Leber Congenital Amaurosis Panel

Leber congenital amaurosis (LCA) is the most 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 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. 2013; Perrault et al. 1996). 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).

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. 2013; Chen et al. 2013). Pathogenic variants in AIPL1, CABP4, CEP290, CNGA3, CNGB3, GNAT2, INPP5E, IQCB1, LCA5, LRAT, MERTK, NMNAT1, RD3, RDH12, RPE65, RPGRIP1, SPATA7, and TULP1 cause autosomal recessive (AR) retinal disorder (Chen et al. 2013). Pathogenic variants in IMPDH1, SNRNP200, and OTX2 cause autosomal dominant (AD) retinal disorder (Bowne et al. 2006; Henderson et al. 2009; Swaroop et al. 1999; Zhao et al. 2006). GUCY2D, PDE6H, PRPH2, KCNJ13, CRB1, and CRX are implicated in both AD and AR retinal disorders (Kohl et. 2012; Piri N. 2005; Wang et al. 2013; Weleber et al. 1993; Udar et al. 2003; Hanein et al. 2002; McKay et al. 2005; Abouzeid et al. 2006; Swaroop et al. 1999; Hejtmancik et al. 2008). DTHD1 gene inheritance mode is currently unknown. Together these genes account for 70-75% of the LCA cases (Wang et al. 2015; den Hollander et al. 2008). 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). Pathogenic variants in these genes cause not only LCA but also other retinal disorders (Weleber. 2002; Wang et al. 2015; Wang et al. 2013; http://www.omim.org/; Human Gene Mutation Database).See individual gene test descriptions for more information on molecular biology of gene products.

Clinical sensitivity for the AIPL1 (4-8%), CEP290 (<20%), CRB1 (10%), CRX (3%), GUCY2D (21%), LCA5 (1-2%), RDH12 (4%), RPE65 (3-16%), RPGRIP1 (5%), TULP1 (1.7%) genes is known (Weleber et al. 2013). However, for other genes, due to the limited number of cases, estimation of clinical sensitivity is difficult (Hanein et al. 2004; Weleber et al. 2013).

A study by Perrault et al. (2000) identified two gross deletions and one duplication in GUCY2D out of 118 patients affected with Leber Congenital Amaurosis (Perrault et al. 2000). Copy number variants have also been reported in CEP290, CRB1, CRX, GUCY2D, LCA5, MERTK, NMNAT1, PRPH2, RDH12, RPE65, RPGRIP1, and TULP1 genes (Human Gene Mutation Database).

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

This panel typically provides 99.9% coverage of all coding exons of the genes 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 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).