Medicine and Health Sciences Commons^™

Recessive Mutations In Polr1c Cause A Leukodystrophy By Impairing Biogenesis Of Rna Polymerase Iii., Isabelle Thiffault, Nicole I Wolf, Diane Forget, Kether Guerrero, Luan T. Tran, Karine Choquet, Mathieu Lavallée-Adam, Christian Poitras, Bernard Brais, Grace Yoon, Laszlo Sztriha, Richard I. Webster, Dagmar Timmann, Bart P. Van De Warrenburg, Jürgen Seeger, Alíz Zimmermann, Adrienn Máté, Cyril Goizet, Eva Fung, Marjo S. Van Der Knaap, Sébastien Fribourg, Adeline Vanderver, Cas Simons, Ryan J. Taft, John R. Yates, Benoit Coulombe, Geneviève Bernard

Manuscripts, Articles, Book Chapters and Other Papers

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first …

A Patient With Polymerase E1 Deficiency (Pole1): Clinical Features And Overlap With Dna Breakage/Instability Syndromes., Isabelle Thiffault, Carol Saunders, Janda Jenkins, Nikita Raje, Kristi Canty, Mukta Sharma, Lauren Grote, Holly I. Welsh, Emily Farrow, Greyson Twist, Neil Miller, David Zwick, Lee Zellmer, Stephen F. Kingsmore, Nicole P. Safina

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage, often leading to immunodeficiency, growth retardation and increased risk of malignancy.

CASE PRESENTATION: We performed exome sequencing on a girl with a suspected chromosome instability syndrome that manifested as growth retardation, microcephaly, developmental delay, dysmorphic features, poikiloderma, immune deficiency with pancytopenia, and myelodysplasia. She was homozygous for a previously reported splice variant, c.4444 + 3A > G in the POLE1 gene, which encodes the catalytic subunit of DNA polymerase E.

CONCLUSION: This is the second family with POLE1-deficency, with the affected individual demonstrating a more …

Oseltamivir-Warfarin Interaction In Hypoplastic Left Heart Syndrome: Case Report And Review., Jonathan B. Wagner, Susan M. Abdel-Rahman

Manuscripts, Articles, Book Chapters and Other Papers

An 8-year-old boy with hypoplastic left heart syndrome with a previous history of thrombosis within the inferior vena cava receiving stable warfarin dosing for anticoagulation was diagnosed with influenza B. He was subsequently placed on oseltamivir therapy according to the Centers for Disease Control and Prevention clinical practice guidelines. During the hospitalization, his international normalized ratio steadily increased to supratherapeutic levels and returned to baseline after discontinuation of oseltamivir therapy. This case represents a drug-drug interaction that has not been previously reported in children or adolescents. An extensive review of the pharmacokinetic and pharmacodynamic literature did not uncover a definitive …

Cyp2d7 Sequence Variation Interferes With Taqman Cyp2d6 (*) 15 And (*) 35 Genotyping., Amanda K. Riffel, Mehdi Dehghani, Toinette Hartshorne, Kristen C. Floyd, J Steven Leeder, Kevin P. Rosenblatt, Andrea Gaedigk

Manuscripts, Articles, Book Chapters and Other Papers

TaqMan™ genotyping assays are widely used to genotype CYP2D6, which encodes a major drug metabolizing enzyme. Assay design for CYP2D6 can be challenging owing to the presence of two pseudogenes, CYP2D7 and CYP2D8, structural and copy number variation and numerous single nucleotide polymorphisms (SNPs) some of which reflect the wild-type sequence of the CYP2D7 pseudogene. The aim of this study was to identify the mechanism causing false-positive CYP2D6 (*) 15 calls and remediate those by redesigning and validating alternative TaqMan genotype assays. Among 13,866 DNA samples genotyped by the CompanionDx® lab on the OpenArray platform, 70 samples were identified as …