ABCMdb

PMID: 23769331

Fujinami K, Sergouniotis PI, Davidson AE, Mackay DS, Tsunoda K, Tsubota K, Robson AG, Holder GE, Moore AT, Michaelides M, Webster AR
The clinical effect of homozygous ABCA4 alleles in 18 patients.
Ophthalmology. 2013 Nov;120(11):2324-31. doi: 10.1016/j.ophtha.2013.04.016. Epub 2013 Jun 12., [PubMed]

Sentences

No. Mutations Sentence Comment

7 ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Arg212Cys ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp ABCA4 p.Cys1488Arg ABCA4 p.Leu2027Phe ABCA4 p.Arg1705Gln ABCA4 p.Val931Met Results: Eleven disease-associated homozygous ABCA4 alleles were identified, including 1 frame shift, 2 stops, 1 intronic variant causing splice-site alteration, 2 complex missense variants, and 5 missense variants: p.Glu905fsX916, p.Arg1300X, p.Gln2220X, c.4253&#fe;4 C>T, p.Leu541Pro and p.Ala1038Val (homozygosity for complex allele), p.Val931Met and p.Arg1705Gln (complex allele), p.Arg212Cys, p.Cys1488Arg, p.Arg1640Trp, p.Gly1961Glu, and p.Leu2027Phe. Login to comment 10 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp Two patients with homozygous missense variants (p.Leu541Pro and p.Ala1038Val [complex], and p.Arg1640Trp) presented with a severe phenotype. Login to comment 11 ABCA4 p.Gly1961Glu Three patients with homozygous p.Gly1961Glu had adult-onset disease and a mild phenotype. Login to comment 12 ABCA4 p.Leu2027Phe One patient with homozygous p.Leu2027Phe showed a spared fovea and preserved visual acuity. Login to comment 13 ABCA4 p.Gly1961Glu ABCA4 p.Leu2027Phe Conclusions: The phenotypes represented in patients identified as homozygous for presumed disease-associated ABCA4 variants gives insight into the effect of individual alleles. Null alleles have severe functional effects, and certain missense variants are similar to nulls, suggesting complete abrogation of protein function. The common alleles identified, p.Gly1961Glu and p. Leu2027Phe, both have a mild structural and functional effect on the adult retina; the latter is associated with relatively retained photoreceptor architecture and function at the fovea. Login to comment 18 ABCA4 p.Gly1961Glu There are a number of reports of families or small case series describing the phenotypic features of homozygous patients,6,10,11,22,25e28 and 1 report features homozygous patients with 1 specific common allele (p.Gly1961Glu).12 However, studies of large cohorts are still lacking because of the rarity of such homozygous cases. Login to comment 60 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Arg212Cys ABCA4 p.Arg212Cys ABCA4 p.Leu541Pro ABCA4 p.Arg1640Trp ABCA4 p.Cys1488Arg ABCA4 p.Cys1488Arg ABCA4 p.Leu2027Phe ABCA4 p.Arg1705Gln ABCA4 p.Val931Met Sex Ethnicity Consanguinity Age at Onset (yrs) Age (yrs) Duration of Disease (yrs) LogMAR VA Fundus Appearance AF Pattern ERG Group OCT Central Foveal Thickness (mm) Mutation Status RE LE RE LE 1 1 M S Asian Yes (1st cousin) 11 33 22 1.0 1.0 2 2 1 64 69 c.634 C>T, p.Arg212Cys 2 1 F S Asian Yes (1st cousin) 11 36 25 1.0 1.0 2 2 3 31 41 c.634 C>T, p.Arg212Cys 3* 2 M European No 3 8 5 1.2 1.2 2 2 3y 41 36 c.1622 T>C, p.Leu541Pro / c.3113 C>T, p.Ala1038Val 4 3 F S Asian Yes (2nd cousin once removed) 5 8 3 1.0 1.0 2 2 3 NA NA c.2713delG, p.Glu905fsX916 5 4 M S Asian Yes (unknown) 10 25 15 1.0 1.08 2 2 3 64 60 c.2791 G>A, p.Val931Met / c.5114 G>A, p.Arg1705Gln 6 5 M S Asian Yes (1st cousin) 10 30 20 1.0 1.0 2 2 3 NA NA c.4462 T>C, p.Cys1488Arg 7 5 F S Asian Yes (1st cousin) 10 22 12 2.0 1.0 2 2 3 NA NA c.4462 T>C, p.Cys1488Arg 8 6 M ME Asian Yes (1st cousin) 30 36 6 1.08 2.0 3 3 3 103 95 c.4918 C>T, p.Arg1640Trp 9 7 F S Asian Yes (2nd cousin) 19 27 8 1.78 2.0 1 2 1 128 90 c.5882 G>A, p.Gly1961Glu 10 7 M S Asian Yes (2nd cousin) 30 34 4 0.48 0.48 1 2 1 NA NA c.5882 G>A, p.Gly1961Glu 11 8 F S Asian Yes (1st cousin) 17 26 9 0.78 0.78 1 1 1 54 47 c.5882 G>A, p.Gly1961Glu 12 9 F European No 44 44 0 0.18 0.0 2 2 1 NA NA c.6079 C>T, p.Leu2027Phe 13 10 M ME Asian Yes (1st cousin) 5 11 6 1.3 1.0 3 2 3 62 68 c.3898 C>T, p.Arg1300X 14 11 M S Asian Yes (unknown) 8 11 3 1.0 1.0 2 2 3 NA NA c.4253&#fe;4 C>T 15 12 M S Asian Yes (1st cousin) 9 48 39 3.0 3.0 3 NA 3 NA NA c.6658 C>T, p.Gln2220X 16 13 M S Asian Yes (uncle and niece) 4 7 3 1.08 1.08 1 NA 3 NA NA c.6658 C>T, p.Gln2220X 17 13 M S Asian Yes (uncle and niece) 6 8 2 1.08 1.0 1 NA 3 NA NA c.6658 C>T, p.Gln2220X 18 13 M S Asian Yes (1st cousin) 17 25 8 1.78 1.78 3 NA 3 NA NA c.6658 C>T, p.Gln2220X AF &#bc; autofluorescence; ERG &#bc; electroretinography; F &#bc; female; FM No. Login to comment 80 ABCA4 p.Cys1488Arg ABCA4 p.Leu2027Phe ABCA4 p.Arg1705Gln ABCA4 p.Val931Met One putative novel variant (p.Glu905fsX916) was identified by NGS, and 7 have not been described in the homozygous state before: p.Val931Met, p.Cys1488Arg, p.Arg1705Gln, p.Leu2027Phe, p.Arg1300X, c.4253&#fe;4C>T, and p.Gln2220X (Table 4, available at http://aaojournal.org). Login to comment 89 ABCA4 p.Leu2027Phe Three heterozygous changes were found in patient 12, suggesting that the p.Leu2027Phe had occurred recurrently on 2 distinct chromosomal backgrounds. Login to comment 90 ABCA4 p.Val931Met In patient 5, 1 of 9 polymorphisms was heterozygous, c.1356&#fe;5delG, 29.7 kb from the disease-causing variant (p.Val931Met). Login to comment 95 ABCA4 p.Gly1961Glu Three patients from 2 families (patients 9, 10, and 11), homozygous for p.Gly1961Glu, showed similar mild findings: adult onset (17e30 years), type 1 fundus appearance, type 1 or 2 AF pattern, and ERG group 1 but variable visual acuity and OCT findings. Login to comment 96 ABCA4 p.Leu2027Phe A very mild phenotype was observed in patient 12, homozygous for p.Leu2027Phe, with late onset (44 years), well-preserved visual acuity (0.18 and 0.0 for each eye), type 2 fundus appearance, type 2 AF pattern with spared AF signal at the fovea, and normal full-field ERGs (group 1). Login to comment 97 ABCA4 p.Arg212Cys Two siblings (patients 1 and 2), homozygous for p.Arg212Cys, showed a similar moderate findings: age of onset (11 years), logMAR visual acuity (1.0), type 2 fundus appearance, type 2 AF pattern, and atrophic change at the fovea on OCT, but ERG grouping was discordant (group 1 and 3). Login to comment 98 ABCA4 p.Arg1705Gln ABCA4 p.Val931Met Patient 5, homozygous for both p.Val931Met and p.Arg1705Gln, had moderate findings: age of onset (10 years), visual acuity (1.0 and 1.08 for each eye), type 2 fundus appearance, type 2 AF pattern, and ERG group 3. Login to comment 99 ABCA4 p.Cys1488Arg Two siblings (patients 6 and 7), homozygous for p.Cys1488Arg, also had a similar moderate findings: age of onset (10 years), type 2 fundus appearance, type 2 AF pattern, and ERG group 3 but variable visual acuity. Login to comment 100 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Patient 3, homozygous for both p.Leu541Pro and p.Ala1038Val, showed a very severe phenotype: age of onset (3 years), visual acuity (1.2 for both eyes), type 2 fundus appearance, type 2 AF pattern, and ERG group 3. Login to comment 101 ABCA4 p.Arg1640Trp Patient 8, homozygous for p.Arg1640Trp, had severe disease but of adult onset: visual acuity Figure 4. Login to comment 116 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu Three patients, homozygous for p.Gly1961Glu, had localized dysfunction confined to the macula with no evidence of generalized retinal dysfunction, consistent with previous reports.12,20 Burke et al12 reported that patients homozygous for p.Gly1961Glu usually have milder disease, with severe phenotypes linked to the presence of additional ABCA4 variants. Login to comment 117 ABCA4 p.Gly1961Glu ABCA4 p.Asn96Lys ABCA4 p.His1838Asp ABCA4 p.Leu2027Phe The 2 previously reported variants (p.Asn96Lys and p.His1838Asp) in complex with p.Gly1961Glu that were associated with a very severe phenotype were not detected in our patients.12 We observed a particularly late-onset mild disorder, with numerous flecks and foveal sparing, associated with p.Leu2027Phe, suggesting primary disease of the parafoveal RPE with preservation of foveal structure, a "foveal sparing" phenotype. Login to comment 118 ABCA4 p.Gly1961Glu ABCA4 p.Arg212Cys ABCA4 p.Cys1488Arg ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Arg1705Gln ABCA4 p.Val931Met This supports previous reports of p.Leu2027Phe in heterozygous patients.14,23 Of note, p.Gly1961Glu and p.Leu2027Phe are both situated in the nucleotide-binding domain 2 subunit, shown to be the site of adenosine triphosphatase activity (Fig 5, available at http://aaojournal.org).39,40 Subjects homozygous for p.Arg212Cys had phenotypes of moderate severity, and these findings are generally in keeping with previous reports.19 Patient 5, homozygous for p.Val931Met and p.Arg1705Gln in complex, and subjects 6 and 7, homozygous for p.Cys1488Arg, had "typical" Stargardt`s disease fundus and AF findings with macular atrophy surrounded by flecks with electrophysiologic evidence of generalized rod and cone system dysfunction. Login to comment 120 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Patient 3, homozygous for p.Leu541Pro and p.Ala1038Val, had a very early onset associated with severe disease. Login to comment 121 ABCA4 p.Arg1640Trp ABCA4 p.Arg1640Trp These findings are similar to genetically identical patients reported by Wiszniewski et al.22 A very severe phenotype also was observed in patient 8 (p.Arg1640Trp), in keeping with the severe findings of genetically identical subjects, homozygous for p.Arg1640Trp, in a previous report by Briggs et al.10 In contrast, patients with homozygous null variants consistently showed a very severe phenotype: 6 of 7 had early-onset disease (<10 years), and all 7 had electrophysiologic evidence of generalized rod and cone system dysfunction. Login to comment 123 ABCA4 p.Gly1961Glu Haplotype analysis in 2 probands homozygous for p.G1961E and 2 homozygous for p.Gln2220X suggested a founder effect for these mutations in these consanguineous families from South Asia, although some of the screened variants were not rare. Login to comment 124 ABCA4 p.Gly1961Glu ABCA4 p.Arg212Cys ABCA4 p.Cys1488Arg Concordance in phenotypic features between patients with an identical disease-causing variant was observed in individuals homozygous for p.Arg212Cys, p.Cys1488Arg, p.Gly1961Glu, and p.Gln2220X, suggesting that few modifiers exist. Login to comment 125 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro ABCA4 p.Arg1705Gln ABCA4 p.Val931Met In conclusion, 2 patients were homozygous for 2 variants previously reported as associated with disease (patient 3, p.Leu541Pro and p.Ala1038Val; patient 5, p.Val931Met and p.Arg1705Gln; Table 4, available at http://aaojournal.org). Login to comment 126 ABCA4 p.Ala1038Val ABCA4 p.Val931Met However, p.Ala1038Val and p.Val931Met were present in a relatively high number of chromosomes on the Exome Variant Server database and were predicted to be tolerant by Sorting Intolerant from Tolerance analysis. Login to comment