Integrative analysis reveals regulatory effects of tandem repeat expansions in tetralogy of Fallot.

Rare tandem repeat expansions enriched in 5' untranslated and splicing regions, associated with locus-specific DNA methylation changes

The contribution of tandem repeat expansions to structural congenital heart disease remains poorly understood. The authors analysed short-read genome sequencing from 835 individuals with tetralogy of Fallot and 386 controls, complemented by PacBio HiFi long-read sequencing, DNA methylation profiling, myocardial RNA sequencing and fetal human heart single-cell data. They report 1,043 rare expansions in cases, i.e. 1.25 per individual versus 0.85 in controls, enriched for GC-rich motifs and preferentially located in 5' untranslated regions (OR 7.0; p = 2.1 × 10⁻²) and splicing regions (OR 3.0; p = 9 × 10⁻⁴). Ninety-one recurrent genic loci were identified, including expansions in PACS1 and TRIP4, and repeat size was associated with DNA methylation at 36 loci. The excess burden of rare genic expansions is estimated at approximately 4.4%, and is higher among patients without a positive clinical genetic testing result.

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

The most interesting argument is that repeat expansion burden is higher in patients who stayed negative after standard testing: that is precisely the population where repeat calling on already generated genomes could yield something, with no new sampling. A 4.4% excess nonetheless remains a group-level statistic, with no locus individually attributable to a given patient, and the regulatory effect rests on methylation-expression correlations rather than on functional proof. Non-peer-reviewed preprint, to be confirmed.

Analysis by Dr Thibaut Benquey