Case Report: Identification of a De novo C19orf12 Variant in a Patient With Mitochondrial Membrane Protein-Associated Neurodegeneration

Yue Yang, Shijie Zhang, Wenming Yang, Taohua Wei, Wenjie Hao, Ting Cheng, Jiuxiang Wang, Wei Dong, Nannan Qian, Yue Yang, Shijie Zhang, Wenming Yang, Taohua Wei, Wenjie Hao, Ting Cheng, Jiuxiang Wang, Wei Dong, Nannan Qian

Abstract

Background: Mitochondrial membrane protein-associated neurodegeneration (MPAN) mostly arises as an autosomal recessive disease and is caused by variants in the chromosome 19 open reading frame 12 (C19orf12) gene. However, a few C19orf12 monoallelic truncating de novo variants have been reported and segregated as autosomal dominant traits in some cases. Methods: We performed whole-exome sequencing and analyzed genes related to neurodegeneration associated with brain iron accumulation for pathogenic variants. The identified variants were confirmed by Sanger sequencing and tested using in silico tools. Results: The patient had an onset of depression at the age of 22 years, which rapidly progressed to severe dystonia, dementia, and bladder and bowel incontinence. Neuroimaging showed hypointensity in the substantia nigra and the globus pallidum, with additional frontotemporal atrophy. Genetic analysis revealed a single complex de novo variant [c.336_338delinsCACA (p.Trp112CysfsTer40)] in the C19orf12 gene. Conclusion: This study enriches the genetic spectrum and clinical features of C19orf12 variants and provides additional evidence of the variable inheritance pattern of MPAN.

Keywords: C19orf12; de novo variant; iron accumulation; mitochondrial membrane protein–associated neurodegeneration; whole-exome sequencing.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Yang, Zhang, Yang, Wei, Hao, Cheng, Wang, Dong and Qian.

Figures

FIGURE 1
FIGURE 1
Clinical characteristics and mutation analysis of the family in this study. (A) Pedigree of the family in this study. Black symbol denotes the proband. (B) Brain MRI results: red arrows show hypointensity in the substantia nigra and globus pallidum along with additional frontotemporal atrophy. (C) Sanger sequencing results of the C19orf12 gene: red arrows indicate the locations of the mutations. (D)C19orf12 variants in the MPAN proband and frequency diagram of protein mutations. The locations of the W112 and D114 sites are indicated via red arrows.
FIGURE 2
FIGURE 2
Representation of MPAN-related C19orf12 variants. The variants shown above the gene structure are monoallelic, and those shown below are biallelic. The variant reported in this study is shown in bold.

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