[Pedigree analysis of C19ORF12 p.Asp18Tyr mutation in a family with mitochondrial membrane protein associated neurodegeneration].

Objective: To explore the clinical features and analyze the chromosome 19 open reading frame 12(C19ORF12) gene mutation of a family with mitochondrial membrane protein-associated neurodegeneration (MPAN). Methods: The pedigree diagnosed as neurodegeneration with brain iron accumulation (NBIA) in Henan Provincial People's Hospital in May 2018 was collected, and clinical data of the patients in this family was further analyzed. Furthermore, whole exome sequencing (WES) was employed to identify the disease-causing genes. Subsequently, the pathogenic mutation was validated by Sanger sequencing. Results: We identified 3 brothers, born of consanguineous Chinese parents. These patients were thought to carry autosomal recessive genes. The age of the onset ranged from 8 to 10 years old. All of the patients exhibited a chronic course, then got worse progressively. Parkinsonism was the first symptom. Other clinical features included cognitive decline, ataxia, gait abnormality, dysarthria and spastic paraplegia. All cases showed hypo-intensity in bilateral substantia nigra and globus pallidus on T(2)WI, FLAIR and SWI of MRI. However, the "eye-of-the-tiger sign" , which was commonly found in pantothenate kinase-associated neurodegeneration was absent. Further findings included cerebellar atrophy (all 3 patients) and the atrophy of temporal lobe (only one brother of the proband). The homozygous mutation c.52G>T (p.Asp18Tyr) was found through WES and Sanger sequencing. The proband's mother was heterozygous. This novel mutation was not reported in mutation database. Consequently, the pathogenic mutation in C19ORF12 gene (exon2, c.2327C>T, p.P776L) was identified from the patients according to the American College of Medical Genetics and Genomics (ACMG) guideline. The final diagnosis of the family was MPAN. Conclusions: We successfully identify a novel p.Asp18Tyr mutation in a family with MPAN. Our finding enriches the known MPAN mutation types and provides evidence for further research.

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