Leber Congenital Amaurosis 4 (LCA4) via the AIPL1 Gene

Leber congenital amaurosis (LCA) is an early-onset and most severe form of inherited retinopathy that is typically noticeable in the first year of life (Weleber et al. GeneReviews, 2013). Less severe forms are usually considered juvenile retinitis pigmentosa (Gu et al. Nature Genetics 17(2):194-197, 1997). LCA is clinically heterogeneous. One of the forms, LCA4 (LCA4; OMIM 604393) is characterized by peripheral retinal bone spicule-like pigmentation with prominent maculopathy, optic nerve pallor, profound loss of foveal as well as extrafoveal photoreceptors, which becomes more evident in patients older than 6 years of age, low visual acuity, ranging from 20/600 to no light perception, little or no detectable visual fields, abnormal or flat electroretinogram (ERG) and significant prevalence of bilateral keratoconus associated with cataract (Testa et al. Invest Ophthalmol Vis Sci 52(8):5618-5624, 2011). 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 variety 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 early-childhood and even adult-onset retinal degenerations (Weleber et al. Ophthalmic Genet 23(2):71-97, 2002).

Retina and pineal-specific AIPL1, which encodes Aryl hydrocarbon receptor interacting protein like-1, was the fourth gene identified as associated with LCA4 and is located on chromosome 17p13.1 (Sohocki et al. Nat Genet 24(1):79-83, 2000). A high prevalence of severe macular lesions was observed in LCA patients associated with AIPL1 mutations as compared to other genes implicated in LCA. The AIPL1 protein is known to be essential for visual phototransduction and shown to interact with the NUB1 protein (NEDD8 ultimate buster-1). The NUB1 protein stimulates the proteasomal degradation of proteins modified with the ubiquitin-like modifiers (UBLs) NEDD8 and FAT10. The AIPL1 protein is shown to bind the NUB1protein and prevents the NUB1-mediated proteasomal degradation. The amino acid residues 181-330 on AIPL1 are the binding sites for NUB1 and many LCA-associated AIPL1 mutations have been found at this site, indicating that the NUB1 and AIPL1 interaction is altered in LCA4 patients (Kanaya et al. Biochem Biophys Res Commun 317(3):768-773, 2004). These results suggest that the normal functioning of AIPL1 is important for cone and rod photoreceptor development and/or survival following differentiation (Akey et al. Hum Mol Genet 11(22):2723-2733, 2002). AIPL1 mutations are associated with ~7% of the LCA cases worldwide and also dominant retinopathy (Sohocki et al. Mol Genet Metab 70(2):142-150, 2000). Approximately, fifty disease-associated mutations have been identified in AIPL1, where the majority of them are missense/nonsense variants. Splicing, small insertion and deletions have also been reported (Human Gene Mutation Database).

Sohocki et al. (2000) identified causative AIPL1 mutations in ~20% (3/14) of the LCA families (Sohocki et al. Nat Genet 24(1):79-83, 2000). A study done by Li et al. (2011) found AIPL1 mutations in 1.1 % (1/87) of the unrelated Chinese patients with Leber congenital amaurosis, whereas16.1% (14/87) cases had GUCY2D mutations (Li et al. PLoS One 6(5): e19458, 2011). Among all LCA genes, AIPL1 and GUCY2D are known to function in visual phototransduction (den Hollander, et al. Prog Retin Eye Res 27(4): 391-419, 2008).

No gross deletions or duplications have been reported to date in AIPL1 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the AIPL1 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).