Objective: Establish novel molecular predictors of phenotypic variation using screening of genomic, transcriptomic, mitochondrial, microbiome, and clinical features.

Background: Pantothenate Kinase Associated Neurodegeneration (PKAN), also called NBAI1, an autosomal recessive disorder affecting 1-2 subjects per million worldwide, causes childhood onset dystonia, dysphagia, bradykinesia, chorea and parkinsonism. PKAN shows variability in symptoms, severity, age of onset, rate of progression and >50 causal mutations in PANK2. In the southwest Dominican Republic, the prevalence is much higher with >1 per 1,000. Over the past decade we established 4 distinct phenotypes in the DR (65 PKAN subjects c.680A>G, except for one family with compound heterozygosity), including oromandibular, glossopharyngeal, appendicular, and low expression.  Using molecular and clinical measures, we sought to establish phenotypic predictors.

Method: Whole exome sequencing (45 PKAN subjects and 50 first-degree relative carriers and non-carriers), whole transcriptome profiling of salivary microRNA, mitochondrial haplotype, and oral microbiome analysis were performed. We screened mitochondrial and nuclear DNA variant data of >30 genes involved in pantothenate and coenzyme A metabolism, other NBIA syndromes, dystonia, Parkinson’s and Wilson’s disease. These molecular measures were examined for associations with neurologic, phenotypic, neurocognitive, medical, and metabolic outcomes.

Results: Genetically, screening of mitochondrial and nuclear DNA variant data failed to reveal any systematic patterns that differentiated the phenotypic clusters. Examination of more than 300 salivary microRNAs revealed robust positive and negative correlations between a subset of microRNAs and specific demographic, clinical, and behavioral phenotypes. These included miRNAs associated with the age of onset, balance, UPDRS, UDRS or PKAN scores, tremor amplitude, and BMI.  A secondary analysis also identified a set of microRNA and clinical features that strongly distinguished subjects in the different phenotypic groups. Examination of the oral microbiome data also revealed alterations in the different phenotypic clusters.

Conclusion: Whole transcriptome profiling of salivary microRNA and the oral microbiome may serve as a novel molecular tool to complement functional assessments in PKAN.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/comprehensive-screening-of-genetic-genomic-mitochondrial-and-microbiome-associations-with-phenotypic-measures-in-the-dominican-republic-pkan-cohort/