Intraflagellar Transport 140 Mutations in Taiwan Polycystic Kidney Disease

Background: Autosomal dominant polycystic kidney disease (ADPKD) is primarily caused by PKD1 and PKD2, followed by a small portion of cases caused by GANAB and DNAJB11. Other genes, including ALG8, ALG9, PKHD1, and COL4A can cause similar cystic ab-normality and mimic ADPKD. We previously performed the genetic analysis in a total of 920 ADPKD families and identified nearly 70% of the genetic causes. However, many families remained undiagnosed or had only a variant of uncertain significance identified. We performed exome sequencing in a total of 286 families aiming to identify their disease-causing genes. Methods: A total of 286 probands from 286 families were included in this study. The study was approved by the institutional review boards of the Kaohsiung Medical University Hospital. Nextera Flex for Enrichment and Exome panel (CEX V2, Illumina) was used for exome library creation. The resulting fastq data were aligned to the reference human genome sequence and performed nucleotide variant calling using the DRAGEN Bio-IT platform (Illumina). The VCF file was analyzed in CLC Genomics Workbench (Qiagen). FastreeR was used to calculate distances, build phylogenetic trees, and perform hierarchical clustering between the samples. Results: A total of 11 families were identified to have 6 different heterozygous IFT140 truncation or obligatory splicing variants, including p.Glu51*, p.Leu540*, p.Gln667*, p.Asp738fs, p.Tyr923fs, and p.Gln1162* in the Taiwan ADPKD cohort. Two recurrent mutations, p.Glu51* and p.Leu540* were identified. Phylogenetic analysis showed that the two families with the p.Leu540* variant should be close relatives, while the 5 families with p.Glu51* have various degrees of kinship. Most affected individuals have relatively fewer and larger kidney cysts than classical ADPKD individuals. Their kidney function deterioration rate differs significantly in these 11 affected individuals. Conclusions: Our data showed that heterozygous IFT140 pathogenic mutations represented a small but significant 1.2 percent of ADPKD in Taiwan. All our IFT140 pathogenic mutations are different from the report by Senum et. al. in 2022, although 4 of them existed in the GnomAD database. Missense variants of IFT140, as well as variants in the other intraflagellar proteins, were also identified. However, their role in the pathogenicity of ADPKD needs further evidence and functional analysis. Funding: Government Support - Non-U.S.