Retinitis Pigmentosa 35 (RP35) and Cone-Rod Dystrophy 10 (CORD10) via the SEMA4A Gene

Retinitis pigmentosa (RP; OMIM # 268000) represents a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. J Med Genet 42 (11): e67, 2005). RP is clinically characterized by retinal pigment deposits visible on fundus examination, nyctalopia ("night blindness"), followed by progressive degeneration of the photoreceptors, which eventually leads to blindness (van Soest et al. Surv Ophthalmol 43(4):321-34, 1999). Cone rod dystrophies (CORDs/CRDs) are 10 times less common than RP (1/40,000) and are characterized by dysfunction or degeneration of cone photoreceptors with relative preservation of rod function in the initial stages. The most common symptoms are photophobia and epiphora in bright light, decreased visual acuity, and dyschromatopsia. Fundus changes may vary from mild pigment granularity to a distinct atrophic lesion in the central macula. As the disease progresses, degeneration of rod photoreceptors also occurs and leads to progressive night blindness and peripheral visual field loss (Hamel. Orphanet J Rare Dis 2:7, 2007).

SEMA4A (Semaphorin; OMIM # 607292), which encodes a transmembrane protein, is predominantly expressed in the brain and eyes. During embryonic development, specifically when the photoreceptor outer segments elongate, SEMA4A is expressed in the inner retina and retinal pigment epithelium (RPE). It has been shown that disruption of SEMA4A in a mouse model results in retinal degeneration, attenuation of retinal blood vessels and depigmentation of the RPE (Rice et al. Invest Ophthalmol Vis Sci 45(8):2767–2777, 2004). Notably, SEMA4A has been shown to regulate two distinct endosomal-sorting pathways that are essential for the maintenance of homeostatic balance between RPEs and photoreceptors and to help in photoreceptor survival and phototransduction during the transition between daylight and darkness (Toyofuku et al. Genes Dev 26(8):816-829, 2012). So far, only missense mutations in SEMA4A have been identified to be causative for autosomal dominant retinal degenerations (RP35, OMIM # 6102832 and CORD10, OMIM # 610283 (Human Gene Mutation Database), which was supported by the structural modeling analyses of the c.1049T>G (p.Phe350Cys) mutation. This analysis revealed that the c.1049T>G mutation reduces the amino-acid side-chain volume and generates a hollow space in the protein interior, which affects the protein overall stability. Moreover, photoreceptor degeneration was rescued by SEMA4A gene supplementation in an animal model (Nojima et al. Nat Commun 4:1406, 2013).

Mutational screening in 190 patients (135 with RP, 25 CORD and 30 with congenital blindness) in a Pakistani population identified two SEMA4A mutations in 8 probands (~4%), which were not identified in 100 control subjects (Abid et al. J Med Genet 43(4):378-381, 2006).

So far, no gross deletions or duplications have been reported in SEMA4A (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SEMA4A 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).