Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability

Peter Balicza; Renata Bencsik; Andras Lengyel; Aniko Gal; Zoltan Grosz; Dora Csaban; Gabor Rudas; Krisztina Danics; Gabor G Kovacs; Maria Judit Molnar

doi:10.1212/NXG.0000000000000515

Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability

Neurol Genet. 2020 Sep 8;6(5):e515. doi: 10.1212/NXG.0000000000000515. eCollection 2020 Oct.

Authors

Affiliation

¹ Institute of Genomic Medicine and Rare Diseases (P.B., R.B., A.L., A.G., Z.G., D.C., M.J.M.), Semmelweis University, Budapest, Hungary; Neurology Outpatient Clinic (A.L.), General Medical Clinic, Motala Hospital, Sweden; Department of Neuroradiology (G.R.), and Department of Forensic and Insurance Medicine (K.D.), Semmelweis University, Budapest, Hungary; Tanz Centre for Research in Neurodegenerative Disease (G.G.K.), and Department of Laboratory Medicine and Pathobiology (G.G.K.), University of Toronto; and Laboratory Medicine Program (G.G.K.), University Health Network, Toronto, Canada.

Abstract

Objective: Our aim was to study a Hungarian family with autosomal dominantly inherited neurodegeneration with brain iron accumulation (NBIA) with markedly different intrafamilial expressivity.

Methods: Targeted sequencing and multiplex ligation-dependent probe amplification (MLPA) of known NBIA-associated genes were performed in many affected and unaffected members of the family. In addition, a trio whole-genome sequencing was performed to find a potential explanation of phenotypic variability. Neuropathologic analysis was performed in a single affected family member.

Results: The clinical phenotype was characterized by 3 different syndromes-1 with rapidly progressive dystonia-parkinsonism with cognitive deterioration, 1 with mild parkinsonism associated with dementia, and 1 with predominantly psychiatric symptoms along with movement disorder. A heterozygous stop-gain variation in the C19Orf12 gene segregated with the phenotype. Targeted sequencing of all known NBIA genes, and MLPA of PLA2G6 and PANK2 genes, as well as whole-genome sequencing in a trio from the family, revealed a unique constellation of oligogenic burden in 3 NBIA-associated genes (C19Orf12 p.Trp112Ter, CP p.Val105PhefsTer5, and PLA2G6 dup(ex14)). Neuropathologic analysis of a single case (39-year-old man) showed a complex pattern of alpha-synucleinopathy and tauopathy, both involving subcortical and cortical areas and the hippocampus.

Conclusions: Our study expands the number of cases reported with autosomal dominant mitochondrial membrane protein-associated neurodegeneration and emphasizes the complexity of the genetic architecture, which might contribute to intrafamilial phenotypic variability.