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BackgroundThe genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population.MethodsA total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases.ResultsWe successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658*) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.ConclusionsEast Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

Key Points Question Which cancer types and their clinical characteristics are associated with pathogenic variants in BRCA1 and BRCA2 in addition to breast, ovarian, prostate, and pancreatic cancers? Findings In this case-control study of 63 828 patients with 14 common cancer types and 37 086 controls, pathogenic variants in BRCA1 were associated with biliary tract cancer, in BRCA2 with esophageal cancer, and in BRCA1/2 with gastric cancer. Meaning The study results suggest that the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is broader than that determined from previous analyses, potentially indicating the broader clinical relevance of BRCA1/2 genetic testing.

Whole exome sequencing (WXS) is widely used to identify causative genetic mutations of diseases. However, not only have several commercial human exome capture platforms been developed, but substantial updates have been released in the past few years. We report a performance comparison for the latest release of four commercial platforms, Roche/NimbleGen’s SeqCap EZ Human Exome Library v3.0, Illumina’s Nextera Rapid Capture Exome (v1.2), Agilent’s SureSelect XT Human All Exon v5 and Agilent’s SureSelect QXT, using the same DNA samples. Agilent XT showed the highest target enrichment efficiency and the best SNV and short indel detection sensitivity in coding regions with the least amount of sequencing. Agilent QXT had slightly inferior target enrichment than Agilent XT. Illumina, with additional sequencing, detected SNVs and short indels at the same quality as Agilent XT, and showed the best performance in coverage of medically interesting mutations. NimbleGen detected more SNVs and indels in untranslated regions than the others. We also found that the platforms, which enzymatically fragment the genomic DNA (gDNA), detected more homozygous SNVs than those using sonicated gDNA. We believe that our analysis will help investigators when selecting a suitable exome capture platform for their particular research.