TY - JOUR
T1 - Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome
AU - Wambach, Jennifer A.
AU - Wegner, Daniel J.
AU - Patni, Nivedita
AU - Kircher, Martin
AU - Willing, Marcia C.
AU - Baldridge, Dustin
AU - Xing, Chao
AU - Agarwal, Anil K.
AU - Vergano, Samantha A.Schrier
AU - Patel, Chirag
AU - Grange, Dorothy K.
AU - Kenney, Amy
AU - Najaf, Tasnim
AU - Nickerson, Deborah A.
AU - Bamshad, Michael J.
AU - Cole, F. Sessions
AU - Garg, Abhimanyu
N1 - Funding Information:
The authors thank the families and referring physicians for participation in these studies. The authors thank Hillary Heins and Ping Yang of Washington University for their assistance with DNA isolation and preparation. The authors also thank Pei-Yun Tseng, Mary Tunison, and Claudia Quittner of UT Southwestern for help with DNA isolation, RNA analysis, and nursing support. The authors thank GeneDx for sharing VCF and BAM files from a non-diagnostic, clinician-referred, whole exome for research analysis performed at Washington University School of Medicine. Some sequencing was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute grant HG006493 to Debbie Nickerson, Michael Bamshad, and Suzanne Leal. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health . The authors thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison; a full list of contributing groups can be found at http://exac.broadinstitute.org/about . This work was also supported by grants from the National Institutes of Health ( K08 HL105891 [J.A.W.], K12 HL120002 [F.S.C.], R01 HL065174 [F.S.C.], R21/33 HL120760 [F.S.C.], R01-DK105448 [A.G., A.K.A.], CTSA grants UL1RR024982 , UL1TR001105 to UT Southwestern Medical Center, and U54 HG006493 to the University of Washington Center for Mendelian Genomics [D.A.N., M.J.B.]), the Children’s Discovery Institute (F.S.C.) and University of Texas Southwestern Medical Foundation (A.G.).
Publisher Copyright:
© 2018 American Society of Human Genetics
PY - 2018/12/6
Y1 - 2018/12/6
N2 - 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.
AB - 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.
KW - POLR3A, RNA polymerase 3A
KW - Wiedemann-Rautenstrauch syndrome
KW - neonatal progeroid syndrome
UR - http://www.scopus.com/inward/record.url?scp=85056863617&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.10.010
DO - 10.1016/j.ajhg.2018.10.010
M3 - Article
C2 - 30414627
AN - SCOPUS:85056863617
SN - 0002-9297
VL - 103
SP - 968
EP - 975
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -