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

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.

SUBMITTER: Balicza P

PROVIDER: S-EPMC7577556 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Balicza Peter P Bencsik Renata R Lengyel Andras A Gal Aniko A Grosz Zoltan Z Csaban Dora D Rudas Gabor G Danics Krisztina K Kovacs Gabor G GG Molnar Maria Judit MJ

Neurology. Genetics 20200908 5

<h4>Objective</h4>Our aim was to study a Hungarian family with autosomal dominantly inherited neurodegeneration with brain iron accumulation (NBIA) with markedly different intrafamilial expressivity.<h4>Methods</h4>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 ...[more]

PMID: 33134513

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Project description:In all organisms, the majority of traits vary continuously between individuals. Explaining the genetic basis of quantitative trait variation requires comprehensively accounting for genetic and nongenetic factors as well as their interactions. The growth of microbial cells can be characterized by a lag duration, an exponential growth phase, and a stationary phase. Parameters that characterize these growth phases can vary among genotypes (phenotypic variation), environmental conditions (phenotypic plasticity), and among isogenic cells in a given environment (phenotypic variability). We used a high-throughput microscopy assay to map genetic loci determining variation in lag duration and exponential growth rate in growth rate-limiting and nonlimiting glucose concentrations, using segregants from a cross of two natural isolates of the budding yeast, Saccharomyces cerevisiae We find that some quantitative trait loci (QTL) are common between traits and environments whereas some are unique, exhibiting gene-by-environment interactions. Furthermore, whereas variation in the central tendency of growth rate or lag duration is explained by many additive loci, differences in phenotypic variability are primarily the result of genetic interactions. We used bulk segregant mapping to increase QTL resolution by performing whole-genome sequencing of complex mixtures of an advanced intercross mapping population grown in selective conditions using glucose-limited chemostats. We find that sequence variation in the high-affinity glucose transporter HXT7 contributes to variation in growth rate and lag duration. Allele replacements of the entire locus, as well as of a single polymorphic amino acid, reveal that the effect of variation in HXT7 depends on genetic, and allelic, background. Amplifications of HXT7 are frequently selected in experimental evolution in glucose-limited environments, but we find that HXT7 amplifications result in antagonistic pleiotropy that is absent in naturally occurring variants of HXT7 Our study highlights the complex nature of the genotype-to-phenotype map within and between environments.

Dataset Information

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

Publications

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

Similar Datasets

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