Macular Dystrophy, Vitelliform, 4

A number sign (#) is used with this entry because of evidence that vitelliform macular dystrophy-4 (VMD4) is caused by heterozygous mutation in the IMPG1 gene (602870) on chromosome 6q14.1. Patients in some families with VMD4 have been reported to have compound heterozygous or homozygous mutations in IMPG1; in these families, asymptomatic heterozygous carriers have been found to have fundus changes.

Description

Macular dystrophies are inherited retinal dystrophies in which various forms of deposits, pigmentary changes, and atrophic lesions are observed in the macula lutea, the cone-rich region of the central retina. Vitelliform macular dystrophies (VMDs) form a subset of macular dystrophies characterized by round yellow deposits, usually at the center of the macula and containing lipofuscin, a chemically heterogeneous pigment visualized by autofluorescence imaging of the fundus (summary by Manes et al., 2013). Vitelliform macular dystrophy-4 is characterized by late-onset moderate visual impairment, small satellite drusen-like lesions in the foveal area, preservation of retinal pigment epithelium (RPE) reflectivity, deposits above the RPE between the ellipsoid and outer segment interdigitation lines on spectral-domain optical coherence tomography (SD-OCT), and normal or borderline results on electrooculography (EOG) (Meunier et al., 2014).

For a discussion of genetic heterogeneity of vitelliform macular dystrophy, see VMD1 (153840).

Clinical Features

Manes et al. (2013) examined 8 affected individuals from a large 6-generation French family with VMD. Age of onset ranged from 20 to 45 years, and mean visual acuity was 20/30. Six of the 8 individuals had a single subfoveal vitelliform lesion, and 2 individuals had several small vitelliform deposits in both eyes. In most individuals, rod responses on electroretinography (ERG) were above the lower limit, and cone responses were either normal or moderately decreased. All individuals but 1 had a normal or slightly decreased Arden ratio on EOG.

Mapping

Manes et al. (2013) performed a genomewide scan of 8 affected and 7 unaffected members of a large 6-generation French family with VMD and identified a common 95.2-Mb haplotype at chromosome 6p12.1-q24.3 in affected individuals, between SNPs rs1076701 and rs6910680. The authors confirmed linkage with microsatellite markers, obtaining a maximum lod score of 3.02 for D6S1622 on 6q13.

Molecular Genetics

By whole-exome sequencing in 7 affected members of a large 6-generation French family with VMD mapping to chromosome 6q13, Manes et al. (2013) identified heterozygosity for a missense mutation in exon 7 of the IMPG1 gene (L238R; 602870.0001) that segregated with the disease in the family and was not found in public SNP databases or in 114 ethnically matched chromosomes. Sequencing of exon 7 of IMPG1 in a series of 251 probands with VMD and various other forms of macular dystrophy revealed 2 more VMD families, 1 from France and 1 from Spain, in which heterozygosity for the same L238R mutation segregated with disease. Haplotype analysis suggested that the 3 families might be distantly related. Manes et al. (2013) then sequenced all 17 exons and flanking intronic regions of IMPG1 in 144 probands, a subset of the previously screened probands, and identified a French family in which an affected brother and sister were compound heterozygous for a nonsense (R507X; 602870.0002) and a missense (L154P; 602870.0003) mutation, as well as a consanguineous Italian family in which an affected brother and sister were homozygous for a splice site mutation (602870.0004). Some asymptomatic heterozygous carriers from both of the latter families were found to exhibit minor fundus changes, but the macular vitelliform disc with decreased visual acuity was present only in compound heterozygotes or homozygotes. In the proband from another French family, an IMPG1 splice site mutation was identified that was also carried by her unaffected mother and 2 unaffected sisters; however, the unaffected sisters shared a paternal allele different from that of the proband, suggesting that the proband also harbored an unidentified paternal mutation. Screening of the IMPG1 gene in patients with other forms of inherited macular dystrophy or macular drusen failed to reveal any mutations.