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 6 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, US National Institutes of Health, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance, and Australian Mito Foundation.
Original language | English |
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Pages (from-to) | 49-73.e10 |
Journal | Med |
Volume | 2 |
Issue number | 1 |
DOIs | |
Publication status | Published - 15 Jan 2021 |
Bibliographical note
Funding Information:We thank Meredith Wilson, Stefanie Eggers, Natalie Tan, Katherine Neas, Tegan Stait, Sabrina Kaminsky, and Wendy Fagan for technical assistance, contributions to data collection, and/or clinical discussions. We appreciate the kind gifts of antibodies from Ian Holt and Antonella Spinazzola (anti-ATAD3) and Diana Stojanovski (anti-ANT3). We acknowledge the Melbourne Mass Spectrometry and Proteomics Facility (MMSPF) for providing instrumentation, training, and technical support. This research was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) (1164479 [D.R.T. J.C. D.A.S. and A.G.C.], 1155244 [D.R.T.], 1068278 [C.S.], and 1140851 [D.A.S.]), the US Department of Defense Congressionally Directed Medical Research Programs PR170396 (D.R.T. J.C. M.T.R. and D.A.S.), the New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant (J.C.), the Victorian Government's Operational Infrastructure Support Program (D.R.T. and J.C.), the Australian Mito Foundation (A.E.F. A.G.C. C.S. D.R.T. J.C. D.A.S. D.H.H. and M.T.R.), the National Council on Science and Technology (CONACYT) (R.R.), the Vincent Chiodo Charitable Trust (D.R.T.), the Angela Wright Bennett Foundation and the McCusker Charitable Foundation (G.B.), the US National Institutes of Health R35GM122455 (V.K.M.), and the Howard Hughes Medical Institute Investigator Program (V.K.M.). Diagnosis of two patients was supported by the Australian Genomics Health Alliance (J.C. D.R.T. C.S. and G.B.), which is funded by the National Health and Medical Research Council (NHMRC) (1113531) and the Medical Research Future Fund. This work was supported in part by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) (19ek0109273 and 18ek0109177) to K.M. A.O. and Y.O.; the Program for an Integrated Database of Clinical and Genomic Information from AMED (19kk0205014 and 18kk0205002) to Y.O.; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Supported Program for the Private University Research Branding Project; and the Japan Society for the Promotion of Science (JSPS) KAKENHI 19H03624 (Grant-in-Aid for Scientific Research (B)) to Y.O. and Y.K. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, the National Cancer Institute (NCI), the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). A.E.F. A.G.C. C.S. D.R.T. and J.C. conceived the study. A.E.W. A.E.F. Y.K. A.G.C. R.R. D.H.H. D.A.S. S.S.C.A. S.E.C. N.J.L. L.E.F. and D.F. acquired the data. A.E.F. A.G.C. Y.K. D.H.H. D.A.S. R.R. L.E.F. D.R.T. C.S. D.F. M.T.R. and Y.O. analyzed and interpreted the data. A.E.F. A.E.W. A.G.C. Y.K. N.J.L. R.R. C.S. R.J.T. A.E.M. J.S.J. A.L. K.R.N. M.W. S.S. M.J.C. S.E.C. V.K.M. D.H.H. and D.A.S. performed the bioinformatic, genomic, or proteomic analyses. A.I.-O. A.O. K.M. M.S.v.d.K. R.J.V. G.B. J.C. D.J.A. G.M. F.Y.W. E.J.W. J.M.F. B.L. C.E. S.B. K.B. M.L.F. S.A. M.R. S.T. and D.R.T. recruited patients, liaised with families, and collected and reviewed clinical and diagnostic data. A.E.F. A.G.C. D.R.T. and D.A.S. wrote the manuscript, with input from all of the authors. All of the authors reviewed and approved the manuscript. R.J.T. is an employee of Illumina, Inc.
Funding Information:
We thank Meredith Wilson, Stefanie Eggers, Natalie Tan, Katherine Neas, Tegan Stait, Sabrina Kaminsky, and Wendy Fagan for technical assistance, contributions to data collection, and/or clinical discussions. We appreciate the kind gifts of antibodies from Ian Holt and Antonella Spinazzola (anti-ATAD3) and Diana Stojanovski (anti-ANT3). We acknowledge the Melbourne Mass Spectrometry and Proteomics Facility (MMSPF) for providing instrumentation, training, and technical support. This research was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) ( 1164479 [D.R.T., J.C., D.A.S., and A.G.C.], 1155244 [D.R.T.], 1068278 [C.S.], and 1140851 [D.A.S.]), the US Department of Defense Congressionally Directed Medical Research Programs PR170396 (D.R.T., J.C., M.T.R., and D.A.S.), the New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant (J.C.), the Victorian Government’s Operational Infrastructure Support Program (D.R.T. and J.C.), the Australian Mito Foundation (A.E.F., A.G.C., C.S., D.R.T., J.C., D.A.S., D.H.H., and M.T.R.), the National Council on Science and Technology (CONACYT) (R.R.), the Vincent Chiodo Charitable Trust (D.R.T.), the Angela Wright Bennett Foundation and the McCusker Charitable Foundation (G.B.), the US National Institutes of Health R35GM122455 (V.K.M.), and the Howard Hughes Medical Institute Investigator Program (V.K.M.). Diagnosis of two patients was supported by the Australian Genomics Health Alliance (J.C., D.R.T., C.S., and G.B.), which is funded by the National Health and Medical Research Council (NHMRC) ( 1113531 ) and the Medical Research Future Fund . This work was supported in part by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) ( 19ek0109273 and 18ek0109177 ) to K.M., A.O., and Y.O.; the Program for an Integrated Database of Clinical and Genomic Information from AMED ( 19kk0205014 and 18kk0205002 ) to Y.O.; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Supported Program for the Private University Research Branding Project; and the Japan Society for the Promotion of Science (JSPS) KAKENHI 19H03624 (Grant-in-Aid for Scientific Research (B)) to Y.O. and Y.K. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health , the National Cancer Institute (NCI), the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS).
Publisher Copyright:
© 2020 Elsevier Inc.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
Funding
We thank Meredith Wilson, Stefanie Eggers, Natalie Tan, Katherine Neas, Tegan Stait, Sabrina Kaminsky, and Wendy Fagan for technical assistance, contributions to data collection, and/or clinical discussions. We appreciate the kind gifts of antibodies from Ian Holt and Antonella Spinazzola (anti-ATAD3) and Diana Stojanovski (anti-ANT3). We acknowledge the Melbourne Mass Spectrometry and Proteomics Facility (MMSPF) for providing instrumentation, training, and technical support. This research was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) (1164479 [D.R.T. J.C. D.A.S. and A.G.C.], 1155244 [D.R.T.], 1068278 [C.S.], and 1140851 [D.A.S.]), the US Department of Defense Congressionally Directed Medical Research Programs PR170396 (D.R.T. J.C. M.T.R. and D.A.S.), the New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant (J.C.), the Victorian Government's Operational Infrastructure Support Program (D.R.T. and J.C.), the Australian Mito Foundation (A.E.F. A.G.C. C.S. D.R.T. J.C. D.A.S. D.H.H. and M.T.R.), the National Council on Science and Technology (CONACYT) (R.R.), the Vincent Chiodo Charitable Trust (D.R.T.), the Angela Wright Bennett Foundation and the McCusker Charitable Foundation (G.B.), the US National Institutes of Health R35GM122455 (V.K.M.), and the Howard Hughes Medical Institute Investigator Program (V.K.M.). Diagnosis of two patients was supported by the Australian Genomics Health Alliance (J.C. D.R.T. C.S. and G.B.), which is funded by the National Health and Medical Research Council (NHMRC) (1113531) and the Medical Research Future Fund. This work was supported in part by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) (19ek0109273 and 18ek0109177) to K.M. A.O. and Y.O.; the Program for an Integrated Database of Clinical and Genomic Information from AMED (19kk0205014 and 18kk0205002) to Y.O.; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Supported Program for the Private University Research Branding Project; and the Japan Society for the Promotion of Science (JSPS) KAKENHI 19H03624 (Grant-in-Aid for Scientific Research (B)) to Y.O. and Y.K. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, the National Cancer Institute (NCI), the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). A.E.F. A.G.C. C.S. D.R.T. and J.C. conceived the study. A.E.W. A.E.F. Y.K. A.G.C. R.R. D.H.H. D.A.S. S.S.C.A. S.E.C. N.J.L. L.E.F. and D.F. acquired the data. A.E.F. A.G.C. Y.K. D.H.H. D.A.S. R.R. L.E.F. D.R.T. C.S. D.F. M.T.R. and Y.O. analyzed and interpreted the data. A.E.F. A.E.W. A.G.C. Y.K. N.J.L. R.R. C.S. R.J.T. A.E.M. J.S.J. A.L. K.R.N. M.W. S.S. M.J.C. S.E.C. V.K.M. D.H.H. and D.A.S. performed the bioinformatic, genomic, or proteomic analyses. A.I.-O. A.O. K.M. M.S.v.d.K. R.J.V. G.B. J.C. D.J.A. G.M. F.Y.W. E.J.W. J.M.F. B.L. C.E. S.B. K.B. M.L.F. S.A. M.R. S.T. and D.R.T. recruited patients, liaised with families, and collected and reviewed clinical and diagnostic data. A.E.F. A.G.C. D.R.T. and D.A.S. wrote the manuscript, with input from all of the authors. All of the authors reviewed and approved the manuscript. R.J.T. is an employee of Illumina, Inc. We thank Meredith Wilson, Stefanie Eggers, Natalie Tan, Katherine Neas, Tegan Stait, Sabrina Kaminsky, and Wendy Fagan for technical assistance, contributions to data collection, and/or clinical discussions. We appreciate the kind gifts of antibodies from Ian Holt and Antonella Spinazzola (anti-ATAD3) and Diana Stojanovski (anti-ANT3). We acknowledge the Melbourne Mass Spectrometry and Proteomics Facility (MMSPF) for providing instrumentation, training, and technical support. This research was supported by grants and fellowships from the Australian National Health and Medical Research Council (NHMRC) ( 1164479 [D.R.T., J.C., D.A.S., and A.G.C.], 1155244 [D.R.T.], 1068278 [C.S.], and 1140851 [D.A.S.]), the US Department of Defense Congressionally Directed Medical Research Programs PR170396 (D.R.T., J.C., M.T.R., and D.A.S.), the New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant (J.C.), the Victorian Government’s Operational Infrastructure Support Program (D.R.T. and J.C.), the Australian Mito Foundation (A.E.F., A.G.C., C.S., D.R.T., J.C., D.A.S., D.H.H., and M.T.R.), the National Council on Science and Technology (CONACYT) (R.R.), the Vincent Chiodo Charitable Trust (D.R.T.), the Angela Wright Bennett Foundation and the McCusker Charitable Foundation (G.B.), the US National Institutes of Health R35GM122455 (V.K.M.), and the Howard Hughes Medical Institute Investigator Program (V.K.M.). Diagnosis of two patients was supported by the Australian Genomics Health Alliance (J.C., D.R.T., C.S., and G.B.), which is funded by the National Health and Medical Research Council (NHMRC) ( 1113531 ) and the Medical Research Future Fund . This work was supported in part by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) ( 19ek0109273 and 18ek0109177 ) to K.M., A.O., and Y.O.; the Program for an Integrated Database of Clinical and Genomic Information from AMED ( 19kk0205014 and 18kk0205002 ) to Y.O.; the Ministry of Education, Culture, Sports, Science and Technology (MEXT)-Supported Program for the Private University Research Branding Project; and the Japan Society for the Promotion of Science (JSPS) KAKENHI 19H03624 (Grant-in-Aid for Scientific Research (B)) to Y.O. and Y.K. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health , the National Cancer Institute (NCI), the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS).
Funders | Funder number |
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Australian Mito Foundation | |
Medical Research Future Fund | |
Melbourne Mass Spectrometry and Proteomics Facility | |
New South Wales Office of Health and Medical Research Council | |
Vincent Chiodo Charitable Trust | |
National Institutes of Health | |
Howard Hughes Medical Institute | |
National Institute of Mental Health | |
National Institute on Drug Abuse | |
National Heart, Lung, and Blood Institute | |
National Human Genome Research Institute | |
National Cancer Institute | |
National Institute of General Medical Sciences | R35GM122455 |
National Institute of Neurological Disorders and Stroke | |
Congressionally Directed Medical Research Programs | PR170396 |
Japan Agency for Medical Research and Development | 19ek0109273, 18ek0109177, 19kk0205014, 18kk0205002 |
McCusker Charitable Foundation | |
National Health and Medical Research Council | 1155244, 1113531, 1164479, 1140851, 1068278 |
Japan Society for the Promotion of Science | 19H03624 |
Ministry of Education, Culture, Sports, Science and Technology | |
Consejo Nacional de Ciencia y Tecnología | |
State Government of Victoria | |
Australian Genomics Health Alliance | |
Angela Wright Bennett Foundation |
Keywords
- ATAD3
- cardiomyopathy
- de novo duplication
- genomics
- mitochondrial disease
- perinatal death
- quantitative proteomics
- segmental duplication
- Translation to Patients