Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism
dc.contributor.author | Gunning, AC | |
dc.contributor.author | Strucinska, K | |
dc.contributor.author | Muñoz Oreja, M | |
dc.contributor.author | Parrish, A | |
dc.contributor.author | Caswell, R | |
dc.contributor.author | Stals, KL | |
dc.contributor.author | Durigon, R | |
dc.contributor.author | Durlacher-Betzer, K | |
dc.contributor.author | Cunningham, MH | |
dc.contributor.author | Grochowski, CM | |
dc.contributor.author | Baptista, J | |
dc.contributor.author | Tysoe, C | |
dc.contributor.author | Baple, E | |
dc.contributor.author | Lahiri, N | |
dc.contributor.author | Homfray, T | |
dc.contributor.author | Scurr, I | |
dc.contributor.author | Armstrong, C | |
dc.contributor.author | Dean, J | |
dc.contributor.author | Fernandez Pelayo, U | |
dc.contributor.author | Jones, AWE | |
dc.contributor.author | Taylor, RW | |
dc.contributor.author | Misra, VK | |
dc.contributor.author | Yoon, WH | |
dc.contributor.author | Wright, CF | |
dc.contributor.author | Lupski, JR | |
dc.contributor.author | Spinazzola, A | |
dc.contributor.author | Harel, T | |
dc.contributor.author | Holt, IJ | |
dc.contributor.author | Ellard, S | |
dc.date.accessioned | 2020-02-13T16:07:51Z | |
dc.date.issued | 2020-01-30 | |
dc.description.abstract | Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data. | en_GB |
dc.description.sponsorship | Wellcome Trust | en_GB |
dc.description.sponsorship | Basque Government | |
dc.description.sponsorship | University of the Basque Country | |
dc.description.sponsorship | Carlos III Health Program | |
dc.description.sponsorship | País Vasco Department of Health | |
dc.description.sponsorship | Medical Research Council (MRC) | |
dc.description.sponsorship | Israel Science Foundation | |
dc.description.sponsorship | National Institutes of Health (NIH) | |
dc.description.sponsorship | US National Institute of Neurological Disorders and Stroke | |
dc.description.sponsorship | National Institute of General Medical Sciences | |
dc.description.sponsorship | National Human Genome Research Institute | |
dc.description.sponsorship | National Heart Lung and Blood Institute | |
dc.description.sponsorship | Wellcome Centre for Mitochondrial Research | |
dc.description.sponsorship | International Centre for Genomic Medicine in Neuromuscular Disease, Mitochondrial Disease Patient Cohort (UK) | |
dc.description.sponsorship | UK NIHR Biomedical Research Centre for Aging and Age-related disease | |
dc.description.sponsorship | MRC/EPSRC Molecular Pathology Node | |
dc.description.sponsorship | Lily Foundation | |
dc.description.sponsorship | UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children | |
dc.description.sponsorship | Health Innovation Challenge Fund | |
dc.identifier.citation | Vol. 106 (2), pp. 272-279 | en_GB |
dc.identifier.doi | 10.1016/j.ajhg.2020.01.007 | |
dc.identifier.grantnumber | 200990 | en_GB |
dc.identifier.grantnumber | PRE_2018_1_0253 | |
dc.identifier.grantnumber | UPV/EHU, PIF 2018 | |
dc.identifier.grantnumber | PI17/00380 | |
dc.identifier.grantnumber | 2018111043 | |
dc.identifier.grantnumber | 2018222031 | |
dc.identifier.grantnumber | MC_PC_13029 | |
dc.identifier.grantnumber | 1663/17 | |
dc.identifier.grantnumber | 5 P20 GM103636-07 | |
dc.identifier.grantnumber | R35NS105078 | |
dc.identifier.grantnumber | R01GM106373 | |
dc.identifier.grantnumber | UM1 HG006542 | |
dc.identifier.grantnumber | 203105/Z/16/Z | |
dc.identifier.grantnumber | G0800674 | |
dc.identifier.grantnumber | HICF-1009-003 | |
dc.identifier.uri | http://hdl.handle.net/10871/40843 | |
dc.language.iso | en | en_GB |
dc.publisher | Elsevier (Cell Press) | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/32004445 | en_GB |
dc.rights | © The Authors. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/). | en_GB |
dc.subject | ATAD3 | en_GB |
dc.subject | ATAD3 gene cluster | en_GB |
dc.subject | Harel-Yoon | en_GB |
dc.subject | NAHR | en_GB |
dc.subject | cardiomyopathy | en_GB |
dc.subject | cholesterol | en_GB |
dc.subject | metabolic disorder | en_GB |
dc.subject | mitochondrial DNA | en_GB |
dc.subject | non-allelic homologous recombination | en_GB |
dc.title | Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2020-02-13T16:07:51Z | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the final version. Available on open access from Elsevier via the DOI in this record | en_GB |
dc.identifier.eissn | 1537-6605 | |
dc.identifier.journal | American Journal of Human Genetics | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2020-01-10 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2020-01-30 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2020-02-13T16:02:21Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2020-02-13T16:08:08Z | |
refterms.panel | A | en_GB |
Files in this item
This item appears in the following Collection(s)
Except where otherwise noted, this item's licence is described as © The Authors. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).