Learning from massive testing of mitochondrial disorders: UPD explaining unorthodox transmission

Here, we describe the cases of two children, each with a clinical diagnosis of MD, in whom chromosomal microarray analysis (CMA) allowed detection of UPD and helped to substantiate a homozygous variant identified by NGS. This study was conducted in accordance with Italian National Health System guidelines and the Declaration of Helsinki. Our data reinforce the suggestion that NGS testing should be supported by high-density SNP arrays in order to decrease the number of uncertain diagnoses and to identify cases of UPD. Reaching a conclusive genetic diagnosis is important not only for family planning and counselling purposes, but also to prepare correct follow-up and future optimisation of therapies. Identification of specific chromosomal UPDs might also shed new light on the role of imprinted genes in the affected region, and their potential to drive the full phenotype, and perhaps explain, in more detail, any genotype-phenotype correlations.