Late-Onset Autosomal Dominant Retinitis Pigmentosa 42 (RP42) and Crisponi/Cold-Induced Sweating Syndrome Type 1(CISS1)-Like Phenotype Associated with Early-Onset Autosomal Recessive Retinitis Pigmentosa via the KLHL7 Gene

Retinitis pigmentosa (RP) represents a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4,000 (Booij et al. 2005. PubMed ID: 16272259). 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. 1999. PubMed ID: 10025514).

Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1)-like phenotype is a complex phenotype and genetically heterogeneous disorder, which is inherited in an autosomal recessive manner. CS/CISS1-like Phenotype is characterized by hyperthermia and feeding difficulties in the neonatal period, scoliosis, and paradoxical sweating induced by cold in early childhood with high neonatal lethality.

Nonsyndromic RP is remarkably heterogeneous both clinically and genetically and exhibits autosomal dominant (AD), autosomal recessive (AR) or X-linked (XL) inheritance. To date, over 50 loci have been linked to nonsyndromic RP and 18, 27 and 2 genes have been identified that are associated with AD, AR, and XL RP, respectively (RetNet).

Pathogenic variants in KLHL7 have been documented causative for late-onset ADRP or Crisponi/CISS1-like phenotype associated with early-onset ARRP (Friedman et al. 2009. PubMed ID: 19520207; Angius et al. 2016. PubMed ID: 27392078). KLHL7 encodes a BTB-Kelch related protein, which is highly expressed in rod photoreceptor cells. This protein participates as an adaptor and/or chaperone in the ubiquitination of target proteins through Cullin E3 ligases for proteasome-mediated degradation. This protein consists of one BTB (codons 44 through 111), one BACK (codons 146 through 248) and one Kelch domain (also known as Kelch repeat β-propeller domain; codons 294 through 575) (Friedman et al. 2009. PubMed ID: 19520207). The variants that cause ADRP have been reported to be clustered in the BACK domain, and the variants that cause CS/CISS1-like Phenotype associated ARRP affect the kelch domain. Bi-allelic variants in this gene may lead to complete failure in the ubiquitination of the target substrate(s) and may result in severe CS/CISS1-like Phenotype (Angius et al. 2016. PubMed ID: 27392078). To date, ~10 pathogenic variants (missense and a small frameshift deletion and splicing) in KLHL7 have been connected to RP (Human Gene Mutation Database).

Friedman et al. estimated that the KLHL7 accounts for 1-2% of the autosomal dominant retinitis pigmentosa cases (Friedman et al. 2009. PubMed ID: 19520207). However, predicting clinical sensitivity for this gene for the Crisponi/CISS1-like phenotype associated with early-onset autosomal recessive retinitis pigmentosa is challenging due to the limited number of cases.

This test provides full coverage of all coding exons of the KLHL7 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).