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dc.contributor.authorGunning, AC
dc.contributor.authorStrucinska, K
dc.contributor.authorMuñoz Oreja, M
dc.contributor.authorParrish, A
dc.contributor.authorCaswell, R
dc.contributor.authorStals, KL
dc.contributor.authorDurigon, R
dc.contributor.authorDurlacher-Betzer, K
dc.contributor.authorCunningham, MH
dc.contributor.authorGrochowski, CM
dc.contributor.authorBaptista, J
dc.contributor.authorTysoe, C
dc.contributor.authorBaple, E
dc.contributor.authorLahiri, N
dc.contributor.authorHomfray, T
dc.contributor.authorScurr, I
dc.contributor.authorArmstrong, C
dc.contributor.authorDean, J
dc.contributor.authorFernandez Pelayo, U
dc.contributor.authorJones, AWE
dc.contributor.authorTaylor, RW
dc.contributor.authorMisra, VK
dc.contributor.authorYoon, WH
dc.contributor.authorWright, CF
dc.contributor.authorLupski, JR
dc.contributor.authorSpinazzola, A
dc.contributor.authorHarel, T
dc.contributor.authorHolt, IJ
dc.contributor.authorEllard, S
dc.date.accessioned2022-05-03T18:05:48Z
dc.date.issued2020-02
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.urihttp://hdl.handle.net/10026.1/19166
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.

dc.format.extent272-279
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoeng
dc.publisherElsevier BV
dc.subjectATAD3
dc.subjectATAD3 gene cluster
dc.subjectHarel-Yoon
dc.subjectNAHR
dc.subjectcardiomyopathy
dc.subjectcholesterol
dc.subjectmetabolic disorder
dc.subjectmitochondrial DNA
dc.subjectnon-allelic homologous recombination
dc.subjectATPases Associated with Diverse Cellular Activities
dc.subjectAmino Acid Sequence
dc.subjectBrain Diseases
dc.subjectCardiomyopathies
dc.subjectCholesterol
dc.subjectCorneal Opacity
dc.subjectDNA Copy Number Variations
dc.subjectFemale
dc.subjectGene Duplication
dc.subjectGene Rearrangement
dc.subjectHomologous Recombination
dc.subjectHumans
dc.subjectInfant
dc.subjectInfant, Newborn
dc.subjectMale
dc.subjectMembrane Proteins
dc.subjectMitochondria
dc.subjectMitochondrial Diseases
dc.subjectMitochondrial Proteins
dc.subjectMuscle Hypotonia
dc.subjectMutation
dc.subjectProtein Conformation
dc.subjectSeizures
dc.subjectSequence Homology
dc.titleRecurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism
dc.typejournal-article
dc.typeArticle
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/32004445
plymouth.issue2
plymouth.volume106
plymouth.publisher-urlhttp://dx.doi.org/10.1016/j.ajhg.2020.01.007
plymouth.publication-statusPublished
plymouth.journalThe American Journal of Human Genetics
dc.identifier.doi10.1016/j.ajhg.2020.01.007
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
dc.publisher.placeUnited States
dcterms.dateAccepted2020-01-10
dc.rights.embargodate9999-12-31
dc.identifier.eissn1537-6605
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1016/j.ajhg.2020.01.007
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2020-02-06
rioxxterms.typeJournal Article/Review


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