Cone-Rod Dystrophy 20 via the POC1B 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. PubMed ID: 17270046).

Non syndromic CRD is genetically heterogeneous and exhibits autosomal dominant (AD), autosomal recessive (AR) and, rarely, X-linked (XL) inheritance (Hamel. 2007. PubMed ID: 17270046). To date, over 25 genes have been implicated in different forms of CRD (RetNet). Causative variants in the genes ABCA4, ADAM9, AIPL1, C21orf2, C8orf37, CABP4, CACNA2D4, CDHR1, CERKL, CNGB3, CNNM4, DRAM2, KCNV2, PDE6C, POC1B, RAB28, RPGRIP1, RGS9, RGS9BP and TTLL5 are inherited in an AR manner. Causative variants in the genes CRX, GUCA1A, GUCY2D, PITPNM3, RAX2, RIMS1, SEMA4A, UNC119 show AD inheritance. Pathogenic variants in BEST1, PDE6H, PROM1 and PRPH2 are inherited in both AD and AR manner. CACNA1F and RPGR are the only genes associated with XL-CRD in male patients. Due to the genetic heterogeneity, screening of all the CRD-associated genes is recommended. Most of the CRD-associated genes are also involved in other types of retinal dystrophies such as Retinitis Pigmentosa, macular dystrophies and cone dystrophies. Many of these genes encode proteins that have major roles in disc morphogenesis and the membrane- trafficking of photoreceptors (Sung and Chuang. 2010. PubMed ID: 20855501).

Bi-allelic pathogenic variants in POC1B cause nonsyndromic early childhood onset (first decade of life) slowly progressive cone rod dystrophy without night blindness, as well as syndromic retinal ciliopathy (Durlu et al. 2014. PubMed ID: 24945461; Beck et al. 2014. PubMed ID: 25044745). POC1B encodes a POC1 centriolar protein B, which is predominantly expressed in the ciliary region of photoreceptor cells and synapses of the outer plexiform layer (Beck et al. 2014. PubMed ID: 25044745). Depletion studies indicated that this protein is involved in ciliogenesis and is colocalized with another retinal-ciliopathy-associated protein FAM161A at the plasma membrane, basal body and is associated with the microtubule network photoreceptor homeostasis (Roosing et al. 2014. PubMed ID: 25018096). In vitro studies suggested that pathogenic POC1B variants in the WD40 domain of the protein strongly decreased its interaction with FAM161A, which might induce photoreceptor degeneration (Roosing et al. 2014. PubMed ID: 25018096). To date, ~5 pathogenic variants (missense, nonsense, splicing and small in-frame deletion) have been documented causative (Human Gene Mutation Database).

Due to the genetic heterogeneity and limited number of reported cases, it is difficult to predict clinical sensitivity. Analytical sensitivity should be high as all reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the POC1B 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).