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Learning from massive testing of mitochondrial disorders: UPD explaining unorthodox transmission
  1. Deborah Tolomeo1,
  2. Anna Rubegni2,
  3. Claudia Nesti2,
  4. Melissa Barghigiani2,
  5. Roberta Battini1,
  6. Francesca D'Amore2,
  7. Stefano Doccini2,
  8. Maria Alice Donati3,
  9. Daniele Galatolo2,
  10. Sabrina Giglio4,5,
  11. Silvia Guarducci4,
  12. Marilena Pantaleo4,
  13. Rosa Pasquariello1,
  14. Elena Procopio3,
  15. Francesca Pochiero3,
  16. Alessandra Tessa2,
  17. Filippo M M Santorelli1,2
  1. 1 Neurology, IRCCS Fondazione Stella Maris, Pisa, Toscana, Italy
  2. 2 Molecular Medicine, IRCCS Stella Maris, Pisa, Italy
  3. 3 Metabolic and Neuromuscular Unit, Meyer Hospital, Florence, Italy
  4. 4 Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy, Florence, Italy
  5. 5 Unit of Medical Genetics, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
  1. Correspondence to Dr Filippo M M Santorelli, IRCCS Fondazione Stella Maris, Calambrone, Toscana, Italy; filippo3364{at}

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The heterogeneous group of mitochondrial disorders (MDs) is by far the largest class of inborn errors of metabolism, having a collective incidence of 1.6 in 5000.1 Over the past decade, routine clinical use of next-generation sequencing (NGS) has allowed a considerable number of cases to receive a precise molecular diagnosis. At present, however, NGS approaches, including targeted multigene panels and exome sequencing, still fail to achieve molecular definition in about half of patients with MD with a confirmed biochemical and clinical diagnosis.2 These unresolved cases could be due to new (‘hyper-rare’) genes/loci; alternatively, they could be linked to limits of current NGS strategies: indeed, mosaicisms requiring high sequencing depth for detection, genomic rearrangements including small and large deletions/insertions (<50 bp and >50 bp, respectively), and structural changes such as chromosomal rearrangements (inversions, translocations, deletions, duplications) all usually escape traditional NGS analysis pipelines. The chronic limited use of whole-genome sequencing in diagnostic settings may contribute to the substantial number of unresolved cases. The presence of repeat expansions and variants in deep intronic and regulatory regions2 may also provide an explanation for ‘missing heritability’. Although relatively rare, UPD might explain the unsolved transmission of homozygous mutations or aberrant patterns of imprinting,3 even in MDs. 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.

Patient 1 is a child who, when first seen by us, presented with generalised tonic-clonic seizures, hypotonia and …

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  • DT, AR and CN contributed equally.

  • Contributors All the authors contributed significantly to this work. DT and AR wrote the first draft. CN, MB, AT, MP, DF, DG performed NGS studies. RB, MAD, FP, EP, RP, SG, SG performed clinical studies. SD, DT performed biochemical investigations. FMS coordinated this study.

  • Funding This study was partially supported by a grant from the Italian Ministry of Health-Ricerca Corrente 5X1000 (to RB and FMS), and research projects MITO-NEXT, Mit-OMICS, and AUT-Omics (to FMS).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.