Two intronic cis-acting variants in both alleles of the POLR3A gene cause progressive spastic ataxia with hypodontia

Avi Fellner*, Alexander Lossos, Elena Kogan, Zohar Argov, Claudia Gonzaga-Jauregui, Alan R. Shuldiner, Malak Darawshe, Lily Bazak, Gabriel Lidzbarsky, Noam Shomron, Lina Basel-Salmon, Yael Goldberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

POLR3A encodes the largest subunit of the DNA-dependent RNA polymerase III. Pathogenic variants in this gene are associated with dysregulation of tRNA production and other non-coding RNAs. POLR3A-related disorders include variable phenotypes. The genotype–phenotype correlation is still unclear. Phenotypic analysis and exome sequencing were performed in four affected siblings diagnosed clinically with hereditary spastic ataxia, two healthy siblings and their unaffected mother. All four affected siblings (ages 46–55) had similar clinical features of early childhood-onset hypodontia and adolescent-onset progressive spastic ataxia. None had progeria, gonadal dysfunction or dysmorphism. All affected individuals had biallelic POLR3A pathogenic variants composed by two cis-acting intronic splicing-altering variants, c.1909 + 22G > A and c.3337–11 T > C. The two healthy siblings had wild-type alleles. The mother and another unaffected sibling were heterozygous for the allele containing both variants. This is the first report addressing the clinical consequence associated with homozygosity for a unique pathogenic intronic allele in the POLR3A gene. This allele was previously reported in compound heterozygous combinations in patients with Wiedemann-Rautenstrauch syndrome, a severe progeroid POLR3A-associated phenotype. We show that homozygosity for this allele is associated with spastic ataxia with hypodontia, and not with progeroid features. These findings contribute to the characterization of genotype–phenotype correlation in POLR3A-related disorders.

Original languageEnglish
Pages (from-to)713-718
Number of pages6
JournalClinical Genetics
Volume99
Issue number5
DOIs
StatePublished - May 2021

Keywords

  • Hypodontia
  • Intronic
  • POLR3A
  • genotype
  • phenotype
  • spastic ataxia

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