TY - JOUR T1 - MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. JF - Hum Mutat Y1 - 2014 A1 - Pecci, Alessandro A1 - Klersy, Catherine A1 - Gresele, Paolo A1 - Lee, Kieran J D A1 - De Rocco, Daniela A1 - Bozzi, Valeria A1 - Russo, Giovanna A1 - Heller, Paula G A1 - Loffredo, Giuseppe A1 - Ballmaier, Matthias A1 - Fabris, Fabrizio A1 - Beggiato, Eloise A1 - Kahr, Walter H A A1 - Pujol-Moix, Núria A1 - Platokouki, Helen A1 - Van Geet, Christel A1 - Noris, Patrizia A1 - Yerram, Preethi A1 - Hermans, Cedric A1 - Gerber, Bernhard A1 - Economou, Marina A1 - De Groot, Marco A1 - Zieger, Barbara A1 - De Candia, Erica A1 - Fraticelli, Vincenzo A1 - Kersseboom, Rogier A1 - Piccoli, Giorgina B A1 - Zimmermann, Stefanie A1 - Fierro, Tiziana A1 - Glembotsky, Ana C A1 - Vianello, Fabrizio A1 - Zaninetti, Carlo A1 - Nicchia, Elena A1 - Güthner, Christiane A1 - Baronci, Carlo A1 - Seri, Marco A1 - Knight, Peter J A1 - Balduini, Carlo L A1 - Savoia, Anna KW - Adult KW - Age of Onset KW - Amino Acid Substitution KW - Cataract KW - Female KW - Genetic Association Studies KW - Genotype KW - Hearing Loss, Sensorineural KW - Humans KW - Italy KW - Linear Models KW - Male KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Phenotype KW - Risk Factors KW - Thrombocytopenia AB -

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.

VL - 35 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24186861?dopt=Abstract ER -