Autosomal Dominant Vitelliform Macular Dystrophy via the IMPG1 Gene

IMPG1-associated vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by macular or multifocal vitelliform (egg-yolk) deposits visible upon fundus examination in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD) (Manes et al. 2013. PubMed ID: 23993198).

Macular dystrophies BMD and AVMD are heterogeneous. The majority of cases have pathogenic variants in BEST1 nad PRPH2 (Manes et al. 2013. PubMed ID: 23993198). However, IMPG1 and IMPG2 are new causal genes in 8% of cases that are negative for BEST1 and PRPH2 causative variants (Meunier et al. 2014. PubMed ID: 25085631).

Pathogenic variants in IMPG1 have been documented causative for autosomal dominant (AD) late-onset vitelliform macular dystrophy (Meunier et al. 2014. PubMed ID: 25085631). IMPG1 and another gene IMPG2 encode the interphotoreceptor matrix proteoglycan 1 and 2, respectively. IMPG1 and IMPG2 are also known as sialoprotein associated with cones and rods (SPACR) and SPACRCAN (a proteoglyCan related to SPACR), respectively. These are large glycosylated protein components of the insoluble interphotoreceptor matrix (IPM). Both these proteins consist of hyaluronan (HA) binding motifs and it is believed that they bind to HA and that their interaction stabilizes or modulates the IPM scaffold (Brandl et al. 2017. PubMed ID: 28644393). To date, ~10 pathogenic variants (missense, nonsense and splicing) in IMPG1 have been connected to vitelliform macular dystrophies (Human Gene Mutation Database).

Predicting clinical sensitivity for the IMPG1 gene is challenging due to genetic heterogeneity. However, IMPG1 and IMPG2 are new causal genes in 8% of cases that are negative for BEST1 and PRPH2 causative variants (Meunier et al. 2014. PubMed ID: 25085631).

This test provides full coverage of all coding exons of the IMPG1 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).

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).