Angioid streaks (AS; OMIM #607140) are a hereditary retinal disease involving irregular streaks that radiate from the optic disc due to cracking of Bruch’s membrane. There are numerous systemic associations with AS, including pseudoxanthoma elasticum (PXE; OMIM #264800), Paget’s disease of bone, sickle cell anemia, and Ehlers-Danlos syndrome [
The ATP-binding cassette subfamily C member 6 (
The purpose of this study was to determine whether frequent
This was a single-center cohort study. The medical records of 20 patients (11 males and 9 females, aged 16 to 81 years, mean: 53 years) with AS from 18 unrelated Japanese families and eight unaffected family members of these patients were retrospectively reviewed at the Jikei University Hospital from June 2006 to February 2010. There was no consanguinity of parents of all probands (Table
Clinical profiles and
Family number | Case number | Gender | Age at examination | AS | CNV | PXE | Consanguinity | Genotype | Exon | Nucleotide changes | Amino acid changes | Notes |
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1 (JU#0376) | 1 | F | 70 | + | + | + | − | Homo | 19 | c.2542delG | p.V848CfsX83 | |
19 | c.2542delG | p.V848CfsX83 | ||||||||||
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2 (JU#0390) | 2 | F | 49 | + | − | + | − | Hetero | 9 | c.1132C>T | p.Q378X | |
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3 (JU#0446) | 3 | M | 46 | + | + | + | − | Compound hetero | 9 | c.1132C>T | p.Q378X | Father of case 4 |
19 | c.2542delG | p.V848CfsX83 | ||||||||||
4 | F | 16 | + | − | + | − | Compound hetero | 9 | c.1132C>T | p.Q378X | Daughter of case 3 | |
10 | c.1256G>A | p.R419Q | ||||||||||
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4 (JU#0448) | 5 | M | 57 | + | − | + | − | Compound hetero | 19 | c.2542delG | p.V848CfsX83 | |
29 | c.4069C>T | p.R1357W | ||||||||||
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5 (JU#0451) | 6 | F | 45 | + | + | + | − | Compound hetero | 9 | c.1132C>T | p.Q378X | Described in Figure |
29 | c.4069C>T | p.R1357W | ||||||||||
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6 (JU#0458) | 7 | F | 60 | + | + | + | − | Homo | 9 | c.1132C>T | p.Q378X | |
9 | c.1132C>T | p.Q378X | ||||||||||
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7 (JU#0481) | 8 | M | 44 | + | − | − | − | Compound hetero | 10, 15 | c.1283A>G, c.1939C>T | p.N428S, p.H647Y | |
19 | c.2542delG | p.V848CfsX83 | ||||||||||
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8 (JU#0483) | 9 | M | 51 | + | − | ND | − | − | − | − | − | |
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9 (JU#0489) | 10 | F | 23 | + | − | + | − | Hetero | 24 | c.3340C>T | p.R1114C | |
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10 (JU#0554) | 11 | M | 71 | + | + | + | − | Compound hetero | 19 | c.2542delG | p.V848CfsX83 | Father of case 12 |
24 | c.3374C>T | p.S1125F | ||||||||||
12 | M | 36 | + | − | + | − | Homo | 19 | c.2542delG | p.V848CfsX83 | Son of case 11 | |
19 | c.2542delG | p.V848CfsX83 | ||||||||||
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11 (JU#0602) | 13 | M | 73 | + | + | + | − | Compound hetero | 9 | c.1132C>T | p.Q378X | |
19 | c.2542delG | p.V848CfsX83 | ||||||||||
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12 (JU#0476) | 14 | F | 49 | + | − | − | − | Compound hetero | 19 | c.2542delG | p.V848CfsX83 | |
29 | c.4069C>T | p.R1357W | ||||||||||
13 (JU#MD196) | 15 | M | 77 | + | + | ND | − | Compound hetero | 19 | c.2542delG | p.V848CfsX83 | |
29 | c.4069C>T | p.R1357W | ||||||||||
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14 (JU#0627) | 16 | F | 81 | + | − | ND | − | Hetero | 19 | c.2542delG | p.V848CfsX83 | |
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15 (JU#0630) | 17 | M | 28 | + | − | + | − | Compound hetero | 10 | c.1256G>A | p.R419Q | |
29 | c.4069C>T | p.R1357W | ||||||||||
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16 (JU#0639) | 18 | M | 57 | + | − | + | − | Compound hetero | 19 | c.2542delG | p.V848CfsX83 | |
29 | c.4069C>T | p.R1357W | ||||||||||
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17 (JU#0651) | 19 | F | 51 | + | + | + | − | Compound hetero | 10 | c.1256G>A | p.R419Q | |
19 | c.2542delG | p.V848CfsX83 | ||||||||||
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18 (JU#0653) | 20 | M | 77 | + | ND | + | − | Hetero | 10 | c.1256G>A | p.R419Q |
F = female; M = male; AS = angioid streaks; CNV = choroidal neovascularization; PXE = pseudoxanthoma elasticum; ND = not determined; homo = homozygous; hetero = heterozygous.
Fundus and fluorescein angiography images of the right eye. Images from a 45-year-old female proband (case 6, JU#0451). The color image (a) shows irregular streaks radiating from the optic disc and a small retinal hemorrhage in the macula. A peau d’orange appearance is also seen temporal to the macula. Fluorescein leakage is observed from the early (b) to the late (c) phases due to choroidal neovascularization.
Blood samples were obtained from all affected cases and some of their family members. Genomic DNA was isolated from peripheral white blood cells using a Gentra Puregene Blood Kit (Qiagen, Hilden, Germany); the DNA was used as a template for amplifying human
To predict the functional impact of the
In total, eight
Variants in the
Exon | Nucleotide | Amino acid | Homozygous | Heterozygous | Total (alleles) | dbSNP ID | HGVD (allele frequency) | ExAC East Asian (allele frequency) | ExAC total (allele frequency) | Polyphen-2 results (HumVar) | SIFT results | PROVEAN results | Pathogenicity | References |
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9 | c.1132C>T | p.Q378X | 1 | 5 | 7/40 | rs72650699 | 0.002% (2/427) | 0.000% (0/8646) | 0.000% (1/121188) | Pathogenic | Le Saux et al. [2001], Pulkkinen et al. [2001] | |||
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10 | c.1256G>A | p.R419Q | 0 | 4 | 4/40 | rs772434460 | 0.001% (2/1077) | 0.001% (10/8204) | 0.000% (10/111520) | 0.742 (possibly damaging) | 0.00 (damaging) | −3.27 (deleterious) | Pathogenic | Iwanaga et al. [2017] |
c.1283A>G | p.N428S | 0 | 1 | 1/40 | rs201880691 | 0.009% (20/1123) | 0.001% (12/8524) | 0.000% (13/117386) | 0.999 (probably damaging) | 0.00 (damaging) | −4.69 (deleterious) | Pathogenic | Sato et al. [2009] (reported in the controls) | |
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15 | c.1939C>T | p.H647Y | 0 | 1 | 1/40 | Not reported | Not reported | Not reported | Not reported | 0.127 (benign) | 0.01 (damaging) | −3.32 (deleterious) | Pathogenic | N/A (novel variant) |
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19 | c.2542delG | p.V848CfsX83 | 2 | 10 | 14/40 | rs67867306 | Inconclusive | 0.003% (27/8654) | 0.000% (27/121324) | Pathogenic | Sato et al. [2009] | |||
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24 | c.3340C>T | p.R1114C | 0 | 1 | 1/40 | rs63749794 | Not reported | 0.000% (0/8608) | 0.000% (12/120184) | 0.998 (probably damaging) | 0.00 (damaging) | −7.13 (deleterious) | Pathogenic | Gheduzzi et al. [2004] |
c.3374C>T | p.S1125F | 0 | 1 | 1/40 | Not reported | Not reported | Not reported | Not reported | 0.992 (probably damaging) | 0.00 (damaging) | −4.85 (deleterious) | Pathogenic | N/A (novel variant) | |
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29 | c.4069C>T | p.R1357W | 0 | 6 | 6/40 | rs63750428 | 0.006% (14/1099) | 0.001% (5/7944) | 0.000% (6/107190) | 1.000 (probably damaging) | 0.00 (damaging) | −6.56 (deleterious) | Pathogenic | Miksch et al. [2005] |
N/A = not applicable; HGVD = Human Genetic Variation database (
Pedigrees of three Japanese families with angioid streaks (AS). Two novel
Among the 18 families,
In the current study, we identified eight disease-causing variants (p.Q378X, p.R419Q, p.V848CfsX83, p.R1114C, p.R1357W, p.N428S, p.H647Y, and p.S1125F) in the
Only one large-scale
Our study revealed four frequent
Two novel
The current study had several limitations, including case selection bias (as a single-center cohort), the small number of cases (
In conclusion, our results suggest that
The authors declare that there are no conflicts of interest.
The authors thank the patients and their family members for participating in this study. This study was supported by JSPS KAKENHI Grant nos. 19592042 (Takaaki Hayashi) and 17K11434 (Takaaki Hayashi).