Recurrent t(9;12) translocation disrupting ACVRL1 intron 9 causes hereditary haemorrhagic telangiectasia missed by standard exome sequencing in four unrelated families.
case_series · Level IV
Where this comes from
- Record sourced from PubMed, PMID 42250987.
- Also identified by DOI 10.1016/j.ejim.2026.106991.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder most commonly caused by pathogenic variants in ACVRL1 or ENG. Most pathogenic variants are coding missense, nonsense, splice-site variants, or small insertions/deletions, as well as exon-level deletions or duplications, and are typically detectable by next-generation sequencing (NGS). However, balanced structural rearrangements and deep intronic variants are not reliably detected by standard exome-based approaches and may contribute to genetically unresolved cases. We investigated four unrelated families with clinical features of HHT in whom prior whole exome sequencing (WES) was inconclusive. All affected individuals reported recurrent miscarriages, and further clinical review identified prior karyotype analyses. These cytogenetic findings prompted targeted reanalysis of WES datasets to assess potential disruption of HHT-associated genes. All four families carried an apparently balanced translocation, t(9;12)(p21.2;q13.13). Breakpoint mapping revealed disruption of a CT-rich region within intron 9 of ACVRL1, a known mutational hotspot. Reanalysis of WES data supported ACVRL1 disruption as the likely pathogenic mechanism. The translocation co-segregated with disease in all families and was absent in unaffected relatives. All carriers fulfilled clinical diagnostic criteria for HHT. A history of recurrent miscarriages emerged as a key clinical clue that prompted cytogenetic investigation and enabled molecular diagnosis. We identify a recurrent translocation, t(9;12)(p21.2;q13.13), that disrupts intron 9 of ACVRL1 and is undetectable by standard exome-based approaches, as a previously unrecognised cause of HHT in genetically unresolved patients. Our findings highlight and support the need to extend genomic testing beyond conventional exome sequencing in unresolved HHT cases.