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

TitleRecurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.
Publication TypeJournal Article
Year of Publication2020
AuthorsGunning, AC, Strucinska, K, Oreja, MMuñoz, 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, Pelayo, UFernandez, Jones, AWE, Taylor, RW, Misra, VK, Yoon, WHee, Wright, CF, Lupski, JR, Spinazzola, A, Harel, T, Holt, IJ, Ellard, S
JournalAm J Hum Genet
Date Published2020 Feb 06
KeywordsAmino Acid Sequence, ATPases Associated with Diverse Cellular Activities, Brain Diseases, Cardiomyopathies, Cholesterol, Corneal Opacity, DNA Copy Number Variations, Female, Gene Duplication, Gene Rearrangement, Homologous Recombination, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Diseases, Mitochondrial Proteins, Muscle Hypotonia, Mutation, Protein Conformation, Seizures, Sequence Homology

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.

Alternate JournalAm J Hum Genet
PubMed ID32004445
PubMed Central IDPMC7010973
Grant ListMC_PC_13029 / MRC_ / Medical Research Council / United Kingdom
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
MC_PC_13029/2 / MRC_ / Medical Research Council / United Kingdom
R01 GM106373 / GM / NIGMS NIH HHS / United States
P20 GM103636 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom

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