Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome

Jennifer A. Wambach, Daniel J. Wegner, Nivedita Patni, Martin Kircher, Marcia C. Willing, Dustin Baldridge, Chao Xing, Anil K Agarwal, Samantha A.Schrier Vergano, Chirag Patel, Dorothy K. Grange, Amy Kenney, Tasnim Najaf, Deborah A. Nickerson, Michael J. Bamshad, F. Sessions Cole, Abhimanyu Garg

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is a rare disorder of unknown etiology. It has been proposed to be autosomal-recessive and is characterized by variable clinical features, such as intrauterine growth restriction and poor postnatal weight gain, characteristic facial features (triangular appearance to the face, convex nasal profile or pinched nose, and small mouth), widened fontanelles, pseudohydrocephalus, prominent scalp veins, lipodystrophy, and teeth abnormalities. A previous report described a single WRS patient with bi-allelic truncating and splicing variants in POLR3A. Here we present seven additional infants, children, and adults with WRS and bi-allelic truncating and/or splicing variants in POLR3A. POLR3A, the largest subunit of RNA polymerase III, is a DNA-directed RNA polymerase that transcribes many small noncoding RNAs that regulate transcription, RNA processing, and translation. Bi-allelic missense variants in POLR3A have been associated with phenotypes distinct from WRS: hypogonadotropic hypogonadism and hypomyelinating leukodystrophy with or without oligodontia. Our findings confirm the association of bi-allelic POLR3A variants with WRS, expand the clinical phenotype of WRS, and suggest specific POLR3A genotypes associated with WRS and hypomyelinating leukodystrophy.

Original languageEnglish (US)
Pages (from-to)968-975
Number of pages8
JournalAmerican Journal of Human Genetics
Volume103
Issue number6
DOIs
StatePublished - Dec 6 2018

Keywords

  • POLR3A, RNA polymerase 3A
  • Wiedemann-Rautenstrauch syndrome
  • neonatal progeroid syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Vergano, S. A. S., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., & Garg, A. (2018). Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome. American Journal of Human Genetics, 103(6), 968-975. https://doi.org/10.1016/j.ajhg.2018.10.010