Format

Send to

Choose Destination
Am J Hum Genet. 2020 Feb 6;106(2):272-279. doi: 10.1016/j.ajhg.2020.01.007. Epub 2020 Jan 30.

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

Author information

1
Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter EX2 5DW, UK.
2
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
3
Biodonostia Health Research Institute, 20014 San Sebastián, Spain.
4
Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
5
Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter EX2 5DW, UK.
6
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London NW3 2PF, UK.
7
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
8
Department of Pediatrics, Division of Genetic, Genomic, and Metabolic Disorders, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI 48201, USA.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
10
South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
11
South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK; St George's University of London, London SW17 0RE, UK.
12
Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8EG, UK.
13
Department of Paediatric Cardiology, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, UK.
14
Clinical Genetics Service, NHS Grampian, Aberdeen Royal Infirmary, Aberdeen AB25 2ZA, UK.
15
Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
16
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
17
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London NW3 2PF, UK; MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
18
Biodonostia Health Research Institute, 20014 San Sebastián, Spain; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London NW3 2PF, UK; IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain; CIBERNED (Center for Networked Biomedical Research on Neurodegenerative Diseases, Ministry of Economy and Competitiveness, Institute Carlos III), 28031 Madrid, Spain.
19
Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter EX2 5DW, UK. Electronic address: sian.ellard@nhs.net.

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.

KEYWORDS:

ATAD3; ATAD3 gene cluster; Harel-Yoon; NAHR; cardiomyopathy; cholesterol; metabolic disorder; mitochondrial DNA; non-allelic homologous recombination

PMID:
32004445
PMCID:
PMC7010973
[Available on 2020-08-06]
DOI:
10.1016/j.ajhg.2020.01.007
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center