At least 1 disease-causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; ≥2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD.

c.1A>G, p.Met1Val

This work reported presence of 22 alterations, including two changes not found in other populations, c.2T>C (p.Met1Thr) and c.4036_4037delAC (p.Thr1346fs), and two novel disease associated variants, c.400C>T (p.Gln134X) and c.4720G>T (p.Glu1574X).

ilename Description aos14218-sup-0001-TableS1.xlsxMS Excel, 27.1 KB Table S1. List of genetic variants found in IRD patients, Norway, 2018. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The locations of ABCA4 homozygous and hypomorphic missense mutations characterized in the present study are shown in Fig 1. These mutations are distributed throughout ABCA4 with 4 in ECD1 (p.Asn96Asp, p.Asn96His, p.Arg212Cys, p.Arg602Trp), 4 in ECD2 (p.Leu1430Pro, p.Gly1439Asp, p.Pro1486Leu, p.Ala1598Asp), 6 within or close to NBD1 (p.Gly863Ala, p.Asn965Ser, p.Thr1019Met, p.Glu1087Lys, p.Arg1108Cys, p.Arg1129Leu), and 6 within NBD2 (p.Leu1940Pro, p.Gly1977Ser, p.Leu2027Phe, p.Arg2030Gln, p.Arg2107His, p.Cys2137Tyr). The p.Asn1868Ile mutation is present in a loop connecting the V-shaped α-helical hairpin with membrane spanning segment 12 (TM12). Several mutations occur in well-defined motifs crucial for the binding and hydrolysis of ATP. The p.Asn965Ser and p.Glu1087Lys mutations occur in the Walker A (Gly-His-Asn-Gly-Ala-Gly-Lys-Thr) and Walker B (Val-Ile-Leu-Asp-Glu) motifs of NBD1, respectively, and the p.Gly1977Ser mutation is present in the Walker A (Gly-Val-Asn-Gly-Ala-Gly-Lys-Thr) motif of NBD2. The p.Arg2030Gln variant reported to display a mild disease phenotype in compound heterozygous STGD1 patients has been included in our analysis although this variant has yet to be found in a homozygous state.

Sixteen patients from 13 families with signs of Stargardt macular dystrophy/fundus flavimaculatus and known mutations on both alleles of the ABCA4 gene (15 compound heterozygous, one homozygous) were characterized by clinical examination, fundus autofluorescence, psychophysics (color vision, kinetic and two-color dark- and light-adapted static threshold perimetry), and electrophysiology (Ganzfeld, multifocal ERG, EOG).

Additional file 2: All supplemental tables cited in the text. Enclosed data include data set meta-information, CAP scores for all drug-related genes, DRP scores for all drugs, CAP and DRP differences between populations, and a comparison between allele frequencies in the studied data set and CPIC guidelines. (XLSX 776 kb)13073_2017_502_MOESM2_ESM.xlsx (776K)GUID: B02AAF40-A613-411F-A471-357C45A33F82

Screening of reported pathogenic variants in ABCA4 for Stargardt (STGD) The disease prevalence of STGD is estimated as 1 in 10000 individuals4. It has been estimated that about 70% of STGD patients carry variants in ABCA45. Therefore, this represents the scenario of a recessive disease with a relatively homogeneous genetic cause. We screened 945 reported pathogenic variants in ABCA4 genes collected in HGMD. Among them, 11 variants are likely benign, as their population AF in is higher than 0.7% (1/20000‾‾‾‾‾‾‾‾√)<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="M11"><mrow><mrow><mo>(</mo><mrow><msqrt><mrow><mn>1</mn><mo>/</mo><mn>20000</mn></mrow></msqrt></mrow><mo>)</mo></mrow></mrow></math>, the cutoff based on STGD disease prevalence, therefore were excluded from further analysis. The remaining 934 variants were subjected to our test model. As a result, 26 variants with the AF in the range of 0.46% to 0.03% were identified as likely benign (Binomial test1, Bonferroni correction p-value ≤ 0.05/934 and test2 Bonferroni correction p-value > 0.05/934) (Figure 3A).

Table S2. ABCA4 variant categorization:

To determine the overall CF for all AR-IRD–causing mutations in different subpopulations, we initially calculated CF for each of the 10,044 likely pathogenic variants in each subpopulation (SI Appendix, Tables S2 and S3).

To determine the overall CF for all AR-IRD–causing mutations in different subpopulations, we initially calculated CF for each of the 10,044 likely pathogenic variants in each subpopulation (SI Appendix, Tables S2 and S3).

Supplementary TableS5

In humans, clinical studies have implicated mutations in 19 of the 48 known ABC transporters in diseases such as cystic fibrosis and adrenoleukodystrophy.

We found statistically significant association for six variations (c.1268A>G, c.4203C>A, c.5603A>T, c.5682G>C, c.5843C>T, c.6249C>T) (FDR < 0.05, Supplementary Table S4)

Table S2. ABCA4 variant categorization:

Table S2. ABCA4 variant categorization:

Summary genetic testing data is available on the eyeGENE website (eyeGENE.nih.gov/data), including the number of participants for each of the 38 diagnostic categories, variants detected per gene, and variant classification by gene. As of the time of this writing, 3,448 eyeGENE participants have been reported to have at least one pathogenic or likely pathogenic genetic variant. The 10 most frequently reported genes were ABCA4 (1799, 37%), USH2A (316, 7%), RPGR (283, 6%), CHM (219, 5%), PRPH2 (161, 3%), RS1 (142, 3%), RHO (130, 3%), BEST1 (114, 2%), EYS (67, 1%), and PRPF31 (62, 1%). These 10 genes represent 68% of all pathogenic and likely pathogenic variants in eyeGENE. Two thousand one hundred and four participants have genetic results where no pathogenic or likely pathogenic variant was found. Variants of uncertain significance were identified in 1,712 individuals.

Eighty-four unrelated STGD1 patients were found to carry two or more disease-causing ABCA4 mutations, and cosegregation analyses were performed in 54 (64.3%). (See Supplementary Table S3 for a summary of clinical phenotype of STGD1 patients). The mean disease onset age of the patients was 13.1 years (range, 2–44 years), and half of these patients experienced their symptoms of visual impairment in their first decade. We classified the patients into three groups by their disease onset age. For the patients in the first group, whose disease onset ages were between 1 and 10 years, the fraction (45.3%, 19/42) of patients carrying compound heterozygous or homozygous deleterious mutations (nonsense, frameshift insertion or deletion, or splicing mutations) or complex alleles was much higher than those observed for the patients in the group 2 (24.1%, 7/29) and group 3 (15.4%, 2/13), whose disease onset ages were from 11 to 20 years or older than 20 years, respectively. In contrast, the percentage of patients carrying compound heterozygous or homozygous missense mutations was higher in group 3 than in group 1 or group 2 (Table 2). The most common mutation (p.Y808X) was detected in 12 patients, and all were heterozygous compound with missense (6 patients), splicing (1 patient), and insertion or deletion (5 patients) mutations. The two most frequent missense mutations (p.F2188S and p.N965S) were identified as heterozygous. In 84 patients, 9 patients carried complex mutations, and 4 of those 9 patients carried a common complex allele p.E328V/p.E1036K. All these patients had early onset age and relatively severe visual acuity defects. One patient (010222) also carried three heterozygous mutations (p.E328, p.E1036K, and p.R1843W); however, he did not harbor the common complex allele p.E328V/p.E1036K, as only p.E1036K was detected in his son in the subsequent cosegregation analysis. Compared to the four patients carrying the common complex alleles (p.E328V/p.E1036K), patient 010221 had a late onset age (44 years old).  Table 2 View Table Correlations Between Onset Age of STGD Patients and Their Carrying Mutations

We identified 1319 distinct causative variants (Supplementary Table S1) in 132 different genes (Table ​(Table3).3). The ten most commonly mutated genes were ABCA4 (n = 535 [26.3%]), USH2A (n = 228 [11.2%]), RPGR (n = 102 [5%]), CHM (n = 72 [3.5%]), RHO (n = 72 [3.5%]), MYO7A (n = 69 [3.4%]), CRB1 (n = 55 [2.7%]), RPE65 (n = 40 [2%]), RP1 (n = 37 [1.8%]), and GUCY2D (n = 34 [1.7%]) (Table ​(Table3,3, Fig. 2a). The other 122 genes had a lower contribution to IRDs. One hundred genes were mutated in 15 patients or less and were collectively responsible for disease pathogenesis in 18% of the solved cohort (Fig. 2a, Table ​Table3).3). Thirty-two genes were mutated in only one patient (Table ​(Table3).3). Mutations in the mitochondrial DNA accounted for 2.1% of the cohort and were implicated almost exclusively in the pathogenesis of LHON.

Table S2. ABCA4 variant categorization:

Table S2. ABCA4 variant categorization:

Table S2. ABCA4 variant categorization:

5137 Mo 25 3/10 / FC ND / c.32T>C(1) ND/p.Leu11Pro

Microarray-based mutation analysis of the ABCA4 gene in Spanish patients with Stargardt disease: evidence of a prevalent mutated allele

Screening of reported pathogenic variants in ABCA4 for Stargardt (STGD) The disease prevalence of STGD is estimated as 1 in 10000 individuals4. It has been estimated that about 70% of STGD patients carry variants in ABCA45. Therefore, this represents the scenario of a recessive disease with a relatively homogeneous genetic cause. We screened 945 reported pathogenic variants in ABCA4 genes collected in HGMD. Among them, 11 variants are likely benign, as their population AF in is higher than 0.7% (1/20000‾‾‾‾‾‾‾‾√)<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="M11"><mrow><mrow><mo>(</mo><mrow><msqrt><mrow><mn>1</mn><mo>/</mo><mn>20000</mn></mrow></msqrt></mrow><mo>)</mo></mrow></mrow></math>, the cutoff based on STGD disease prevalence, therefore were excluded from further analysis. The remaining 934 variants were subjected to our test model. As a result, 26 variants with the AF in the range of 0.46% to 0.03% were identified as likely benign (Binomial test1, Bonferroni correction p-value ≤ 0.05/934 and test2 Bonferroni correction p-value > 0.05/934) (Figure 3A).

Screening of reported pathogenic variants in ABCA4 for Stargardt (STGD) The disease prevalence of STGD is estimated as 1 in 10000 individuals4. It has been estimated that about 70% of STGD patients carry variants in ABCA45. Therefore, this represents the scenario of a recessive disease with a relatively homogeneous genetic cause. We screened 945 reported pathogenic variants in ABCA4 genes collected in HGMD. Among them, 11 variants are likely benign, as their population AF in is higher than 0.7% (1/20000‾‾‾‾‾‾‾‾√)<math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" id="M11"><mrow><mrow><mo>(</mo><mrow><msqrt><mrow><mn>1</mn><mo>/</mo><mn>20000</mn></mrow></msqrt></mrow><mo>)</mo></mrow></mrow></math>, the cutoff based on STGD disease prevalence, therefore were excluded from further analysis. The remaining 934 variants were subjected to our test model. As a result, 26 variants with the AF in the range of 0.46% to 0.03% were identified as likely benign (Binomial test1, Bonferroni correction p-value ≤ 0.05/934 and test2 Bonferroni correction p-value > 0.05/934) (Figure 3A).

ABCA4

rs2799573 10 18641934 CACNB2 T/C 0·715 0·825 4·29×10−8 1·08 (1·05–1·12) 0·57 Five disorder¶