Ann E Frazier1,2,3, Alison G Compton1,2,3, Yoshihito Kishita4, Daniella H Hock5, AnneMarie E Welch1, Sumudu S C Amarasekera1,2, Rocio Rius1,2, Luke E Formosa6, Atsuko Imai-Okazaki4,7, David Francis8, Min Wang1, Nicole J Lake1,2,9, Simone Tregoning1,8, Jafar S Jabbari10, Alexis Lucattini10, Kazuhiro R Nitta4, Akira Ohtake11, Kei Murayama12, David J Amor1,2, George McGillivray8, Flora Y Wong13, Marjo S van der Knaap14,15, R Jeroen Vermeulen16, Esko J Wiltshire17, Janice M Fletcher18, Barry Lewis19, Gareth Baynam20,21, Carolyn Ellaway22,23, Shanti Balasubramaniam22, Kaustuv Bhattacharya22,23, Mary-Louise Freckmann24, Susan Arbuckle25, Michael Rodriguez26, Ryan J Taft27, Simon Sadedin1,8, Mark J Cowley28,29, André E Minoche29, Sarah E Calvo30, Vamsi K Mootha30, Michael T Ryan6, Yasushi Okazaki4, David A Stroud5, Cas Simons1,31, John Christodoulou1,2,8,23, David R Thorburn1,2,8,32. 1. Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia. 2. Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia. 3. These authors contributed equally: A.E. Frazier, A.G. Compton. 4. Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Juntendo University, Graduate School of Medicine, Tokyo, 113-8421, Japan. 5. Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC 3052, Australia. 6. Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia. 7. Division of Genomic Medicine Research, Medical Genomics Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan. 8. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia. 9. Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA. 10. Australian Genome Research Facility Ltd, Victorian Comprehensive Cancer Centre, Melbourne VIC 3052, Australia. 11. Department of Pediatrics & Clinical Genomics, Saitama Medical University Hospital, Saitama, 350-0495, Japan. 12. Department of Metabolism, Chiba Children's Hospital, Chiba, 266-0007, Japan. 13. Ritchie Centre, Hudson Institute of Medical Research; Department of Paediatrics, Monash University; and Monash Newborn, Monash Children's Hospital, Melbourne, VIC 3168, Australia. 14. Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit and Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands. 15. Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit and Amsterdam Neuroscience, 1081 HV Amsterdam, The Netherlands. 16. Department of Neurology, Maastricht University Medical Center, 6229 HX, Maastricht, The Netherlands. 17. Department of Paediatrics and Child Health, University of Otago Wellington and Capital and Coast District Health Board, Wellington 6021, New Zealand. 18. Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA 5000, Australia. 19. Department of Clinical Biochemistry, PathWest Laboratory Medicine Western Australia, Nedlands, WA 6009, Australia. 20. Western Australian Register of Developmental Anomalies and Genetic Services of Western Australia and King Edward Memorial Hospital for Women Perth, Subiaco, WA 6008, Australia. 21. Telethon Kids Institute and School of Paediatrics and Child Health, The University of Western Australia, Perth, WA 6009, Australia. 22. Genetic Metabolic Disorders Service, Sydney Children's Hospital Network, The Children's Hospital at Westmead, Sydney, NSW 2145, Australia. 23. Disciplines of Genomic Medicine and Child and Adolescent Health, Sydney Medical School, University of Sydney, NSW 2145, Australia. 24. Clinical Genetics, The Canberra Hospital, Garran, ACT 2605, Australia. 25. Department of Histopathology, The Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW 2145, Australia. 26. Discipline of Pathology, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia. 27. Illumina, Inc., San Diego, CA 92121, USA. 28. Children's Cancer Institute, Kensington, NSW 2750, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, NSW 2010, Australia. 29. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia. 30. Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02446, USA. 31. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072 Australia. 32. Lead contact.
Abstract
BACKGROUND: In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosis. A contributing factor is the difficulty with repetitive regions of the genome, such as those generated by segmental duplications. The ATAD3 locus is one such region, in which recessive deletions and dominant duplications have recently been reported to cause lethal perinatal mitochondrial diseases characterized by pontocerebellar hypoplasia or cardiomyopathy, respectively. METHODS: Whole exome, whole genome and long-read DNA sequencing techniques combined with studies of RNA and quantitative proteomics were used to investigate 17 subjects from 16 unrelated families with suspected mitochondrial disease. FINDINGS: We report six different de novo duplications in the ATAD3 gene locus causing a distinctive presentation including lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently corneal clouding or cataracts and encephalopathy. The recurrent 68 Kb ATAD3 duplications are identifiable from genome and exome sequencing but usually missed by microarrays. The ATAD3 duplications result in the formation of identical chimeric ATAD3A/ATAD3C proteins, altered ATAD3 complexes and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue. CONCLUSIONS: ATAD3 duplications appear to act in a dominant-negative manner and the de novo inheritance infers a low recurrence risk for families, unlike most pediatric mitochondrial diseases. More than 350 genes underlie mitochondrial diseases. In our experience the ATAD3 locus is now one of the five most common causes of nuclear-encoded pediatric mitochondrial disease but the repetitive nature of the locus means ATAD3 diagnoses may be frequently missed by current genomic strategies. FUNDING: Australian NHMRC, US Department of Defense, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance and Australian Mito Foundation.
BACKGROUND: In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosis. A contributing factor is the difficulty with repetitive regions of the genome, such as those generated by segmental duplications. The ATAD3 locus is one such region, in which recessive deletions and dominant duplications have recently been reported to cause lethal perinatal mitochondrial diseases characterized by pontocerebellar hypoplasia or cardiomyopathy, respectively. METHODS: Whole exome, whole genome and long-read DNA sequencing techniques combined with studies of RNA and quantitative proteomics were used to investigate 17 subjects from 16 unrelated families with suspected mitochondrial disease. FINDINGS: We report six different de novo duplications in the ATAD3 gene locus causing a distinctive presentation including lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently corneal clouding or cataracts and encephalopathy. The recurrent 68 Kb ATAD3 duplications are identifiable from genome and exome sequencing but usually missed by microarrays. The ATAD3 duplications result in the formation of identical chimeric ATAD3A/ATAD3C proteins, altered ATAD3 complexes and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue. CONCLUSIONS: ATAD3 duplications appear to act in a dominant-negative manner and the de novo inheritance infers a low recurrence risk for families, unlike most pediatric mitochondrial diseases. More than 350 genes underlie mitochondrial diseases. In our experience the ATAD3 locus is now one of the five most common causes of nuclear-encoded pediatric mitochondrial disease but the repetitive nature of the locus means ATAD3 diagnoses may be frequently missed by current genomic strategies. FUNDING: Australian NHMRC, US Department of Defense, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance and Australian Mito Foundation.
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