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Am J Hum Genet. 2018 Dec 6;103(6):968-975. doi: 10.1016/j.ajhg.2018.10.010. Epub 2018 Nov 7.

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

Author information

1
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; St. Louis Children's Hospital, St. Louis, MO 63110, USA. Electronic address: wambachj@wustl.edu.
2
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; St. Louis Children's Hospital, St. Louis, MO 63110, USA.
3
Department of Pediatrics and Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA.
4
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
5
McDermott Center for Human Growth and Development, Department of Bioinformatics and Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX 75390, USA.
6
Division of Nutrition Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
7
Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
8
Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.
9
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA; St. Louis Children's Hospital, St. Louis, MO 63110, USA; Fetal Care Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
10
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
11
Division of Nutrition Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: abhimanyu.garg@utsouthwestern.edu.

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.

KEYWORDS:

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

PMID:
30414627
PMCID:
PMC6288318
[Available on 2019-06-06]
DOI:
10.1016/j.ajhg.2018.10.010

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