Leigh map: A novel computational diagnostic resource for mitochondrial disease

Rahman, Joyeeta; Noronha, Alberto; Thiele, Ines; Rahman, Shamima

doi:10.1002/ana.24835

Cited by 68 publications

(64 citation statements)

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“…Leigh syndrome (MIM# 256000) is the most common pediatric presentation of mitochondrial disease (Lake, Compton, Rahman, & Thorburn, ). It can be caused by mutations in over 85 genes encoding proteins required for the activity of either oxidative phosphorylation (OXPHOS) or pyruvate dehydrogenase (PDH) complexes (Lake et al, ; J. Rahman, Noronha, Thiele, & Rahman, ). Here we report a patient diagnosed with Leigh‐like syndrome, characterized by persistent lactic acidosis, seizures, spastic quadriplegia, and neuroradiological abnormalities (Table S1).…”

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confidence: 99%

A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein‐truncating variant

et al. 2019

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Leigh syndrome is a mitochondrial disease caused by pathogenic variants in over 85 genes. Whole exome sequencing of a patient with Leigh‐like syndrome identified homozygous protein‐truncating variants in two genes associated with Leigh syndrome; a reported pathogenic variant in PDHX (NP_003468.2:p.(Arg446*)), and an uncharacterized variant in complex I (CI) assembly factor TIMMDC1 (NP_057673.2:p.(Arg225*)). The TIMMDC1 variant was predicted to truncate 61 amino acids at the C‐terminus and functional studies demonstrated a hypomorphic impact of the variant on CI assembly. However, the mutant protein could still rescue CI assembly in TIMMDC1 knockout cells and the patient's clinical phenotype was not clearly distinct from that of other patients with the same PDHX defect. Our data suggest that the hypomorphic effect of the TIMMDC1 protein‐truncating variant does not constitute a dual diagnosis in this individual. We recommend cautious assessment of variants in the C‐terminus of TIMMDC1 and emphasize the need to consider the caveats detailed within the American College of Medical Genetics and Genomics (ACMG) criteria when assessing variants.

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confidence: 99%

A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein‐truncating variant

et al. 2019

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“…The situation becomes more complicated with the realisation that a single gene defect may give rise to a multitude of different recognisable clinical syndromes/ phenotypes and that sometimes affected siblings who share the same mutation may present differently, suggesting a role for other genetic and/or environmental modifiers. Even more puzzlingly, unrelated individuals with pathogenic mutations in different genes may share the same clinical phenotype (8). This presents a diagnostic challenge in the clinic when assessing an individual with suspected disease who may present with clinical features that are not specific enough to indicate a single gene defect or clinical syndrome, and also when faced with the task of having to deliver accurate prognostic information to affected individuals and families (9).…”

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confidence: 99%

Natural history of mitochondrial disorders: a systematic review

Keshavan

Rahman

2018

Essays in Biochemistry

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The natural history of a disease defines the age of onset, presenting features, clinical phenotype, morbidity and mortality outcomes of disease that is unmodified by treatments. A clear understanding of the natural history of mitochondrial disorders is essential for establishing genotype-phenotype-prognosis correlations. We performed a systematic review of the reported natural history of mitochondrial disease by searching the literature for all published natural history studies containing at least 20 individuals. We defined a phenotype as 'common' if it was observed in ≥30% of cases in a study, thereby highlighting common and uncommon phenotypes for each disorder. Thirty-seven natural history studies were identified encompassing 29 mitochondrial disease entities. Fifty-nine percent of disorders had an onset before 18 months and 81% before 18 years. Most disorders had multisystemic involvement and most often affected were the central nervous system, eyes, gastrointestinal system, skeletal muscle, auditory system and the heart. Less frequent involvement was seen for respiratory, renal, endocrine, hepatic, haematological and genitourinary systems. Elevated lactate was the most frequent biochemical abnormality, seen in 72% of disorders. Age of death was <1 y in 13% of disorders, <5 y in 57% and <10 y in 74%. Disorders with high mortality rates were generally associated with earlier deaths. The most robust indicators of poor prognosis were early presentation of disease and truncating mutations. A thorough knowledge of natural history has helped to redefine diagnostic criteria for classical clinical syndromes and to establish a clinical baseline for comparison in single-arm clinical trials of novel therapies.

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“…We harnessed this information to determine whether phenomics could be used to create a computational diagnostic resource for mitochondrial disease, to be used in concert with next‐generation sequencing methods. We initially used Leigh syndrome as a prototype paediatric mitochondrial disorder and showed that use of the ‘Leigh Map’ computational resource placed the correct disease gene amongst the top‐ranked genes in 80% of test cases [134].…”

Section: Approach To Diagnosismentioning

confidence: 99%