Key result
Novel AluYa5 insertion in APOB identified as a cause of familial hypobetalipoproteinemia.
Why the study?
Mobile element insertions in APOB are an underrecognized cause of hypobetalipoproteinemia that may be missed by routine genetic testing pipelines.
Does the inclusion of MEI-callers in NGS pipelines improve the genetic diagnosis of primary dyslipidemia in patients with hypobetalipoproteinemia?
Does the inclusion of MEI-callers in NGS pipelines improve the genetic diagnosis of primary dyslipidemia in patients with hypobetalipoproteinemia?
The inclusion of mobile element insertion (MEI) callers in routine next-generation sequencing pipelines is valuable for improving the genetic diagnosis of primary dyslipidemia such as hypobetalipoproteinemia.
Identifies novel APOB AluYa5 insertion causing hypobetalipoproteinemia; leaves open whether routine MEI callers improve dyslipidemia NGS diagnostics.
Mobile elements (ME) can transpose by copy-and-paste mechanisms. A heterozygous insertion in APOB exon 3 coding sequence was suspected in a patient with hypobetalipoproteinemia (HBL), by gel electrophoresis of the PCR products. An insertion of a 85 bp fragment flanked by a polyA stretch and a target replication site duplication was identified as a ME insertion (MEI) from the AluYa5 subfamily, NM_000384.3(APOB):c.135_136ins(160). Then, the DNA was reanalyzed using our NGS custom panel. Routine analysis did not reveal any causative variant, but manual inspection of the alignments and MELT enabled us to detect this MEI from NGS data. A functional study revealed that this MEI introduces a stop codon p.(Phe46Alafs*2) and additionally leads to p.(Lys41Serfs*2) due to an exon skipping. This is the first report of a MEI into APOB, as a cause of HBL. Furthermore, our study highlights the value of including MEI-callers in routine pipelines to improve primary dyslipidemia diagnosis.
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Surles et al. (2024) conducted a review in Hypobetalipoproteinemia (HBL) / Familial hypobetalipoproteinemia (FHBL). Mobile element insertion (MEI) in the APOB gene was evaluated. A mobile element insertion from the AluYa5 subfamily in the APOB exon 3 coding sequence was identified as a novel cause of hypobetalipoproteinemia, leading to exon skipping and a premature stop codon.
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