Tamar Harel^{1, 31}, Wan Hee Yoon^{2, 3, 31}, Caterina Garone⁴, Shen Gu, ¹, Zeynep Coban-Akdemir¹, Mohammad K. Eldomery¹, Jennifer E. Posey¹, Shalini N. Jhangiani^{1, 5}, Jill A. Rosenfeld^{1, 6}, Megan T. Cho⁷, Stephanie Fox⁸, Marjorie Withers¹, Stephanie M. Brooks⁹, Theodore Chiang⁵, Lita Duraine^{2, 3}, Serkan Erdin^{10, 11}, Bo Yuan^{1, 6}, Yunru Shao¹, Elie Moussallem¹, Costanza Lamperti¹², Maria A. Donati¹³, Joshua D. Smith¹⁴, Heather M. McLaughlin⁷, Christine M. Eng^{1, 6}, Magdalena Walkiewicz^{1, 6}, Fan Xia^{1, 6}, Tommaso Pippucci¹⁵, Pamela Magini¹⁶, Marco Seri^{15, 16}, Massimo Zeviani¹², Michio Hirano¹⁷, Jill V. Hunter¹⁸, Myriam Srour¹⁹, Stefano Zanigni^{20, 21}, Richard Alan Lewis^{1, 22, 23}, Donna M. Muzny⁵, Timothy E. Lotze^{23, 24}, Eric Boerwinkle^{5, 25}, Baylor-Hopkins Center for Mendelian Genomics  University of Washington Center for Mendelian Genomics Richard A. Gibbs^{1, 5}, Scott E. Hickey⁹, Brett H. Graham¹, Yaping Yang^{1, 6}, Daniela Buhas^{8, 26}, Donna M. Martin^{27, 28}, Lorraine Potocki^{1, 23}, Claudio Graziano¹⁵, Hugo J. Bellen^{1, 2, 3, 29, 30}, James R. Lupski^{1, 5, 22, 23}

¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
² Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA
³ Howard Hughes Medical Institute, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA
⁴ MRC Mitochondrial Biology Unit, Cambridge CB2 OXY, UK
⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
⁶ Baylor Genetics, Baylor College of Medicine, Houston, TX 77030, USA
⁷ GeneDx, Gaithersburg, MD 20877, USA
⁸ Medical Genetics Department, Montreal Children’s Hospital, Montreal, QC H4A 3J1, Canada
⁹ Department of Pediatrics, The Ohio State University College of Medicine, Division of Molecular and Human Genetics, Nationwide Children’s Hospital, Columbus, OH 43205, USA
¹⁰ Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
¹¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
¹² Unit of Molecular Neurogenetics, The Foundation “Carlo Besta” Institute of Neurology-IRCCS, Milan 20126, Italy
¹³ Metabolic and Muscular Unit, Meyer Children’s Hospital, University of Florence, Florence 50132, Italy
¹⁴ Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
¹⁵ Medical Genetics Unit, Policlinico Sant’Orsola-Malpighi, University of Bologna, Bologna 40138, Italy
¹⁶ Medical Genetics Unit, Department of Medical and Surgical Science, University of Bologna, Bologna 40138, Italy
¹⁷ Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
¹⁸ Department of Pediatric Radiology, Texas Children’s Hospital, Houston, TX 77030, USA
¹⁹ Department of Pediatrics, Neurology and Neurosurgery, McGill University, Montreal, QC H4A 3J1, Canada
²⁰ Functional MR Unit, Policlinico S. Orsola - Malpighi, Bologna 40138, Italy
²¹ Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna 40123, Italy
²² Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
²³ Texas Children’s Hospital, Houston, TX 77030, USA
²⁴ Department of Pediatric Neurology, Texas Children’s Hospital, Houston, TX 77030, USA
²⁵ Human Genetics Center, The University of Texas Health Science Center, Houston, TX 77030, USA
²⁶ Human Genetics Department, McGill University, Montreal, QC H3A 0G4, Canada
²⁷ Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, 48109
²⁸ Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
²⁹ Program in Developmental Biology, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA
³⁰ Department of Neuroscience, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA
³¹ These authors contributed equally to this work

Corresponding author : James R. Lupski

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor^R534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor^WT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

Keywords : whole-exome sequencing; mitochondrial dynamics; ATAD3A; de novo variant; neuropathy; optic atrophy; cardiomyopathy; CNV; dominant negative