Leber Congenital Amaurosis 10 (LCA10) via the CEP290 Gene

Leber congenital amaurosis (LCA, OMIM# 204000) is the most severe form of inherited retinal dystrophy that is usually evident at birth or during the first months of life. LCA is clinically characterized by poor visual function often accompanied by sensory nystagmus, abnormal pupillary responses, high hyperopia, severely reduced visual acuity, photo-aversion, markedly diminished electroretinogram (ERG) and keratoconus condition due to oculo-digital signs of Franceschetti such as eye poking, pressing, and rubbing the eyes with a knuckle or finger (Weleber et al. GeneReviews, 2013). The estimated prevalence of LCA is 2-3 per 100,000 live births and accounts for 10-18% of congenital blindness (Fazzi et al. Eur J Paediatr Neurol 7(1):13-22, 2003).

LCA is a genetically heterogeneous disorder and is often inherited in an autosomal recessive manner. To date, approximately 19 genes have been implicated in the pathogenesis of different types of LCA (Weleber et al., 2013; Chen et al. Invest Ophthalmol Vis Sci 54(6):4351-4357, 2013). Together these genes account for 70% of the LCA cases. These genes encode proteins that have a wide range of retinal functions, such as photoreceptor morphogenesis, phototransduction, vitamin A cycling, guanine synthesis, and outer segment phagocytosis (den Hollander et al. Prog Retin Eye Res 27(4):391-419, 2008). Mutations in these genes cause not only LCA but also other retinal disorders (Weleber. Ophthalmic Genet 23(2):71-97, 2002). To date, mutations in CEP290 (also known as NPHP6, OMIM 610142) are the most frequent cause of LCA and are referred to as LCA10 (OMIM 611755) (den Hollander et al. Am J Hum Genet 79(3):556-561, 2006). CEP290, which is located on Chromosome 12, encodes a centrosomal protein that localizes primarily to centrosomes of dividing cells and to the connecting ciliated cells of inner and outer segments of the retinal photoreceptors (Chang et al. Hum Mol Genet 15(11):1847-1857, 2006). Perturbations in the photoreceptor ciliary transports due to mutations in CEP290 are associated with retinal degeneration as well as more pleiotropic phenotypes that include Joubert syndrome, Bardet-Biedl syndrome, lethal Meckel-Grüber syndrome (MKS), etc. (Adams et al. Ophthalmic Genet 28:113-125, 2007; Coppieters et al. Hum Mutat 31(10):E1709-1766, 2010; Yzer et al. Molecular Vision 18:412-425, 2012). Over 70 mutations in CEP290 account for ~21% of the LCA cases and two-thirds of all mutant alleles carry the intronic mutation c.2991+1655A>G. This mutation creates a strong splice donor site that leads to insertion of a cryptic exon encoding a premature stop codon (p.Cys998X). Genes with this mutation appear to produce a small amount of residual protein, which might be sufficient for normal cerebellar and renal function but not for the proper function of the photoreceptors and therefore leads specifically to the retinal degeneration (den Hollander et al., 2006).

A study identified the c.2991+1655A>G CEP290 mutation in 21% (16/76 of LCA patients; 62.5% of all mutant alleles) of unrelated patients with LCA, either homozygously or compound heterozygously and reported it as the major LCA-associated gene of European ancestry (den Hollander et al. Am J Hum Genet 79(3): 556-561, 2006). The Perrault et al (2007) study also reported the high frequency of CEP290 mutations in their LCA cohort (22%; 21/96) and suggested that CEP290 is involved in families of European descent only (38/38) (Perrault et al. Hum Mutat 28(4):416, 2007). However, they reported 23 novel mutations and only 43% (33/76) of mutant alleles had c.2991+1655A>G mutations. Moreover, 12 families did not carry this common intronic causative mutation.

To date, no gross deletions have been reported in CEP290 that are associated with Leber congenital amaurosis 10 (The Human Gene Mutation Database).

This test provides full coverage of all coding exons of the CEP290 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.