Stargardt disease, Fundus Flavimaculatus or Retinal Dystrophy, Early-Onset Severe via the ABCA4 Gene

Stargardt disease (STGD) is the most common form of juvenile onset inherited macular degeneration. STGD is characterized by loss of photoreceptor cells in the macula and degeneration of the retinal pigment epithelium (RPE), resulting in a severe reduction of central vision with preservation of peripheral vision. STGD has variable phenotype, age of onset, and severity. It accounts for approximately 7% of all retinal disorders with an estimated prevalence of 1 in 10,000 and a carrier frequency of 2% (Shastry. 2008. PubMed ID: 18506364). A characteristic feature of STGD is yellowish flecks surrounding the macula. At advanced stages, a progressive bilateral atrophy of the RPE, photoreceptors, and choroidal vasculature can be found (Rossi et al. 2012. PubMed ID: 23341817; Fishman et al. 1987. PubMed ID: 3658351). Genetic analysis suggests that STGD and Fundus flavimaculatus (FFM) are allelic disorders with slightly different clinical manifestations. FFM has later age of onset (20-64 years) and slower progression or milder visual loss (Kaplan et al. 1993. PubMed ID: 8275096; Shastry. 2008. PubMed ID: 18506364).

With the advent of gene therapy and other types of treatments, the identification of causative genes and variants is becoming increasingly important. Lentiviral gene therapy in mouse model was found to be a potentially efficient tool for treating ABCA4-associated diseases (Kong et al. 2008. PubMed ID: 18463687).

Please see the following links for clinical trials and management options below:

Management

https://clinicaltrials.gov/ct2/show/NCT03772665

https://clinicaltrials.gov/ct2/show/NCT01736592

http://progstar.org/progstar-home/about-the-study/

Genetically, STGD is a heterogeneous disorder that is usually inherited in an autosomal recessive (AR) manner and, less commonly, as an autosomal dominant (AD) trait (Rossi et al. 2012. PubMed ID: 23341817). Using homozygosity mapping, the STGD/FFM disease locus was mapped to the short arm of chromosome 1 and the causative gene characterized as ABCA4 (Kaplan et al. 1993. PubMed ID: 8275096; Allikmets et al. 1997. PubMed ID: 9295268). ABCA4 is associated with multiple types of retinal disorders (Rozet et al. 1998. PubMed ID: 9781034; Rivera et al. 2000. PubMed ID: 10958763). Bi-allelic pathogenic variants in ABCA4 are found in the majority of AR STGD (66-80%) (Allikmets et al. 1997. PubMed ID: 9295268), age-related macular degeneration (AMD) (Allikmets et al. 1997. PubMed ID: 9295268), two-thirds of cases with AR cone-rod dystrophy (AR CRD) (Cremers et al. 1998. PubMed ID: 9466990) and a small fraction of patients with AR retinitis pigmentosa (arRP) (Martínez-Mir et al. 1998. PubMed ID: 9425888).

The pathogenic variant spectrum of ABCA4 ranges from single base substitutions to deletions of several exons, although the majority are missense variants followed by protein truncating variants and deep intronic variants (Khan et al. 2020. PubMed ID: 32307445; Briggs et al. 2001. PubMed ID: 11527935). To our knowledge, no de novo variants in ABCA4 have been documented causative. The c.2588G>C (p.[Gly863Ala, Gly863del]) variant was found in more than one-third of patients with STGD in the western European population (Maugeri et al. 1999. PubMed ID: 10090887). c.2588 is the first nucleotide of exon 17. The G>C nucleotide substitution at this position results in a mixture of proteins, some with the p.Gly863Ala substitution, and some with deletion of Gly863 due to a shift in the splice acceptor site (Maugeri et al. 1999. PubMed ID: 10090887). Other common pathogenic variants include c.5882G>A (p.Gln1961Glu), which is likely a founder variant in Somalia (Guymer et al. 2001. PubMed ID: 11346402), and c.5461-10T>C (Sangermano et al. 2016. PubMed ID: 26976702; Cornelis et al. 2017. PubMed ID: 28044389). Although uncommon, uniparental isodisomy has also been reported in AR STGD (Khan et al. 2020. PubMed ID: 32307445; Fingert et al. 2006. PubMed ID: 16682602; Riveiro-Alvarez et al. 2007. PubMed ID: 17277736).

ABCA4 encodes a retina-specific ATP-binding transmembrane transporter, located in the discs of rod and foveal cone outer segments. The protein transports retinoids from photoreceptors to the retinal pigment epithelium (RPE) (Sun and Nathans. 1997. PubMed ID: 9288089). Pathogenic variants in this gene result in failure to transport and lead to the accumulation of lipofuscin fluorophore A2-E (N-retinylidene-N-retinylethanolamine). This product could be deleterious to the RPE, with consequent secondary photoreceptor degeneration due to loss of the RPE support role (Weng et al. 1999. PubMed ID: 10412977). 

Shroyer et al. (Shroyer. 2001. PubMed ID: 11726554) screened 22 families with both STGD and AMD and detected causative ABCA4 pathogenic variants in 37/46 (80%), which is higher than previous reports (~63%) (Yatsenko et al. 2003. PubMed ID: 12754711). According to Maugeri et al. (2000), ABCA4 also plays a major role in arCRD. Their study detected ABCA4 pathogenic variants in 65% of the patients (13/20), of which 6 had a pathogenic variant in both ABCA4 alleles and 7 had a pathogenic variant in only one of the alleles (Maugeri et al. 2000. PubMed ID: 10958761). Yatsenko et al. (2003) evaluated 192 chromosomes to detect genomic rearrangements and observed one large deletion in ABCA4, IVS17-905_IVS18+35del, which eliminates exon 18. This study suggests that large deletions account for <1% of causative pathogenic variants in ABCA4 (Yatsenko et al. 2003. PubMed ID: 12754711).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the ABCA4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Of note, the following list of deep intronic variants in ABCA4 are tested when a single pathogenic or likely pathogenic variant is identified:

c.161-23T>A, c.570+1798A>G, c.769-784C>T, c.859-506G>C, c.859-540C>G, c.1937+435C>G, c.1938-619A>G, c.2160+584A>G, c.2919-826T>A, c.3050+370C>T, c.4253+43G>A, c.4539+1100A>G, c.4539+2001G>A, c.4539+2028C>T, c.4539+2064C>T, c.5196+1056A>G, c.5196+1136C>A, c.5196+1137G>T, c.5196+1159G>A, c.5196+1216C>A, c. 6006-609T>A, c.6148-471C>T.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).