Leber Congenital Amaurosis 14 (LCA14) or Early Onset Retinal Dystrophy (EORD) and Juvenile Retinitis Pigmentosa via the LRAT Gene

Leber congenital amaurosis 14 (LCA14; OMIM 613341), also known as Early Onset Retinal Dystrophy (EORD), is a severe form of retinal disease that typically becomes evident in the first year of life (Weleber et al. GeneReviews, 2013), whereas the less severe forms are usually considered juvenile retinitis pigmentosa (Gu et al. Nature Genetics 17: 194 -197, 1997). EORD is typically characterized by poor visual function often accompanied by nystagmus (involuntary movement of eye ball), sluggish or absent pupillary responses, severe vision loss or nyctalopia (night blindness), photoaversion, high hyperopia (far-sightedness) and severely attenuated rod and cone responses on full-field electroretinography (ERG). Additionally, EORD affected individuals present with a special behavior called Franceschetti's oculo-digital signs like eye poking, pressing, and rubbing the eyes with a knuckle or finger that may contribute to deep-set eyes and keratoconus condition (cone-shaped and abnormally thin cornea) (Weleber et al., 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 clinically and genetically heterogenous 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. GeneReviews, 2013; Chen Y et al. Invest Ophthalmol Vis Sci, 2013). LCA14/EORD is caused by causative mutations in the LRAT gene located on chromosome 4q31. LRAT encodes the Lecithin-retinol acyltransferase enzyme present mainly in the retinal pigment epithelium (RPE) and liver. LRAT, RPE-Specific Protein 65 (RPE65) and Retinol dehydrogenase 12 (RDH12)  are responsible for vitamin A metabolism in the visual cycle to synthesize 11-cis-retinaldehyde, a chromophore of all known visual pigments (Ruiz et al. Invest Ophthalmol Vis Sci 42(1):31-7, 2001). Phenotype-genotype analysis shows high penetrance of LCA. However, the phenotypic variations among patients with the same mutation indicates the influence of genetic background, environment and other factors (Li et al. Invest Ophthalmol Vis Sci  50(3):1336-43, 2009). LRAT, RPE65 and RDH12 mutations lead to similar phenotypes, suggesting the need to screen these genes systematically (Sénéchal et al. Am J Ophthalmol 142(4):702-4, 2006). Mutations in these three genes account for ~10% of LCA patients.

Dev Borman, A. et al (2012) suggested that the frequency of LRAT mutations in LCA14 and EORD patients is about 1%, which is consistent with previous studies and confirms that LRAT mutations are a rare cause of LCA and EORD (Dev Borman, A., et al. Invest Ophthalmol Vis Sci 53(7):3927-3938, 2012).

No gross deletions or gross insertion/duplications have been reported in LRAT (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the LRAT gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other 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).