POLR3A-Related Disorder Presenting with Late-Onset Dystonia and Spastic Paraplegia.
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ABSTRACT:
SUBMITTER: de Assis Pereira Matos PCA
PROVIDER: S-EPMC7197309 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
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<i>POLR3A</i>-Related Disorder Presenting with Late-Onset Dystonia and Spastic Paraplegia.
de Assis Pereira Matos Paula Camila Alves PCA Gama Maria Thereza Drumond MTD Bezerra Márcio Luiz Escórcio MLE da Rocha Antônio José AJ Barsottini Orlando G P OGP Pedroso José Luiz JL
Movement disorders clinical practice 20200418 4
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Project description:BackgroundRNA polymerase III (Pol III)-related disorders are autosomal recessive neurodegenerative disorders caused by variants in POLR3A or POLR3B. Recently, a novel phenotype of adult-onset spastic ataxia was identified in individuals with the c.1909+22G>A POLR3A variant in compound heterozygosity.MethodsWhole-exome sequencing was performed in the proband and parents. Variants were confirmed by Sanger sequencing. RNA sequencing was performed to evaluate splicing implications.ResultsA 42-year-old female was evaluated for unexplained neurological findings with a slow progressive decline in gait and walking speed since adolescence. WES revealed a novel missense variant (c.3593A>C, p.Lys1198Arg) in exon 27 of POLR3A in compound heterozygosity with the c.1909+22G>A variant. Summary of previously reported clinical features from individuals with pathogenic biallelic alterations in POLR3A and adult-onset phenotype is consistent with our findings. RNA analysis revealed c.3593A>G drives the production of four RNA transcript products each with different functional impacts.ConclusionThe novel dual-class c.3593A>C variant in POLR3A causes an amino acid substitution and complex disruption of splicing. Our report supports the need to investigate variants near splice junctions for proper interpretation. Current interpretation guidelines need to address best practices for inclusion of predicted or measured transcriptional disruption pending functional activity or reliable transcript abundance estimates.
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