Diagnosing pediatric mitochondrial disease: lessons from 2,000 exomes
Authors: Stenton Sarah L. , Shimura Masaru , Piekutowska-Abramczuk Dorota , Freisinger Peter , Distelmaier Felix , Mayr Johannes A. , Makowski Christine , Büchner Boriana , Alhaddad Bader , Alston Charlotte L. , Ardissone Anna , Ban Rui , Barić Ivo , Berutti Riccardo , Brunet Theresa , Ciara Elżbieta , Deen Dasha , Gagneur Julien , Ghezzi Daniele , Gusic Mirjana , Haack Tobias B. , Hempel Maja , Husain Ralf A. , Karall Daniela , Kölker Stefan , Kotzaeridou Urania , Klopstock Thomas , Kopajtich Robert , Konstantopoulou Vassiliki , Liez Steffen , Lenz Dominic , Lim Albert Z. , Mandel Hanna , McFarland Robert , Müller-Felber Wolfgang , Muñoz-Pujol Gerard , Ohtake Akira , Okazaki Yasushi , Olsen Rikke , Pronicka Ewa , Pyle Angela , Ribes Antonia , Rokicki Dariusz , Santer René , Schiff Manuel , Schuelke Markus , Smirnov Dmitrii , Sperl Wolfgang , Strom Tim , Tort Frederic , Tsygankova Polina , van Coster Rudy , Verloo Patrick , von Kleist-Retzow Jürgen-Christoph , Wilichowski Ekkehard , Wolstein Tekla , Xu Manting , Yépez Vicente , Zech Michael , Wortmann Saskia , Wagner Matias , Lamperti Costanza , Taylor Robert W. , Fang Fang , Rötig Agnés , Murayama Kei , Meitinger Thomas , Prokisch Holger 
Published: June 2021

AbstractBackgroundThe spectrum of mitochondrial disease is genetically and phenotypically diverse, resulting from pathogenic variants in over 400 genes, with aerobic energy metabolism defects as a common denominator. Such heterogeneity poses a significant challenge in making an accurate diagnosis, critical for precision medicine.MethodsIn an international collaboration initiated by the European Network for Mitochondrial Diseases (GENOMIT) we recruited 2,023 pediatric patients at 11 specialist referral centers between October 2010 and January 2021, accumulating exome sequencing and HPO-encoded phenotype data. An exome-wide search for variants in known and potential novel disease genes, complemented by functional studies, followed ACMG guidelines.Results1,109 cases (55%) received a molecular diagnosis, of which one fifth have potential disease-modifying treatments (236/1,109, 21%). Functional studies enabled diagnostic uplift from 36% to 55% and discovery of 62 novel disease genes. Pathogenic variants were identified within genes encoding mitochondrial proteins or RNAs in 801 cases (72%), while, given extensive phenotype overlap, the remainder involved proteins targeted to other cellular compartments. To delineate genotype-phenotype associations, our data was complemented with registry and literature data to develop “GENOMITexplorer”, an open access resource detailing patient- (n=3,940), gene- (n=427), and variant-level (n=1,492) associations (prokischlab.github.io/GENOMITexplorer/).ConclusionsReaching a molecular diagnosis was essential for implementation of precision medicine and clinical trial eligibility, underlining the need for genome-wide screening given inability to accurately define mitochondrial diseases clinically. Key to diagnostic success were functional studies, encouraging early acquisition of patient- derived tissues and routine integration of high-throughput functional data to improve patient care by uplifting diagnostic rate.