Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements

Abstract

Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy (CRD) patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

“…Examples include CEP290, mutations in which can cause either JBS or Leber congenital amaurosis, 38 and CLN3, which is associated with Batten disease and nonsyndromic retinal degeneration. 39 The novel genotype-phenotype correlations described in this study enhance our knowledge of the molecular mechanisms of retinal dystrophies.…”

Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone–rod dystrophy by pseudoexon activation

“…13,14 To the best of our knowledge, this is the first report of a deep intronic variant in PROM1 presumably leading to a functional null allele.…”

A Homozygous Missense Mutation in NEUROD1 Is Associated With Nonsyndromic Autosomal Recessive Retinitis Pigmentosa

“…2,7,8 In particular, raw variants were called using Atlas2 Suite. 9 Considering the rareness of RP, variant with a frequency of >0.5% in any of the variant databases queried, including 1000 Genome, 10 dbSNP135, 11 National Heart, Lung, and Blood Institute Exome Sequencing database, 12 National Institute of Environmental Health Sciences Exome Sequencing database, 13 an internal control database of 11,000 exomes, and an ethnicity-matched control database (approximately 4000 exomes) from Exome Aggregation Consortium (ExAC) 14 was filtered out.…”

“…1 By contrast, missense mutations in CLN3 can cause late-onset retinal degeneration without any syndromic involvements. 2 Uncovering these phenotype-genotype correlations is of clinical importance for molecular diagnosis. Furthermore, a mutation spectrum with corresponding phenotypes can provide structural and functional insights about this gene/ protein.…”