Resolving a complex GPIHBP1 exons 3-4 deletion adjacent to low-complexity repeats using adaptive sampling long-read...

Familial chylomicronaemia syndrome (FCS) is a rare disorder characterised by severe hypertriglyceridaemia. While deletions in GPIHBP1 are a known cause, characterising breakpoints is often challenged by adjacent low-complexity regions that hinder standard polymerase chain reaction (PCR) amplification.

The patient presented with plasma triglycerides of 100.6 mmol/L and eruptive xanthomata. Initial testing suggested a homozygous deletion of GPIHBP1 exons 3-4, but long-range PCR failed to identify breakpoints in a repetitive cytosine-rich region. We subsequently utilised PCR-free Oxford Nanopore long-read sequencing with adaptive sampling to selectively enrich the GPIHBP1 locus.

Adaptive sampling achieved 88× coverage of the target region, compared to 30× in non-enriched samples. This approach identified a homozygous ∼3.5 kb deletion (NC_000008.11:g.143214459_143217987del). Native sequencing revealed that the 3' breakpoint resides within an imperfect variable number tandem repeat region composed of degenerate 12-nucleotide subunits, explaining the failure of previous PCR-based methods.

This study represents the first full characterization of this deletion in GPIHBP1 using native long-read sequencing. We demonstrate that adaptive sampling is a powerful tool for resolving structural variants obscured by low-complexity genomic sequences, providing a diagnosis where conventional methods fail.