Deletion size and background genetic variation shape congenital heart disease phenotypes in 3016 individuals with 22q11.2 deletion syndrome.

Deletion size (LCR22 A–D versus A–B or A–C) and genetic background (principal components, polygenic score) shaping the type of congenital heart disease

This international multicentre study analyses 3016 unrelated individuals with 22q11.2 deletion syndrome, 1868 of them with genome sequencing, to understand the variability of congenital heart disease. The typical 3 Mb LCR22 A–D deletion is present in 92.4%, with smaller A–B (5.7%) and A–C (1.9%) deletions making up the rest of the cohort. Compared with the A–B deletion, the A–D deletion is associated with lower odds of persistent truncus arteriosus (OR 0.37) and higher odds of isolated septal defects (OR 4.68), with precision limited by the small A–B group. Two genome-wide principal components are associated with specific lesions, and a polygenic risk score for proximal pulmonary artery diameter is associated with a lower likelihood of abnormal origin of the subclavian arteries (OR 0.71).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The first practical lesson is that deletion size, already known at diagnosis from microarray or genome data, shapes the type of heart defect and can refine counselling, even though the A–B group remains small. The contribution of genetic background (principal components, polygenic score) is still exploratory: odds ratios are modest and no individual predictive value is shown. Whether these modifiers also explain the extracardiac variability of the syndrome remains open.

Analysis by Dr Thibaut Benquey