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

TitleBi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome.
Publication TypeJournal Article
Year of Publication2018
AuthorsWambach, JA, Wegner, DJ, Patni, N, Kircher, M, Willing, MC, Baldridge, D, Xing, C, Agarwal, AK, Vergano, SASchrier, Patel, C, Grange, DK, Kenney, A, Najaf, T, Nickerson, DA, Bamshad, MJ, F Cole, S, Garg, A
JournalAm J Hum Genet
Volume103
Issue6
Pagination968-975
Date Published2018 Dec 06
ISSN1537-6605
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.

DOI10.1016/j.ajhg.2018.10.010
Alternate JournalAm. J. Hum. Genet.
PubMed ID30414627
PubMed Central IDPMC6288318
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
UL1 TR001105 / TR / NCATS NIH HHS / United States
R01 HL065174 / HL / NHLBI NIH HHS / United States
R21 HL120760 / HL / NHLBI NIH HHS / United States
UL1 RR024982 / RR / NCRR NIH HHS / United States
K08 HL105891 / HL / NHLBI NIH HHS / United States
R33 HL120760 / HL / NHLBI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 DK105448 / DK / NIDDK NIH HHS / United States