Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study

Schon, Katherine; Horvath, Rita; Wei, Wei; Calabrese, Claudia; Tucci, Arianna; Ibáñez, Kristina; Ratnaike, Thiloka; Pitceathly, Robert D S; Bugiardini, Enrico; Quinlivan, R.; Hanna, Michael G.; Clement, Emma; Ashton, Emma; Sayer, John A.; Brennan, Paul M.; Josifova, Dragana; Izatt, Louise; Fratter, Carl; Nesbitt, Victoria; Barrett, Timothy; McMullen, Dominic J; Smith, Audrey; Deshpande, Charulata; Smithson, Sarah; Festenstein, Richard; Canham, Natalie; Caulfield, Mark J.; Houlden, Henry; Rahman, Shamima; Chinnery, Patrick F.

doi:10.1136/bmj-2021-066288

Cited by 44 publications

(55 citation statements)

References 48 publications

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“…Rare disease NUMTs in participants with mitochondrial DNA maintenance disorders. Participants with mitochondrial DNA maintenance disorders 78 were identified from the Genomic Medicine Centre exit questionnaire and from our previous analysis of participants with suspected mitochondrial disorders 79 . We also identified affected family members who had genome sequencing data available.…”

Section: Assessing Clinical Significancementioning

confidence: 99%

Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

Wei

Schon

Elgar

et al. 2022

Nature

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114

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DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event—the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation1–3. Here we analyse whole-genome sequences from 66,083 people—including 12,509 people with cancer—and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 104 births and once in every 103 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape.

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Section: Assessing Clinical Significancementioning

confidence: 99%

Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

Wei

Schon

Elgar

et al. 2022

Nature

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114

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“…As pathogenic mutations resulting in mitochondrial disease have been identified in over 300 genes, genetic screening is impractical at this time. In patients with suspected mitochondrial disease, whole genome sequencing is useful for diagnosis [ 124 ]. The decreasing cost and increasing use of whole genome sequencing for diagnostics will hopefully reduce the time to diagnosis and enable earlier treatment for mitochondrial disease patients in the future.…”

Section: Discussionmentioning

confidence: 99%

AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives

Hanaford

Cho

Nakai

2022

Orphanet J Rare Dis

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Mitochondrial diseases are a group of rare, heterogeneous diseases caused by gene mutations in both nuclear and mitochondrial genomes that result in defects in mitochondrial function. They are responsible for significant morbidity and mortality as they affect multiple organ systems and particularly those with high energy-utilizing tissues, such as the nervous system, skeletal muscle, and cardiac muscle. Virtually no effective treatments exist for these patients, despite the urgent need. As the majority of these conditions are monogenic and caused by mutations in nuclear genes, gene replacement is a highly attractive therapeutic strategy. Adeno-associated virus (AAV) is a well-characterized gene replacement vector, and its safety profile and ability to transduce quiescent cells nominates it as a potential gene therapy vehicle for several mitochondrial diseases. Indeed, AAV vector-based gene replacement is currently being explored in clinical trials for one mitochondrial disease (Leber hereditary optic neuropathy) and preclinical studies have been published investigating this strategy in other mitochondrial diseases. This review summarizes the preclinical findings of AAV vector-based gene replacement therapy for mitochondrial diseases including Leigh syndrome, Barth syndrome, ethylmalonic encephalopathy, and others.

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“…This leads us to advocate for a specialist MDT approach, in which high-throughput clinical scientist analysis is supplemented by additional clinical and bioinformatic oversight for undiagnosed cases. The advantage of such a service is further exemplified when comparing our work to a related study of WGS in PMDs, which relied on a researcher-led approach 18 . Of the 10 newly diagnosed patients overlapping with our study, seven were overlooked by the researcher-led strategy (see Supplementary Table 5 ).…”

Section: Discussionmentioning

confidence: 99%

Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing

Macken

Falabella²,

McKittrick³

et al. 2022

Nat Commun

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Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial ‘no primary findings’ (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk.

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Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study

Cited by 44 publications

References 48 publications

Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

AAV-vector based gene therapy for mitochondrial disease: progress and future perspectives

Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing

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