Sebastian Lunk from the Victorian Clinical Genetics Services (VCGS) in Australia spoke at London Calling 2025 on “Long-read sequencing and adaptive sampling solve complex diagnostic conundrums.” VCGS is a not-for-profit subsidiary of Murdoch Children’s Hospital with forty years of clinical genetic service delivery and 20,000 diagnostic tests performed annually. With 330 staff, they have the ability to develop and implement clinical diagnostics. Lunk provided an example of long-read sequencing at VCGS of a seven-week old girl with congenital heart disease and non-compaction cardiomyopathy. Mom was also affected. Clinical short-read WGS was intriguing with a deletion. With long-range PCR, the team confirmed the presence of the variant in the mother. To determine the level of mosaicism, high-coverage WGS or long-read sequencing were options. Mom had a smaller deletion that was confirmed by Sanger sequencing. Nanopore long-read sequencing provided a clear picture of the complex events, that would have saved time and numerous tests. The second example Lunk provided was a male child with microcephaly and developmental delay. A retrotransposon insertion was found in the last intron of MeCP2. Long-read sequencing provided a clear picture that took several tests. Lunk explained that long-read sequencing has many advantages and phasing can provide useful data. However, long-read WGS is still expensive, especially as a confirmatory/clarifying tests. For Lunk and team, adaptive sampling was a potential solution. The TALOS workflow was automated re-analysis of genomic data for negative cases. In another example, long-read sequencing of an intensive care sample was unable to span the long Titan gene that was the issue; however, the long-read data helped direct the researchers to the potential issue. Lunk shared a table with “dozens of adaptive sampling examples” with some confirmed and others not confirmed. Lunk summarized by saying that long-read sequencing can “provide a clear picture of complex genetic events” and “replace a wide range of complex confirmatory assays” and even be “cost and time efficient with adaptive sampling.”
