OGM and WES Identifies Translocation Breakpoints in PKD1 Gene in an Polycystic Kidney Patient and Healthy Baby Delivered Using PGT

Background: Whole exome sequencing (WES) is a routine tool for diagnostic confirmation of genetic diseases. Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common autosomal dominant genetic diseases and WES was usually performed to confirm the clinical diagnosis in ADPKD. Reciprocal translocation is the most common chromosomal structural abnormalities and the most carriers have normal phenotypes, unless they are encountered infertility problem when they grow up. However, for polycystic kidney disease caused by abnormal chromosome structure, WES is difficult to achieve the purpose of gene diagnosis. Methods: ADPKD-related genes were detected by WES; Chromosomal karyotyping and Optical Genome Mapping (OGM) was used to detect structural variant; The genomic break-point locations and the abnormal splicing was detected by reverse transcription-PCR and Sanger sequencing. The karyomapping gene chip and Next-Generation Sequencing (NGS) were performed to screen aneuploidy and distinguish the noncarrier embryos from carrier embryos. Results: No pathogenic variant was found after first round of WES analysis. Karyotyping data showed 46, XX, t (16; 17) (p13.3; q21.3). With the help of OGM, the translocation breakpoint on chromosome 16 was located within the PKD1 gene. With re-analysis of WES raw data, the breakpoint of translocation was verified to be located at the c.10618+3 of PKD1 gene. Based on this molecular diagnosis, a noncarrier embryo was selected out from three blastocysts, with preimplantation genetic testing (PGT) after in vitro fertilization (IVF), to transferred into uterus. With confirmation by prenatal and postnatal testing, the pedigree delivered a healthy baby. Conclusion: We identified a case of ADPKD caused by balanced translocation and assisted the patient to have a healthy child. When the phenotype was closely related with a monogenic disease and the WES analysis was negative, chromosomal structural analysis would be recommended for further genetic diagnosis. Based on the precision diagnosis, preventing the recurrence of hereditary diseases in offspring would be reachable.