We describe a large four-generational Chinese pedigree segregating MYH9-related disease caused by a V1516L mutation. The clinical findings supported previously established genotype-phenotype correlations, and also demonstrated interindividual variability of disease manifestations even within the same family. The same mutation was previously reported in another Chinese pedigree but resulting from a different DNA substitution. Analyzing the patterns of previously reported mutations revealed a limited spectrum of pathogenic variants. The implications of this finding are discussed.

Keywords:
Bioinformatics, Missense single nucleotide variants, MYH9-related disease, Pathogenic mutations, Thrombocytopenia
1.
Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, Nigro A, Noris P, Gangarossa S, Rocca B, Gresele P, Bizzaro N, Malatesta P, Koivisto PA, Longo I, Musso R, Pecoraro C, Iolascon A, Magrini U, Rodriguez Soriano J, Renieri A, Ghiggeri GM, Ravazzolo R, Balduini CL, Savoia A: MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine 2003;82:203-215.
2.
Pecci A, Panza E, Pujol-Moix N, Klersy C, Di Bari F, Bozzi V, Gresele P, Lethagen S, Fabris F, Dufour C, Granata A, Doubek M, Pecoraro C, Koivisto PA, Heller PG, Iolascon A, Alvisi P, Schwabe D, De Candia E, Rocca B, Russo U, Ramenghi U, Noris P, Seri M, Balduini CL, Savoia A: Position of nonmuscle myosin heavy chain IIa (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. Hum Mutat 2008;29:409-417.
3.
Ma ES, Wong CL, Shek TW, Hui SP: Hematologic and genetic characterization of an MYH9-related disorder in a Chinese family. Haematologica 2006;91:1002-1003.
4.
Savoia A, Germeshausen M, De Rocco D, Henschel B, Kratz CP, Kuhlen M, Rath B, Steuhl KP, Wermes C, Ballmaier M: MYH9-related disease: report on five German families and description of a novel mutation. Ann Hematol 2010b;89:1057-1059.
5.
Franke JD, Dong F, Rickoll WL, Kelley MJ, Kiehart DP: Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIa assembly. Blood 2005;105:161-169.
6.
Savoia A, De Rocco D, Panza E, Bozzi V, Scandellari R, Loffredo G, Mumford A, Heller PG, Noris P, De Groot MR, Giani M, Freddi P, Scognamiglio F, Riondino S, Pujol-Moix N, Fabris F, Seri M, Balduini CL, Pecci A: Heavy chain myosin 9-related disease (MYH9-RD): neutrophil inclusions of myosin-9 as a pathognomonic sign of the disorder. Thrombosis and Haemostasis 2010a;103:826-832.
7.
Balduini CL, Pecci A, Savoia A: Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. Br J Haematol 2011;154:161-174.
8.
Kunishima S, Saito H: Advances in the understanding of MYH9 disorders. Curr Opin Hematol 2010;17:405-410.
9.
Miyazaki K, Kunishima S, Fujii W, Higashihara M: Identification of three in-frame deletion mutations in MYH9 disorders suggesting an important hot spot for small rearrangements in MYH9 exon 24. Eur J Haematol 2009b;83:230-234.
10.
Exome Variant Server: NHLBI Go Exome Sequencing Project (ESP). http://evs.gs.washington.edu/evs/ (accessed 2013).
11.
Liu X, Jian X, Boerwinkle E: dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum Mutat 2011;32:894-899.
12.
Provaznikova D, Geierova V, Kumstyrova T, Kotlin R, Mikulenkova D, Zurkova K, Matoska V, Hrachovinova I, Rittich S: Clinical manifestation and molecular genetic characterization of MYH9 disorders. Platelets 2009;20:289-296.
13.
Heath KE, Campos-Barros A, Toren A, Rozenfeld-Granot G, Carlsson LE, Savige J, Denison JC, Gregory MC, White JG, Barker DF, Greinacher A, Epstein CJ, Glucksman MJ, Martignetti JA: Nonmuscle myosin heavy chain IIa mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am J Hum Genet 2001;69:1033-1045.
14.
Shearer AE, Black-Ziegelbein EA, Hildebrand MS, Eppsteiner RW, Ravi H, Joshi S, Guiffre AC, Sloan CM, Happe S, Howard SD, Novak B, Deluca AP, Taylor KR, Scheetz TE, Braun TA, Casavant TL, Kimberling WJ, Leproust EM, Smith RJ: Advancing genetic testing for deafness with genomic technology. J Med Genet 2013;50:627-634.
15.
Kunishima S, Hamaguchi M, Saito H: Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders. Blood 2008a;111:3015-3023.
16.
Pecci A, Canobbio I, Balduini A, Stefanini L, Cisterna B, Marseglia C, Noris P, Savoia A, Balduini CL, Torti M: Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. Hum Mol Genet 2005;14:3169-3178.
17.
Andreasen C, Nielsen JB, Refsgaard L, Holst AG, Christensen AH, Andreasen L, Sajadieh A, Haunso S, Svendsen JH, Olesen MS: New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet 2013;21:918-928.
18.
Refsgaard L, Holst AG, Sadjadieh G, Haunso S, Nielsen JB, Olesen MS: High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Human Genet 2012;20:905-908.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.