. Molecular diagnosis was performed with a stepwise screening methodology. Patients with RP were initially screened with 15 genes, and additional 27 genes were sequenced when the initial screening failed to detect mutations. Disease-specific genes were sequenced for patients with other IRD.

Figure 2

Retinal dystrophies included in this study. Clinical diagnosis of each retinal disease is shown. Nonsyndromic RP was found in 313 of 349 cases at the rate of 89.6%. We revised the clinical diagnosis in one case after genotyping: the patient diagnosed with cone dystrophy was revised to autosomal recessive enhanced S-cone syndrome (ESC) due to compound heterozygous NR2E3 mutations: c.419A>G and c.488T>C.

Figure 3

A pedigree of adRP with the novel RP11  mutation. A family carrying a novel c.613_615delTAC mutation in RP11 is presented. All of 6 family members who underwent molecular diagnosis carried the heterozygous c.613_615delTAC mutation as indicated with [M];[ = ]. Affected individuals are indicated as filled symbols, and an arrow indicates the proband in this family.

Figure 4

A pedigree of probable adRP with a novel RHO mutation. A family with a novel RHO mutation c.36delC is shown. II-5 in this family carried the heterozygote mutation, and her clinical phenotype was relatively mild with late onset at her age of 62. III-2 showed only marginal clinical signs of RP when she underwent clinical evaluations at the age of 44. A possible carrier of I-1 died before the age when the III-2 presented RP symptoms. Affected individuals are indicated as filled symbols, and an arrow indicates the proband in this family. Bottom images are fundus pictures of II-5.

Figure 5

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.