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Case Reports
. 2020 Sep;8(9):e1341.
doi: 10.1002/mgg3.1341. Epub 2020 Jun 29.

Interpretation challenges of novel dual-class missense and splice-impacting variant in POLR3A-related late-onset hereditary spastic ataxia

Joel A Morales-Rosado  1   2 , Erica L Macke  1   2 , Margot A Cousin  1   2 , Gavin R Oliver  1   2 , Radhika Dhamija  3   4 , Eric W Klee  1   2   5
Affiliations
Case Reports

Interpretation challenges of novel dual-class missense and splice-impacting variant in POLR3A-related late-onset hereditary spastic ataxia

Joel A Morales-Rosado et al. Mol Genet Genomic Med. 2020 Sep.

Abstract

Background: RNA 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.

Methods: Whole-exome sequencing was performed in the proband and parents. Variants were confirmed by Sanger sequencing. RNA sequencing was performed to evaluate splicing implications.

Results: A 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.

Conclusion: The 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.

Keywords: bioinformatics; missense; splicing; variant interpretation.

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Conflict of interest statement

The authors have no conflict of interest to disclose.

Figures

Figure 1
Figure 1
Clinical information with proband's family history (a). MRI studies revealed uniform spinal cord atrophy (b and c). Brain MRI superior cerebellar peduncle hyperintensities were identified in the proband (d)
Figure 2
Figure 2
Sashimi plots of POLR3A from peripheral blood RNA sequencing data. The c.3593A>G exon‐intron junction location (a) shows two in‐frame transcripts (AT1 and AT2) and a third out‐of‐frame transcript (AT3). The c.1909+22G>A in intron 12 leads to an out‐of‐frame product (b) in 6%–7% of transcripts. Circle values represent the number of reads supporting the junction
See this image and copyright information in PMC

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