Dataset Information

Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in the ATAD3 locus.

ABSTRACT:

Background

In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosis. A contributing factor is the difficulty with repetitive regions of the genome, such as those generated by segmental duplications. The ATAD3 locus is one such region, in which recessive deletions and dominant duplications have recently been reported to cause lethal perinatal mitochondrial diseases characterized by pontocerebellar hypoplasia or cardiomyopathy, respectively.

Methods

Whole exome, whole genome and long-read DNA sequencing techniques combined with studies of RNA and quantitative proteomics were used to investigate 17 subjects from 16 unrelated families with suspected mitochondrial disease.

Findings

We report six different de novo duplications in the ATAD3 gene locus causing a distinctive presentation including lethal perinatal cardiomyopathy, persistent hyperlactacidemia, and frequently corneal clouding or cataracts and encephalopathy. The recurrent 68 Kb ATAD3 duplications are identifiable from genome and exome sequencing but usually missed by microarrays. The ATAD3 duplications result in the formation of identical chimeric ATAD3A/ATAD3C proteins, altered ATAD3 complexes and a striking reduction in mitochondrial oxidative phosphorylation complex I and its activity in heart tissue.

Conclusions

ATAD3 duplications appear to act in a dominant-negative manner and the de novo inheritance infers a low recurrence risk for families, unlike most pediatric mitochondrial diseases. More than 350 genes underlie mitochondrial diseases. In our experience the ATAD3 locus is now one of the five most common causes of nuclear-encoded pediatric mitochondrial disease but the repetitive nature of the locus means ATAD3 diagnoses may be frequently missed by current genomic strategies.

Funding

Australian NHMRC, US Department of Defense, Japanese AMED and JSPS agencies, Australian Genomics Health Alliance and Australian Mito Foundation.

SUBMITTER: Frazier AE

PROVIDER: S-EPMC7875323 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Fatal perinatal mitochondrial cardiac failure caused by recurrent <i>de novo</i> duplications in the <i>ATAD3</i> locus.

Frazier Ann E AE Compton Alison G AG Kishita Yoshihito Y Hock Daniella H DH Welch AnneMarie E AE Amarasekera Sumudu S C SSC Rius Rocio R Formosa Luke E LE Imai-Okazaki Atsuko A Francis David D Wang Min M Lake Nicole J NJ Tregoning Simone S Jabbari Jafar S JS Lucattini Alexis A Nitta Kazuhiro R KR Ohtake Akira A Murayama Kei K Amor David J DJ McGillivray George G Wong Flora Y FY van der Knaap Marjo S MS Jeroen Vermeulen R R Wiltshire Esko J EJ Fletcher Janice M JM Lewis Barry B Baynam Gareth G Ellaway Carolyn C Balasubramaniam Shanti S Bhattacharya Kaustuv K Freckmann Mary-Louise ML Arbuckle Susan S Rodriguez Michael M Taft Ryan J RJ Sadedin Simon S Cowley Mark J MJ Minoche André E AE Calvo Sarah E SE Mootha Vamsi K VK Ryan Michael T MT Okazaki Yasushi Y Stroud David A DA Simons Cas C Christodoulou John J Thorburn David R DR

Med (New York, N.Y.) 20200709 1

<h4>Background</h4>In about half of all patients with a suspected monogenic disease, genomic investigations fail to identify the diagnosis. A contributing factor is the difficulty with repetitive regions of the genome, such as those generated by segmental duplications. The <i>ATAD3</i> locus is one such region, in which recessive deletions and dominant duplications have recently been reported to cause lethal perinatal mitochondrial diseases characterized by pontocerebellar hypoplasia or cardiomy ...[more]

PMID: 33575671

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