%0 Journal Article %J Hum Mutat %D 2014 %T MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. %A Pecci, Alessandro %A Klersy, Catherine %A Gresele, Paolo %A Lee, Kieran J D %A De Rocco, Daniela %A Bozzi, Valeria %A Russo, Giovanna %A Heller, Paula G %A Loffredo, Giuseppe %A Ballmaier, Matthias %A Fabris, Fabrizio %A Beggiato, Eloise %A Kahr, Walter H A %A Pujol-Moix, Núria %A Platokouki, Helen %A Van Geet, Christel %A Noris, Patrizia %A Yerram, Preethi %A Hermans, Cedric %A Gerber, Bernhard %A Economou, Marina %A De Groot, Marco %A Zieger, Barbara %A De Candia, Erica %A Fraticelli, Vincenzo %A Kersseboom, Rogier %A Piccoli, Giorgina B %A Zimmermann, Stefanie %A Fierro, Tiziana %A Glembotsky, Ana C %A Vianello, Fabrizio %A Zaninetti, Carlo %A Nicchia, Elena %A Güthner, Christiane %A Baronci, Carlo %A Seri, Marco %A Knight, Peter J %A Balduini, Carlo L %A Savoia, Anna %K Adult %K Age of Onset %K Amino Acid Substitution %K Cataract %K Female %K Genetic Association Studies %K Genotype %K Hearing Loss, Sensorineural %K Humans %K Italy %K Linear Models %K Male %K Molecular Motor Proteins %K Mutation %K Myosin Heavy Chains %K Phenotype %K Risk Factors %K Thrombocytopenia %X

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.

%B Hum Mutat %V 35 %P 236-47 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24186861?dopt=Abstract %R 10.1002/humu.22476