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.APP=amyloid precursor protein; MLPA=multiplex ligation-dependent
probe amplification; MPAN=mitochondrial membrane protein-associated neurodegeneration;
NBIA=neurodegeneration with brain iron accumulation; WGS=whole-genome sequencing
