Next generation sequencing in family with MNGIE syndrome associated to optic atrophy: Novel homozygous POLG mutation in the C-terminal sub-domain leading to mtDNA depletion

Felhi, Rahma; Sfaihi, Lamia; Charif, Majida; Desquiret-Dumas, Valérie; Bris, Céline; Goudenège, David; Keskes, Leila; Hachicha, M.; Bonneau, Dominique; Procaccio, Vincent; Reynier, Pascal; Amati‐Bonneau, Patrizia; Lenaers, Guy; Fakhfakh, Faïza

doi:10.1016/j.cca.2018.11.003

Cited by 16 publications

(11 citation statements)

References 44 publications

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“…The Qubit dsDNA High Sensitivity Assay Kit (Thermo Fisher Scientific) was used to quantify DNA for next-generation sequencing (NGS) library construction. Library preparation for each sample was performed using Ion AmpliSeq technologies, and all sequencing data were processed using a dedicated bioinformatics pipeline, which includes three steps: variant calling, annotation, and prioritization (12,27). The calling module uses a consensus-based approach and combines the prediction of six callers (VariantCaller included with the Torrent Suite, GATK Unified Genotyper, VarScan2, SNVer, LoFreq, and Platypus).…”

Section: Ion Panel Design Library Preparation and Sequencingmentioning

confidence: 99%

Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

et al. 2021

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Advances in next-generation sequencing (NGS) facilitate the diagnosis of genetic disorders. To evaluate its use for the molecular diagnosis of inherited optic neuropathy (ION), a blinding disease caused by the degeneration of retinal ganglion cells, we performed genetic analysis using targeted NGS of 22 already known and candidate genes in a cohort of 1,102 affected individuals. The panel design, library preparation, and sequencing reactions were performed using the Ion AmpliSeq technology. Pathogenic variants were detected in 16 genes in 245 patients (22%), including 186 (17%) and 59 (5%) dominant and recessive cases, respectively. Results confirmed that OPA1 variants are responsible for the majority of dominant IONs, whereas ACO2 and WFS1 variants are also frequently involved in both dominant and recessive forms of ION. All pathogenic variants were found in genes encoding proteins involved in the mitochondrial function, highlighting the importance of mitochondria in the survival of retinal ganglion cells.

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Section: Ion Panel Design Library Preparation and Sequencingmentioning

confidence: 99%

Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

et al. 2021

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“…Thus, thymidine phosphorylase deficiency should be suspected in cases where gastrointestinal and neurological involvement coexist, particularly where there is leukoencephalopathy on MRI or abnormalities of ocular motility [ [122]. Another case study, reports two patients with a MNGIE-like phenotype exhibiting optic atrophy associated with a novel POLG mutation affecting the C-terminal sub-domain of the protein [123].…”

Section: Diagnosis Diagnostic Challengesmentioning

confidence: 99%

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Pacitti¹,

Levene²,

Garone³

et al. 2020

Prime Archives in Genetics

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Mitochondrialneurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterised by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.

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“…Sequencing data were processed using our own dedicated bioinformatics pipeline, as described elsewhere. 20 Candidate pathogenic variants were validated by Sanger sequencing, and their segregation was assessed in DNAs from other members of the families, when available.…”

Section: Genetic Analysismentioning

confidence: 99%

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

et al. 2020

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ObjectiveTo improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.MethodsExonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.ResultsWe identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.ConclusionsOur results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.

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Next generation sequencing in family with MNGIE syndrome associated to optic atrophy: Novel homozygous POLG mutation in the C-terminal sub-domain leading to mtDNA depletion

Cited by 16 publications

References 44 publications

Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy

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