Dual impact of uniparental disomy in imprinting and recessive disorders: a case of UPD(15) with unexpected inheritance and literature review

Background UPD refers to the inheritance of two copies of a chromosome, or part of it, from the same parent. While UPD is often asymptomatic, it can lead to an abnormal phenotype when it involves imprinted genomic regions or unmasks recessive disorders. Methods We report a case of a boy with both Prader-Willi syndrome (PWS) and Tay-Sachs disease (TSD) due to maternal UPD of chromosome 15 (UPD(15)mat). Surprisingly, the mother is homozygous for a pathogenic HEXA variant associated with late-onset TSD, clinically asymptomatic to date. This finding contrasts with previously reported UPD cases, in which recessive disorders typically result from the transmission of a pathogenic variant from a heterozygous carrier parent through isoUPD. Results To contextualise, we conducted a review of all published cases reporting dual diagnoses, in which both an imprinting disorder and a recessive disease resulted from UPD affecting the same chromosome. We identified 35 patients. The most common association was cystic fibrosis and Silver-Russell syndrome (SRS) due to UPD(7)mat. Our case, together with previously reported cases, indicates that the second most frequent combination was TSD and PWS due to UPD(15)mat. Other recurrent associations included Pendred syndrome and SRS, argininosuccinic aciduria and SRS (both with UPD(7)mat) and CERS3-related ichthyosis and PWS with UPD(15)mat. Conclusion This review underscores the importance of considering UPD as a potential unifying mechanism in patients with overlapping or atypical phenotypes. It also highlights the need for further investigations in cases where unexpected biological findings or unexplained clinical features are observed.