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Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability.
Balicza, Peter; Bencsik, Renata; Lengyel, Andras; Gal, Aniko; Grosz, Zoltan; Csaban, Dora; Rudas, Gabor; Danics, Krisztina; Kovacs, Gabor G; Molnar, Maria Judit.
Afiliação
  • Balicza P; 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 M
  • Bencsik R; 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 M
  • Lengyel A; 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 M
  • Gal A; 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 M
  • Grosz Z; 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 M
  • Csaban D; 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 M
  • Rudas G; 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 M
  • Danics K; 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 M
  • Kovacs GG; 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 M
  • Molnar MJ; 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 M
Neurol Genet ; 6(5): e515, 2020 Oct.
Article em En | MEDLINE | ID: mdl-33134513
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.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article