Autosomal Recessive Retinitis Pigmentosa (RP28) via the FAM161A Gene

Retinitis Pigmentosa (RP) or rod cone dystrophies (RCDs) represent 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).

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 involved with AD, AR, and XL forms, respectively (RetNet).

Pathogenic variants in FAM161A have been documented causative for autosomal recessive Retinitis Pigmentosa (Bandah-Rozenfeld et al. 2010. PubMed ID: 20705279; Langmann et al. 2010. PubMed ID: 20705278). The FAM161A protein is highly expressed in retina (Bandah-Rozenfeld et al. 2010. PubMed ID: 20705279; Langmann et al. 2010. PubMed ID: 20705278). Mouse model studies suggest that FAM161A is crucial in the structural composition, maintenance and function of the connecting cilium and participates in the molecular delivery into the outer segment cilium. This process is essential for outer segment disk formation and ultimately visual function (Karlstetter et al. 2014. PubMed ID: 24833722). So far, about 15 pathogenic variants (missense, nonsense, splicing and small frameshift deletions) have been reported in FAM161A-associated Retinitis Pigmentosa (RP28) (The Human Gene Mutation Database).

It has been reported that loss-of-function variants in FAM161A are a major cause of autosomal recessive Retinitis Pigmentosa, accounting for ~12% of patients from Israel and the Palestinian territories. Variants c.1355_1356del (p.Thr452Serfs*3) and c.1567C>T (p.Arg523*) have been reported as founder variants in the in the Israeli Jewish population (Bandah-Rozenfeld et al. 2010. PubMed ID: 20705279). FAM161A accounts for ~1% of recessive RP cases in North America, and Germany (Venturini et al. 2014. PubMed ID: 24651477).

This test provides full coverage of all coding exons of the FAM161A gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.