PRDM9 Deficiency Drives Mosaic Promoter Deletions in Sporadic Hirschsprung Disease and Supports Blood-Based Molecular Stratification.

PRDM9 deficiency is linked to mosaic promoter deletions and impaired enteric neuronal differentiation in sporadic Hirschsprung disease, with blood MPD score AUROC 0.78–0.82.

• Why it matters: Most sporadic HSCR cases lack a molecular explanation, and clinicians need blood-accessible biomarkers to stratify patients beyond existing genetic risk scores.
• What they did: The study used RNA-seq on paired aganglionic vs ganglionic colon biopsies from 103 sporadic HSCR patients, plus colon and blood WGS to call mosaic promoter deletions and compute a blood MPD score.
• The result: PRDM9 perturbation in zebrafish and mice reduced HuC/D-positive differentiated enteric neurons and motility, while the blood MPD score discriminated HSCR from controls (AUROC 0.78 discovery; 0.82 validation) and improved when combined with polygenic risk score (AUROC 0.89 and 0.91).

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