Cone-Rod Dystrophy via the PITPNM3 Gene

Cone-rod dystrophy (CORD/CRD) is a rare hereditary retinal disorder with a worldwide prevalence of ~1 in 40,000. CRD is 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 2007).

Non syndromic CRD is genetically heterogeneous and exhibits autosomal dominant (ad), autosomal recessive (ar) and, rarely, X-linked (xl) inheritance (Hamel 2007). So far, about 25 genes have been implicated in different forms of CRD (RetNet). Mutations in PITPNM3 are associated with autosomal dominant CRD. PITPNM3 mutation analysis in two Swedish families (originating from the same geographical area in Northern Sweden) identified a mutation c.1878G>C (p.Q626H) in all affected family members (33/80), which showed consistent segregation with the disease. Shared haplotypes and presence of the c.1878G>C mutation in both families suggested that the families have a common ancestry (Köhn et al. 2007 and 2008). Only a few pathogenic variations in PITPNM3 have been reported, all missense, which are associated with autosomal dominant cone-rod dystrophy (Human Gene Mutation Database).

PITPNM3 (also called Nir3), which is located on 17p13 (Balciuniene et al. 1995) encodes phosphatidylinositol transfer (PIT) membrane-associated protein (PITPNM3). Three mammalian PIT membrane-associated proteins (PITPNM1, 2 and 3), are known as human homologues of the Drosophila retinal degeneration B (rdgB) protein that is involved in the phototransduction signaling pathway (Lev et al. 1999; Tian and Lev 2002). It is possible that PITPNM proteins also have a similar function.  PITPNM3 is shown to be highly expressed in the mammalian retina, specifically in the inner segment and in the inner and outer plexiform layers. PITPNMs are multidomain proteins that have six putative transmembrane domains, a calcium-binding region, and a carboxyterminal (C-terminal) domain. The C-terminal domain of PITPNMs functions as a PYK2 (a nonreceptor protein tyrosine kinase) -binding site and forms a PYK2 and PITPNM complex, which induces tyrosine phosphorylation of PITPNM proteins (Lev et al. 1999; Ocaka et al. 2005). Tyrosine phosphorylation in turn regulates calcium and phosphoinositide metabolism downstream of G-protein-coupled receptors (Lev et al. 1999).

To study the global impact of PITPNM3 on retinal degenerations, Köhn et al. (2010) screened 163 patients from Denmark, Germany, UK, and the USA (Köhn et al. 2010). They detected PITPNM3 pathogenic variants in only 4 patients (~2%), which indicates that PITPNM3 is an uncommon cause of cone-rod dystrophies.

This test provides full coverage of all coding exons of the PITPNM3 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).