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
Author Information
Avi Fellner: Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel. ORCID
Alexander Lossos: Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Elena Kogan: Department of Neurology, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
Zohar Argov: Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Claudia Gonzaga-Jauregui: Regeneron Genetics Center, Tarrytown, NY, USA.
Alan R Shuldiner: Regeneron Genetics Center, Tarrytown, NY, USA.
Malak Darawshe: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Lily Bazak: Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
Gabriel Lidzbarsky: Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
Noam Shomron: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Lina Basel-Salmon: Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
Yael Goldberg: Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
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.
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