Scientific Background
Familial retinopathies occur in several diseases with overlapping symptoms, such as retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardt disease, Usher syndrome (USH), Bardet-Biedl syndrome (BBS) and Senior-Løken syndrome.
The incidence of RP is 1:3,000-5,000, with syndromic diseases being rarer. In most cases only the retina is clinically affected. Symptoms are characterized by night blindness and a slow, progressive loss of central vision from about the age of 20 that is initially limited to degeneration of the rod photoreceptors on the retina. The cones may also be affected later. However, there are also syndromic diseases in which retinal dystrophy is the first symptom and which are difficult to differentiate in the early stages.
Patients with USH have hearing loss in addition to RP. Even in the case of pure retinopathies, differential diagnosis can be difficult, because the symptoms often overlap and the full spectrum of the disease can only become apparent after decades due to the usually progressive course of disease. In addition, intrafamilial variability is known. The causes of RP are very heterogeneous, as more than 80 causative genes are known. 35-60% of RP cases have autosomal recessive inheritance, 15-25% autosomal dominant inheritance and 15% X-linked inheritance. Pathogenic variants in the USH2A gene cause 10-15% of the syndromic form of RP—autosomal recessive inherited USH. In recessively inherited cases, pathogenic changes in the genes RPGR including ORF15 and RP2 can be detected in up to 85% of cases. Approximately 25% of all non-syndromic RP cases are due to pathogenic variants in the rhodopsin gene (RHO) that have autosomal dominant inheritance. Using NGS, the genes for the different forms of RP can be analyzed in parallel (gene panel diagnostics). Diagnostic sensitivity is 20-30% for autosomal recessive forms, 80-85% for dominant forms and over 85% for syndromic forms.
References
Talib et al. 2018, Invest Ophthalmol Vis Sci 59:4123 / Almoguera et al. 2015, PLoS One 10:e0133624 / Chiang et al. 2015, Expert Rev Mol Diagn 15:1269 / Daiger et al. 2013, Clin Genet 84:132