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Research on Leber congenital amaurosis (LCA) on a Brazilian cohort of 152 patients has identified almost 40 new genetic variants and 4 new complex alleles

Researchers at the Department of Ophthalmology, Universidade Federal de Sao Paulo, Brazil, have reported on a new clinical study detecting 38 new gene variants among 152 Leber congenital amaurosis (LCA) patients, including four new complex alleles.  Hundred and thirty-seven (137) families with syndromic and nonsyndromic LCA/early-onset retinal dystrophy were included in a study, in collaboration with UCL Institute and Moorfields Eye Hospital, London, UK. Novel variants were classified as pathogenic or likely pathogenic when representing a loss of function variants (frameshift or nonsense or copy number variation, or affecting a canonical splice-site).  The study was reported in the journal American Medical Genetics (Am J Med Genet), 2020 (184C:728–752).


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.  Following the original description of the infantile disorder, a subsequent milder form of the same disease presents in the 6th and 7th years of life and leads to blindness by the age of 30 years, which is considered to be on the same spectrum as LCA.  This later-onset disease has been referenced with 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.  At of latest reporting with “RetNet” ( there are now 25 genes causative for LCA.


In the Brazilian clinical study,15 genes were found to be related to the LCA phenotype, among 123 gene variants.  The most common genes identified were CEP290 (c.2991+1655A>G), CRB1 (p.Cys948Tyr), and RPGRIP1(exon10-18 deletion).  While LCA represents almost 5% of all hereditary retinal dystrophies in the world, researchers believe that in Brazil, the frequency is double (10.8%) in their cohorts potentially due to referral bias of severely affected children to the three largest specialist centers in Sao Paulo, Rio de Janeiro and Belo Horizonte.  In summarising the results of the study, the Brazilian cohort listed the most common mutated genes as: CEP290 (~21%), RPE65 (~16%), CRB1 (~14%), RPGRIP1 (~10%), GUCY2D (~8%), and RDH12 (~8%), which accounted approximately for 77% of the cases. In concluding the study, the researchers commented that: “it is clear that LCA/EORD are not independent disease entities, but rather represent a spectrum of severe retinopathy with low vision and nystagmus observed in the first months of life. The determination of each subtype of the disease is only achieved through molecular genetic testing because in many cases the ophthalmic aspects are similar and in some cases are indistinguishable (e.g., LCA5, SPATA7, IQCB1, and RPGRIP1 patients). Due to the advances in diagnoses and gene therapies, perhaps in the near future, inherited retinopathies will be only classified according to the related gene, such as, for example, CEP290-related IRD instead of simply Leber Congenital Amaurosis”.