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

• Published in: Molecular genetics & genomic medicine Vol. 8; no. 9; pp. e1341 - n/a
• Main Authors: Morales‐Rosado, Joel A., Macke, Erica L., Cousin, Margot A., Oliver, Gavin R., Dhamija, Radhika, Klee, Eric W.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2020; John Wiley and Sons Inc; Wiley
• Subjects: Adult; Amino acid substitution; Amino acids; Ataxia; Atrophy; Best practice; bioinformatics; Cerebellar Ataxia - diagnostic imaging; Cerebellar Ataxia - genetics; Cerebellar Ataxia - pathology; Disruption; DNA-directed RNA polymerase; Dysarthria; Evaluation; Family medical history; Female; Gait; Gene expression; Gene sequencing; Genes; Genetic Testing - methods; Genetic Testing - standards; Genotype & phenotype; Heterozygosity; Humans; Laboratories; Magnetic resonance imaging; missense; Mutation, Missense; Neurodegenerative diseases; Original; Phenotype; Phenotypes; RNA polymerase; RNA Polymerase III - genetics; RNA Polymerase III - metabolism; RNA Splicing; Spasticity; Spinal cord; Splice junctions; Splicing; Transcription; variant interpretation; missense; splicing; bioinformatics; variant interpretation
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1341

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. The article highlights a POLR3A‐related adult‐onset spastic ataxia case and describe a novel dual‐class missense and splicing variant. Follow‐up RNA sequencing revealed a complex disruption leading to four RNA transcript products, each with different functional impacts.