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Non-syndromic subjects with mutations in the CEP290 gene have been identified among an Italian cohort of 32 IRD patients

Researchers based at the Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy, have reported a multicentric longitudinal study with mutations in the CEP290 gene. The important study found a mild phenotype among several inherited retinal degenerations (IRDs), including the non-syndromic disorder of Leber congenital amaurosis (LCA), and the systemic disorders including Joubert syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome and Meckel syndrome. The study was characterized by the absence of nystagmus, good visual acuity, considerably preserved retinal morphology and recordable ERG.


The CEP290 gene is localized to chromosome 12q21.32 and encodes a 290 kDa centrosomal protein called nephrocystin-6 (NPHP6).  The protein is important for ciliary assembly and ciliary trafficking and is well characterised by LCA.  Previously defined as a juvenile form of RP, LCA is a severe congenital or early infant-onset form of non-syndromic retinal disease characterised by severe retinal dystrophy, vision loss, nystagmus, an absence of a normal pupil response and an almost non-recordable ERG. LCA was originally identified by a German clinical ophthalmologist, Theodor von Leber in 1869 and this disorder was primarily based on the early infant-onset form of non-syndromic inherited visual loss.  However, following the original description of the infantile disorder, a subsequent milder form of the same disease presented in the 6th and 7thyears of life and led to blindness by the age of 30 years, considered to be on the same spectrum as LCA.  This later-onset disease has been referenced by several different names including juvenile and early-onset retinitis pigmentosa, childhood-onset severe retinal dystrophy, Early Onset Severe Retinal Dystrophy (EOSRD) and Severe Early Childhood Onset Retinal Dystrophy (SECORD). Regardless, the clinical diagnosis does not have a well agreed-upon definition and therefore a more recent structure for nomenclature, aiming to define the basis as being on genotype rather than phenotype (e.g., RPE65-related LCA), is preferable.  As of latest reporting with RetNet, there are now 25 genes or loci causative for LCA.  While this nomenclature continues to be refined, LCA may have an overlap between the genotypic and phenotypic descriptions for EOSRD / SECORD, although the more frequently genes associated with LCA includes GUCY2D (10-20%), CEP290 (15-20%), CRB (10%), AIPL1 (4-8%) and NMNAT1 (uncertain), whereas in an EOSRD phenotype, other genes include RPE65 (5-10%), LRAT (<1%) and RDH12 (4-5%).


In the current Italian study, a detailed longitudinal phenotyping and genetic characterization of 32 Italian patients with a non-syndromic retinal dystrophy was defined among mutations in the CEP290 gene. As reported by the research team, patients (mean age = 19.0±3.4 years) had a mean BCVA of 1.73 ±0.20 logMAR, while central retinal thickness (CRT) declined significantly with age at an exponential rate of 1.0% per year (P = 0.001). At disease onset, most patients (19/32 patients; 49.4%) had nystagmus. The absence of nystagmus was significantly associated with better BCVA and more preserved CRT (P < 0.05). ERG showed undetectable responses in most patients (64.0%), whereas reduced scotopic and photopic responses were observed in four patients (16.0%) who had no nystagmus. According to the researchers, the published report stated that, “we identified 35 different variants in CEP290. They comprised 15 frameshifts, 10 nonsense mutations, 5 splice site variants, 6 missense variants, and one in-frame deletion of a single amino acid. Twelve of the identified variants were novel and included four missense variants whose pathogenicity was hypothesized based on in silico predictions and allele frequency criteria. Interestingly, almost all patients (97%) harboured at least one truncating mutation, whereas only one patient (ID 8) carried two missense variants”.