Homozygous and heterozygous retinal phenotypes in families harbouring IMPG2 mutations

Introduction: Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) have been shown to underlie recessive childhood-onset rod-cone dystrophy with early macular involvement in several families. In other families, heterozygous IMPG2 mutations have been associated with dominant vitelliform macular dystrophy. To date, the retinal phenotype of heterozygotes from families with recessive IMPG2-related retinal dystrophy has not been assessed. This study documents the genotypes and phenotypes observed in both homozygotes and available heterozygotes from additional families with IMPG2-related recessive rod-cone dystrophy. Methods: Retrospective case series (2016-2018). Results: Four families were identified. All were first-cousin marriages and had no known relation to each other. Individuals with biallelic pathogenic variants (7 individuals) had childhood-onset rod-cone dystrophy. Families 1 and 2 harboured the same novel homozygous mutation c.189dup;p.Gln64Thrfs*9 (5 individuals, 4-17 years old). Family 3 harboured the novel homozygous mutation c.533 + 4_533 + 7del;p.? (1 individual, 17 years old), and Family 4 harboured the previously reported homozygous mutation c.3262C>T;p.Arg1088* (1 individual, 45 years old). The 3 available carriers were genetically confirmed (both parents from Family 1 and the father from Family 3) and had macular focal retinal pigment epithelium thickening by optical coherence tomography (OCT). The father from Family 3 also had unilateral sectoral pigmentary retinopathy. Conclusions: Childhood-onset recessive rod-cone dystrophy with early macular involvement should prompt examination of the parents for macular focal retinal pigment epithelium thickening on OCT. If present the possibility of biallelic IMPG2 mutations in the proband should be considered. Young affected relatives of the proband can show multimodal imaging abnormalities before they are overtly symptomatic.