Abstract
We report a kindred referred for molecular investigation of severe hemophilia A in a young female in which extremely skewed X-inactivation was observed in both the proband and her clinically normal mother. Bidirectional Sanger sequencing of all F8 gene coding regions and exon/intron boundaries was undertaken. Methylation-sensitive restriction enzymes were utilized to investigate skewed X-inactivation using both a classical human androgen receptor (HUMARA) assay, and a novel method targeting differential methylation patterns in multiple informative X-chromosome SNPs. Illumina Whole-Genome Infinium microarray analysis was performed in the case-parent trio (proband and both parents), and the proband's maternal grandmother. The proband was a cytogenetically normal female with severe hemophilia A resulting from a heterozygous F8 pathogenic variant inherited from her similarly affected father. No F8 mutation was identified in the proband's mother, however, both the proband and her mother both demonstrated completely skewed X-chromosome inactivation (100%) in association with a previously unreported 2.3 Mb deletion at Xp22.2. At least three disease-associated genes (FANCB, AP1S2, and PIGA) were contained within the deleted region. We ...Continue Reading
References
May 1, 1987·The Journal of Clinical Investigation·J M PuckM E Conley
Jul 1, 1973·Annals of Human Genetics·P J Fialkow
Jul 1, 1997·American Journal of Human Genetics·E PegoraroE P Hoffman
Nov 14, 1997·Nature Genetics·R M PlengeH F Willard
Jan 29, 1998·The New England Journal of Medicine·O ParoliniW Holter
Jan 29, 1998·The New England Journal of Medicine·J M Puck, H F Willard
Jan 5, 2002·Blood·Richard D BagnallFrancesco Giannelli
May 7, 2002·American Journal of Human Genetics·Charles TeaseMaj A Hultén
Aug 20, 2003·British Journal of Anaesthesia·P DharF Gadalla
Jan 1, 1964·Cold Spring Harbor Symposia on Quantitative Biology·W E NANCE
Oct 27, 2004·Nature Genetics·Amom Ruhikanta MeeteiHans Joenje
Apr 8, 2006·Thrombosis and Haemostasis·Nicole L KilianVickie Hanrahan
Sep 7, 2006·Journal of Human Genetics·Milena CauMaria Antonietta Melis
Mar 8, 2007·European Journal of Human Genetics : EJHG·Nisa K RenaultWenda L Greer
Mar 24, 2009·Journal of Thrombosis and Haemostasis : JTH·A PavlovaJ Oldenburg
Apr 7, 2009·American Journal of Human Genetics·Helen V FirthNigel P Carter
Aug 11, 2011·Haemophilia : the Official Journal of the World Federation of Hemophilia·V R ByamsUNKNOWN Haemophilia Treatment Centres Network Investigators
Jan 12, 2012·Clinical Genetics·J M EsquilinN S Green
Apr 21, 2012·Cytogenetic and Genome Research·V JobanputraD Warburton
Jul 3, 2013·Blood Reviews·Massimo Franchini, Pier Mannuccio Mannucci
Jun 14, 2014·Blood·Edward Tuddenham
Nov 8, 2014·Seminars in Thrombosis and Hemostasis·Johannes OldenburgAnna Pavlova
Apr 18, 2015·Orphanet Journal of Rare Diseases·Maja Tarailo-GraovacClara D M van Karnebeek
Citations
Apr 18, 2019·Haemophilia : the Official Journal of the World Federation of Hemophilia·Jane A Mason, Jeremy D Robertson
Nov 17, 2020·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Isaura-Araceli González-RamosAna Rebeca Jaloma-Cruz
Dec 15, 2020·Haemophilia : the Official Journal of the World Federation of Hemophilia·Connie H Miller, Christopher J Bean