Targeted next generation sequencing identifies novel pathogenic variants and provides molecular diagnoses in a cohort of pediatric and adult patients with unexplained mitochondrial dysfunction

Célia Nogueira; Lisbeth Silva; Cristina Pereira; Luís Vieira; Elisa Leão Teles; Esmeralda Rodrigues; Teresa Campos; Patrícia Janeiro; Ana Gaspar; Juliette Dupont; Anabela Bandeira; Esmeralda Martins; Marina Magalhães; Sílvia Sequeira; José Pedro Vieira; Helena Santos; Sílvia Vilarinho; Laura Vilarinho

doi:10.1016/j.mito.2019.02.006

Targeted next generation sequencing identifies novel pathogenic variants and provides molecular diagnoses in a cohort of pediatric and adult patients with unexplained mitochondrial dysfunction

Mitochondrion. 2019 Jul:47:309-317. doi: 10.1016/j.mito.2019.02.006. Epub 2019 Mar 1.

Authors

Célia Nogueira¹, Lisbeth Silva², Cristina Pereira³, Luís Vieira⁴, Elisa Leão Teles⁵, Esmeralda Rodrigues⁵, Teresa Campos⁵, Patrícia Janeiro⁶, Ana Gaspar⁶, Juliette Dupont⁶, Anabela Bandeira⁷, Esmeralda Martins⁷, Marina Magalhães⁸, Sílvia Sequeira⁹, José Pedro Vieira⁹, Helena Santos¹⁰, Sílvia Vilarinho¹¹, Laura Vilarinho¹²

Affiliations

¹ Research & Development Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, Porto, Portugal; Newborn Screening, Metabolism & Genetics Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, Porto, Portugal.
² Research & Development Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, Porto, Portugal.
³ Newborn Screening, Metabolism & Genetics Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, Porto, Portugal.
⁴ Innovation and Technology Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, Lisbon, Portugal.
⁵ Department of Pediatrics, São João Hospital Centre, EPE, Porto, Portugal.
⁶ Department of Pediatrics, Norte Hospital Centre, EPE, Lisboa, Portugal.
⁷ Department of Pediatrics, Porto Hospital and University Centre, EPE, Porto, Portugal.
⁸ Department of Neurology, Porto Hospital and University Centre, EPE, Porto, Portugal.
⁹ Department of Pediatrics, Central Hospital Centre, EPE, Lisboa, Portugal.
¹⁰ Department of Pediatrics, Hospital Centre, EPE, V.N. Gaia, Vila Nova de Gaia, Portugal.
¹¹ Department of Internal Medicine (Digestive Diseases) and of Pathology, Yale University School of Medicine, New Haven, CT, USA.
¹² Research & Development Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, Porto, Portugal; Newborn Screening, Metabolism & Genetics Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, Porto, Portugal. Electronic address: [email protected].

PMID: 30831263
DOI: 10.1016/j.mito.2019.02.006

Abstract

Mitochondrial diseases (MD) are a group of rare inherited disorders, characterized by phenotypic heterogeneity, with hitherto no effective therapeutic options. The aim of this study was to develop a next generation sequencing (NGS) strategy, by using a custom gene panel and whole mitochondrial genome, to identify the disease causing pathogenic variants in 146 patients suspicious of MD. The molecular analysis of this cohort revealed six novel and 15 described pathogenic variants, as well as 26 variants of unknown significance. Our findings are expanding the mutational landscape of these disorders and support the use of a NGS strategy for a higher diagnostic yield.

Keywords: Gene panel; Mitochondrial diseases; Next generation sequencing; Nuclear genes; Respiratory chain; mtDNA.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Child
Child, Preschool
Cohort Studies
Female
Genome, Mitochondrial*
High-Throughput Nucleotide Sequencing*
Humans
Infant
Male
Middle Aged
Mitochondrial Diseases / genetics*
Molecular Diagnostic Techniques*
Sequence Analysis, DNA*