Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles

Abstract

PURPOSE. To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1). METHODS. Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253þ43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769-784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs). RESULTS. Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253þ43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253þ43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5%-39.6%) and c.4253þ43G>A (35.8%-43.1%) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253þ43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15% of the total mRNA (i.e.,~30% of the c.769-784C>T allele alone). CONCLUSIONS. Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene.

Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia

“…Although 76% of registrations related to Stargardt disease were in the working-age group, we found 10% were registered up to the age of 15 and 14% were registered at 65years or older, with a bimodal peak. This is consistent with the extreme variability in phenotype ranging from severe childhood-onset to late-onset disease, which has a median age of onset in the mid-50 with up to 11% of these individuals eligible for blindness registration (23,28). Another retrospective crosssectional study of 361 patients with Stargardt disease found 59% met the criteria for blindness registration and the median time to develop this degree of visual impairment varied from 22 to 29 years depending on the BCVA at the patient's initial visit (29).…”

Detailed Phenotyping and Therapeutic Strategies for Intronic ABCA4 Variants in Stargardt Disease

“…32 It should also be noted, however, that evidence is emerging that some variants that were long considered pathogenic or benign by themselves, such as c.2588G>C; p.[G863A,G863del] and c.5603A>T; p.(N1868I), are fully penetrant only when in combination on the same allele. The same is true for the cis configuration of p.(N1868I) with a recently identified intronic mutation, c.769-784C>T. 9,33,34 In addition, modifier variants, either within or outside of ABCA4, as well as environmental factors will likely play a role in determining disease outcome. 9 Thus, care is warranted when attributing a severity score to individual alleles.…”

Increasing the Genetic Diagnosis Yield in Inherited Retinal Dystrophies: Assigning Pathogenicity to Novel Non-canonical Splice Site Variants

“…A step further in genetic diagnosis has been attained when deep-intronic variants that alter the splicing pattern have been identified, as is the case in Stargardt disease, a macular disorder with a very well defined clinical phenotype and a major causative gene, ABCA4. In fact, the introduction of the whole ABCA4 locus in the target NGS panels clearly helps to increase the genetic yield in Stargardt disease patients [16,17].…”