ABCMdb

PMID: 26527198

Lee W, Xie Y, Zernant J, Yuan B, Bearelly S, Tsang SH, Lupski JR, Allikmets R
Complex inheritance of ABCA4 disease: four mutations in a family with multiple macular phenotypes.
Hum Genet. 2016 Jan;135(1):9-19. doi: 10.1007/s00439-015-1605-y. Epub 2015 Nov 2., [PubMed]

Sentences

No. Mutations Sentence Comment

9 ABCA4 p.Gly1961Glu ABCA4 p.Cys54Tyr Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Login to comment 11 ABCA4 p.Gly1961Glu Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. Login to comment 87 ABCA4 p.Cys54Tyr [302+68C>T;4539+2028C>T] I-2 75 Mother F PD p.C54Y I-3 69 Uncle (P) M STGD1 c.6148-698_c.6670del/insTGTGCA CCTCCCTAG c. Login to comment 88 ABCA4 p.Gly1961Glu [302+68C>T;4539+2028C>T] I-4 68 Aunt F p.G1961E I-5 67 Aunt (P) F STGD1 c.6148-698_c.6670del/insTGTGCA CCTCCCTAG c. Login to comment 89 ABCA4 p.Cys54Tyr [302+68C>T;4539+2028C>T] I-6 63 Uncle (P) M c.6148-698_c.6670del/insTGTGCA CCTCCCTAG I-7 59 Aunt F c.6148-698_c.6670del/insTGTGCA CCTCCCTAG II-1 43 Proband M STGD1 p.C54Y c. Login to comment 91 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu [302+68C>T;4539+2028C>T] p.G1961E II-3 37 Cousin M STGD1 c.6148-698_c.6670del/insTGTGCA CCTCCCTAG p.G1961E 1 3 Remarkably, both parents of the proband were also affected with macular diseases; however, with phenotypes usually not associated with ABCA4 mutations. Login to comment 98 ABCA4 p.Gly1961Glu ABCA4 p.Cys54Tyr Discovery of new diseaseߛassociated variants by nextߛgeneration sequencing Sequencing of the ABCA4 gene and the entire genomic locus in patients II-1 and II-3, at an average depth of coverage of 100&#d7;, identified the disease-associated missense variants, p.C54Y and p.G1961E, respectively. Login to comment 99 ABCA4 p.Gly1961Glu Both of these variants are known to cause STGD1, the p.G1961E being the most frequent disease-associated allele (Burke et al. 2012). Login to comment 102 ABCA4 p.Cys54Tyr a The proband, a 43-year-old man of German descent harboring the p.C54Y and c. Login to comment 110 ABCA4 p.Cys54Tyr This haplotype was on the other allele from the p.C54Y variant in patient II-1, and was detected also in 5/350 other STGD1 cases, all of whom had a second ABCA4 mutation. Login to comment 115 ABCA4 p.Gly1961Glu Analysis of regulatory sequences To assess the potential functional effects of the two newly described ABCA4 intronic variants on putative regulatory regions we compared their location against the chromosome coordinates of the DNaseI hypersensitivity and Fig.Êf;3ߒߙThe paternal cousin (36-year-old son of the paternal uncle) harboring the p.G1961E allele and the c.6148-698_c.6670del/insTGTGCACCTCCCTAG variant presented at a comparatively milder disease stage. Login to comment 118 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Cys54Tyr [302+68C>T;4539+2028C>T] Subject Onset (y) Duration (y) BCVA Geographic atrophy Extent of atrophy Fleck distribution Peripapillary sparing ABCA4 mutation OD OS Allele 1 Allele 2 I-3 5 67 CF CF Posterior pole Choriocapillaris Resorbed Partial del/insa intronicb I-5 5 62 CF 20/400 Extra-macular Choriocapillaris Resorbed Partial del/insa intronicb II-1 9 34 20/400 20/200 Macular Choriocapillaris Resorbed/ reticular Spared p.C54Y intronicb II-2 30 10 20/100 20/100 n/a Outer retina Scattered Spared intronicb p.G1961E II-3 30 7 20/150 20/150 n/a Outer retina Scattered Spared del/insa p.G1961E 1 3 transcription factor-binding clusters from ENCODE. Login to comment 129 ABCA4 p.Cys54Tyr Fig.Êf;4ߒߙMacular findings in the mother and father of the proband who each carry a single ABCA4 variant, p.C54Y and c. Login to comment 161 ABCA4 p.Gly1961Glu This is likely due to the p.G1961E mutation shared by II-2 and II-3 on the opposite, maternal allele, which has been previously associated with a late-onset, milder disease phenotype characterized by more localized disease confined to the central macula (Burke et al. 2012; Cella et al. 2009). Login to comment 162 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu This apparent resistance to disease severity conferred by p.G1961E is clearly exemplified in this family; this could potentially be attributed to G1961E representing a hypomorphic allele, although its precise mechanism remains to be elucidated (Allikmets 2000; Lewis et al. 1999). Login to comment 181 ABCA4 p.Cys54Tyr However, while the patient carried one ABCA4 allele, p.C54Y, and exhibited certain phenotypic characteristics similar to STGD1, the distinct lack of peripapillary sparing (a pathognomonic characteristic of STGD1 Cideciyan et al. 2005) is clinically contraindicative of ABCA4-associated disease. Login to comment