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Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.

Gunning, AC; Strucinska, K; Muñoz Oreja, M; Parrish, A; Caswell, R; Stals, KL; Durigon, R; Durlacher-Betzer, K; Cunningham, MH; Grochowski, CM; et al. Gunning, AC; Strucinska, K; Muñoz Oreja, M; Parrish, A; Caswell, R; Stals, KL; Durigon, R; Durlacher-Betzer, K; Cunningham, MH; Grochowski, CM; Baptista, J; Tysoe, C; Baple, E; Lahiri, N; Homfray, T; Scurr, I; Armstrong, C; Dean, J; Fernandez Pelayo, U; Jones, AWE; Taylor, RW; Misra, VK; Yoon, WH; Wright, CF; Lupski, JR; Spinazzola, A; Harel, T; Holt, IJ; Ellard, S (2020) Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism. Am J Hum Genet, 106 (2). pp. 272-279. ISSN 1537-6605 https://doi.org/10.1016/j.ajhg.2020.01.007
SGUL Authors: Lahiri, Nayana

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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.

Item Type: Article
Additional Information: © 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: ATAD3, ATAD3 gene cluster, Harel-Yoon, NAHR, cardiomyopathy, cholesterol, metabolic disorder, mitochondrial DNA, non-allelic homologous recombination, Genetics & Heredity, 06 Biological Sciences, 11 Medical and Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Clinical Education (INMECE )
Journal or Publication Title: Am J Hum Genet
ISSN: 1537-6605
Language: eng
Dates:
DateEvent
6 February 2020Published
30 January 2020Published Online
10 January 2020Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
200990Wellcome Trusthttp://dx.doi.org/10.13039/100004440
PRE_2018_1_0253Basque GovernmentUNSPECIFIED
PI17/00380Carlos III Health ProgramUNSPECIFIED
2018111043País Vasco Department of HealthUNSPECIFIED
2018222031País Vasco Department of HealthUNSPECIFIED
MC_PC_13029Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
1663/17Israel Science Foundationhttp://dx.doi.org/10.13039/501100003977
5 P20 GM103636-07National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R35NS105078National Institute of Neurological Disorders and Strokehttp://dx.doi.org/10.13039/100000065
R01GM106373National Institute of General Medical Scienceshttp://dx.doi.org/10.13039/100000057
UM1 HG006542National Heart, Lung, and Blood Institutehttp://dx.doi.org/10.13039/100000050
203105/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
G0800674Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
UNSPECIFIEDNational Institute for Health Researchhttp://dx.doi.org/10.13039/501100000272
HICF-1009-003Health Innovation Challenge FundUNSPECIFIED
PubMed ID: 32004445
Web of Science ID: WOS:000512913300012
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111761
Publisher's version: https://doi.org/10.1016/j.ajhg.2020.01.007

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