Leber Congenital Amaurosis- 5 via the LCA5 Gene

Leber congenital amaurosis (LCA) is a severe form of inherited retinal degeneration that is usually evident at birth or during the first months of life. LCA is clinically characterized by poor visual function often accompanied by nystagmus, abnormal pupillary responses, photophobia, high hyperopia, markedly diminished electroretinogram (ERG) and keratoconus due to oculo-digital signs of Franceschetti such as eye poking, pressing, and rubbing the eyes with a knuckle or finger (Weleber et al. 1993. PubMed ID: 20301475; Perrault et al. 1996. PubMed ID: 8944027). The estimated prevalence of LCA is 2-3 per 100,000 live births and accounts for 10-18% of congenital blindness (Fazzi et al. 2003. PubMed ID: 12615170).

With the advent of gene therapy and other types of treatments, the identification of causative genes and variants is becoming increasingly important.

LCA is a genetically heterogeneous disorder and is often inherited in an autosomal recessive manner. To date, over 20 genes have been implicated in the pathogenesis of different types of LCA (Weleber et al. 1993. PubMed ID: 20301475; Chen et al. 2013. PubMed ID: 23661368). Together these genes account for 70-75% of the LCA cases (Wang et al. 2015. PubMed ID: 26047050; den Hollander et al. 2008. PubMed ID: 18632300). 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. 2008. PubMed ID: 18632300). Pathogenic variants in these genes cause not only LCA, but also other retinal disorders such as retinitis pigmentosa (Weleber. 2002. PubMed ID: 12187427; Wang et al. 2015. PubMed ID: 26047050; Wang et al. 2013. PubMed ID: 23847139; http://www.omim.org/; Human Gene Mutation Database).

Pathogenic variants in LCA5 are associated with a severe autosomal recessive form of LCA (Gerber et al. 2007. PubMed ID: 18000884) and also a few cases of Retinitis pigmentosa (Mackay et al. 2013. PubMed ID: 23946133). LCA5 encodes lebercilin protein, which is uniquely localized to connecting cilia that bridges the inner and outer segments of photoreceptor cells. Lebercilin has been shown to physically interact with IFT complex. Mouse model studies demonstrated that Lca5 inactivation resulted in perturbed molecular interconnectivity between lebercilin and the intraflagellar transport (IFT) machinery, which may affect ciliary trafficking and its associated protein transport in photoreceptors, leading to degeneration (Boldt et al. 2011. PubMed ID: 21606596).

Over 50 different LCA5 variants have been documented to be causative. They include missense, nonsense, splicing, and small deletions, indels and insertions and copy number variants. To date, no de novo pathogenic variants have been documented (Human Gene Mutation Database).

Clinical sensitivity for LCA5 is reported to be 1-2% (Weleber et al. 1993. PubMed ID: 20301475; Gerber et al. 2007. PubMed ID: 18000884). Copy number variants have been reported in LCA5 (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the LCA5 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).