A de novo C19orf12 heterozygous mutation in a patient with MPAN

Monfrini, Edoardo; Melzi, Valentina; Buongarzone, Gabriele; Franco, Giulia; Ronchi, Dario; Dilena, Robertino; Scola, Elisa; Vizziello, Paola; Bordoni, Andreina; Bresolin, Nereo; Comi, Giacomo Pietro; Corti, Stefania; Fonzo, Alessio Di

doi:10.1016/j.parkreldis.2017.12.025

Cited by 16 publications

(26 citation statements)

References 4 publications

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“…The C19orf12 (Gregory et al, 2019;Monfrini et al, 2018). So, the new evidence in the literature served to reclassify the result of the exome of this patient from uncertain to positive, facilitating genetic counseling for the proband and the family.…”

Section: Discussionmentioning

confidence: 96%

“…At the time of the original report, the only known mechanism of inheritance for Mitochondrial Membrane Protein Associated Neurodegeneration (MPAN) was autosomal recessive. But, after 2018 a number of cases with dominant MPAN were reported in subjects with a clinical‐radiological phenotype indistinguishable from the recessive ones but carrying variants located in the last exon of C19orf12 (Gregory et al, 2019; Monfrini et al, 2018). So, the new evidence in the literature served to reclassify the result of the exome of this patient from uncertain to positive, facilitating genetic counseling for the proband and the family.…”

Section: Discussionmentioning

confidence: 99%

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The odyssey of complex neurogenetic disorders: From undetermined to positive

Salinas

Vega

Marsili

et al. 2020

American J of Med Genetics Pt C

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The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology. K E Y W O R D S diagnostic odyssey, mosaicism, targeted gene panel sequencing, variants of unknown significance, whole exome sequencing 1 | INTRODUCTION Neurogenetic diseases encompass a vast group of entities with marked genetic and phenotypic heterogeneity. Nowadays, the process of establishing a diagnosis for this subset of neurological conditions requires extensive clinical, radiological, and genetic evaluations, often becoming a "diagnostic odyssey" for the patient and the family (Carmichael, Tsipis, Windmueller, Mandel, & Estrella, 2015). Next Generation Sequencing (NGS) has become a widely used tool for obtaining genetic diagnosis in clinical medicine (Might &

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

The odyssey of complex neurogenetic disorders: From undetermined to positive

Salinas

Vega

Marsili

et al. 2020

American J of Med Genetics Pt C

View full text Add to dashboard Cite

show abstract

“…To date, MPAN has been documented to follow an autosomal recessive pattern of inheritance, except in a few suspect cases (Monfrini et al, ). We provide three lines of evidence that suggest MPAN can also be caused by a heterozygous pathogenic sequence variant in C19orf12 on the basis of: 1) dominant inheritance exhibited by Family 18 and Family 748; 2) the manifestation of classic MPAN in 2 cases with de novo single mutations; and 3) a preponderance of heterozygous cases in our cohort with frameshift/premature stop or nonsense variants all clustering in the last exon.…”

Section: Discussionmentioning

confidence: 99%

Autosomal dominant mitochondrial membrane protein‐associated neurodegeneration (MPAN)

Gregory

Lotia

Jeong

et al. 2019

Molec Gen & Gen Med

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Background Mitochondrial membrane protein‐associated neurodegeneration (MPAN) is caused by pathogenic sequence variants in C19orf12 . Autosomal recessive inheritance has been demonstrated. We present evidence of autosomal dominant MPAN and propose a mechanism to explain these cases. Methods Two large families with apparently dominant MPAN were investigated; additional singleton cases of MPAN were identified. Gene sequencing and multiplex ligation‐dependent probe amplification were used to characterize the causative sequence variants in C19orf12 . Post‐mortem brain from affected subjects was examined. Results In two multi‐generation non‐consanguineous families, we identified different nonsense sequence variations in C19orf12 that segregate with the MPAN phenotype. Brain pathology was similar to that of autosomal recessive MPAN. We additionally identified a preponderance of cases with single heterozygous pathogenic sequence variants, including two with de novo changes. Conclusions We present three lines of clinical evidence to demonstrate that MPAN can manifest as a result of only one pathogenic C19orf12 sequence variant. We propose that truncated C19orf12 proteins, resulting from nonsense variants in the final exon in our autosomal dominant cohort, impair function of the normal protein produced from the non‐mutated allele via a dominant negative mechanism and cause loss of function. These findings impact the clinical diagnostic evaluation and counseling.

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“…However, Monfrini et al 2018 published a case report of a patient with MPAN who had a novel heterozygous pathogenic variant, c.265_266delAT (p.M89Gfs*12), in the C19orf12 . As the subject's pathogenic variant in this paper was de novo , the authors’ proposed a dominant‐negative mechanism leading to the clinical features in their patient (Monfrini et al, 2018 ). Shortly thereafter, Gregory et al 2019 published 18 heterozygous cases of MPAN from 19 families from the Oregon Health & Science University (OSHU) International NBIA Repository.…”

Section: Introductionmentioning

confidence: 98%

A De Novo case of autosomal dominant mitochondrial membrane protein‐associated neurodegeneration

Fraser

Koenig

Farach³

et al. 2021

Molec Gen & Gen Med

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Background Mitochondrial membrane protein‐associated neurodegeneration (MPAN) is a genetic neurodegenerative condition previously thought to be inherited only in an autosomal recessive pattern through biallelic pathogenic variants in C19orf12. Recent evidence has proposed that MPAN can also follow autosomal dominant forms of inheritance. We present a case of a de novo pathogenic variant in C19orf12 identified in a female with clinical features consistent with a diagnosis of MPAN, adding further evidence that the disease can be inherited in an autosomal dominant fashion. Methods A 17‐year‐old Hispanic female was born to non‐consanguineous healthy parents. She developed progressive muscle weakness and dystonia beginning when she was 12 years old. Trio, whole‐exome sequencing with mitochondrial genome sequencing, and deletion/duplication analysis of both nuclear and mitochondrial genomes was performed in December 2019. Results Whole‐exome sequencing analysis revealed a single de novo variant in C19orf12. The specific variant is c.256C>T (p.Q86X) located in exon 3. Conclusion Our clinical report provides further clinical evidence that MPAN can be inherited in an autosomal dominant or recessive fashion. The patient's age of onset and clinical symptoms are very similar to the previous patient published with this specific variant as well as others with heterozygous pathogenic variants in C19orf12 in Gregory et al. 2019. Our case report highlights the importance of considering both autosomal dominant and autosomal recessive version of MPAN with all patients demonstrating clinical features suggestive of MPAN.

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A de novo C19orf12 heterozygous mutation in a patient with MPAN

Abstract: The relevant ethical authorities approved the study and written informed consent was obtained from all involved subjects.

Cited by 16 publications

References 4 publications

The odyssey of complex neurogenetic disorders: From undetermined to positive

The odyssey of complex neurogenetic disorders: From undetermined to positive

Autosomal dominant mitochondrial membrane protein‐associated neurodegeneration (MPAN)

A De Novo case of autosomal dominant mitochondrial membrane protein‐associated neurodegeneration

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