A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families

Human Mutation
Danielle C KimbleSettara C Chandrasekharappa

Abstract

Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two-thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity. Pathogenicity of the 18 novel missense variants was analyzed functionally by determining the ability of the mutant cDNA to improve the survival of a FANCA-null cell line when treated with MMC. Overexpressed pathogenic missense variants were found to reside in the cytoplasm, and nonpathogenic in the nucleus. RNA analysis demonstrated that two variants (c.522G > C and c.1565A > G), predicted to encode missense variants, which were determined to be nonpathogenic by a functional assay, caused skipping of exons 5 and 16, respectively, and are most likely pathogenic. We report 48 novel FANCA sequence variants. Defining both variants in a large patient cohort is a major step toward cataloging all FANCA variants, and permitti...Continue Reading

References

Jan 1, 1978·Scandinavian Journal of Thoracic and Cardiovascular Surgery·K SkagenK H Olesen
Nov 1, 1996·Nature Genetics·J R Lo Ten FoeH Joenje
Nov 1, 1996·Nature Genetics·UNKNOWN Fanconi anaemia/Breast cancer consortium
Dec 16, 1997·Proceedings of the National Academy of Sciences of the United States of America·O LevranA D Auerbach
Aug 26, 1998·Human Mutation·O LevranA D Auerbach
Oct 16, 1999·American Journal of Human Genetics·N V MorganC G Mathew
May 10, 2001·Proceedings of the National Academy of Sciences of the United States of America·A J TippingC G Mathew
Apr 23, 2002·Nature Reviews. Genetics·Luca CartegniAdrian R Krainer
Oct 24, 2002·Blood·Philip S RosenbergBlanche P Alter
Oct 24, 2002·Blood·David I KutlerArleen D Auerbach
Nov 22, 2002·Human Molecular Genetics·Daiki AdachiTakayuki Yamashita
Jan 15, 2003·Archives of Otolaryngology--head & Neck Surgery·David I KutlerBhuvanesh Singh
Oct 11, 2007·Human Mutation·Najim AmezianeHans Joenje
Apr 16, 2009·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Nabil N MoghrabiC Sue Richards
Jul 23, 2009·Mutation Research·Arleen D Auerbach
Jan 18, 2011·Nature Genetics·Yonghwan KimAgata Smogorzewska
Jan 18, 2013·Nature·Molly C Kottemann, Agata Smogorzewska
Apr 25, 2013·Blood·Settara C ChandrasekharappaUNKNOWN NISC Comparative Sequencing Program
Jan 17, 2015·Cell·Anderson T Wang, Agata Smogorzewska
Sep 16, 2015·Cold Spring Harbor Symposia on Quantitative Biology·Stephen C WestHaley D M Wyatt
Mar 31, 2016·American Journal of Medical Genetics. Part a·Blanche P Alter, Neelam Giri
Feb 22, 2017·Cell·Georgios I KarrasSusan Lindquist
Jul 12, 2017·The Journal of Clinical Investigation·Kerstin KniesDetlev Schindler

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Citations

Nov 19, 2018·Transplant Infectious Disease : an Official Journal of the Transplantation Society·Magda Eline Guerrart PortugalCassius Carvalho Torres-Pereira
Sep 20, 2019·Human Genetics·Xi YangYanhua Wu
Oct 7, 2019·Journal of Medical Genetics·Massimo BoglioloJordi Surralles
Feb 28, 2020·Blood·Moonjung JungSettara C Chandrasekharappa
Jul 8, 2020·International Journal of Molecular Sciences·Valentino BezzerriMarco Cipolli
Nov 12, 2020·Cold Spring Harbor Molecular Case Studies·Francis P LachAgata Smogorzewska
May 8, 2021·Molecular Genetics & Genomic Medicine·Ashley S ThompsonSadia Rehman
May 14, 2021·Molecular Cell·Michael F SharpWayne Crismani

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