Stargardt Disease (STGD) and Macular Dystrophies Panel

Stargardt disease (STGD) is a juvenile onset form of macular dystrophy/degeneration (MD) characterized by loss of photoreceptor cells in the macula, resulting in a severe reduction of central vision with a variable phenotype and a variable age of onset and severity. STGD is considered one of the most frequent causes of MD in childhood, accounting for approximately 7% of all retinal degenerative diseases with an estimated prevalence of 1 in 10,000 and a carrier frequency of 2% (Shastry. 2008. PubMed ID: 18506364). Clinical features include progressive bilateral degeneration of the macula and retinal pigment epithelium (RPE) with characteristic orange-yellow flecks located around the macula or the mid peripheral retina (Rossi et al. 2012. PubMed ID: 23341817). The hallmark of STGD is massive accumulation of cellular debris, presumably lipofuscin in the RPE (usually seen in normal aging human eyes) (Fishman et al. 1987. PubMed ID: 3658351), which is clinically similar to fundus flavimaculatus (FFM) that has a later age of onset (20-64 years) and slower progression or milder visual loss compared to STGD (Kaplan et al. 1993. PubMed ID: 8275096).

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 STGD1/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: 9054934). Panel-based next generation sequencing has identified other genes (BEST1, C1QTNF5, CDH3, CNGB3, ELOVL4, FSCN2, PROM1, PRPH2, RDH12, RP1L1, RPGR, TIMP3, RBP3, RPGRIP1, EFEMP1, GUCA1B, CERKL, CRB1, RLBP1, RS1, IMPG2, CTNNA1, HMCN1, CFH, IMPG1, MFSD8, and PRDM13) reported to cause STGD like phenotype or macular dystrophies similar to STGD (Zhang et al. 2014. PubMed ID: 24763286; Strom et al. 2012. PubMed ID: 22863181; Petrukhin et al. 1998. PubMed ID: 9662395; Glöckle et al. 2014. PubMed ID: 23591405; Zaneveld et al. 2015. PubMed ID: 25474345; Saksens et al. 2016. PubMed ID: 26691986; Small et al. 2016. PubMed ID: 26507665).

Please note that this test also targets the five variants in the upstream region of the PRDM13 gene that were reported to segregate with disease in the 102 affected and 39 unaffected members of the 12 North Carolina macular dystrophy (NCMD) families (Small et al. 2016. PubMed ID: 26507665).

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

Due to genetic heterogeneity and phenotypic overlap, determining clinical sensitivity is difficult. A study that screened 23 families with both Stargardt disease (STGD) and Age-related Macular Degeneration (AMD), detected causative ABCA4 pathogenic variants in 37/46 chromosomes (80%), which is substantially higher than the previous reports (~63%) (Shroyer et al. 2001. PubMed ID: 11726554; Yatsenko et al. 2003. PubMed ID: 12754711).

Large deletions/duplications have been reported in ABCA4, BEST1, CDH3,CNGB3, PROM1, PRPH2, RDH12, RPGR, RPGRIP1, CRB1, RLBP1, RS1, CFH, and IMPG2 (Human Gene Mutation Database).

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

This panel typically provides 98.8% coverage of all coding exons of the genes 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 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).

RP1L1 does not have 100% coverage for a few regions in exon 4.

This test also targets the five variants in the upstream region of the PRDM13 gene (see the Genetics section).

We also test a deep intronic variant (c.2077-521A>G) in PROM1 (Mayer et al. 2016. PubMed ID: 26153215).

We do not test for all the deep intronic variants in ABCA4. However, if we find a pathogenic or a likely pathogenic in ABCA4 or another of these genes in this panel, we will perform Sanger backfill of the remainder of the gene.

The following list of deep intronic variants in ABCA4 are tested when a single likely pathogenic or 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.

We do not have coverage for the RPGR ORF15 region in this panel.

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).