MYH9‐Related Disease: A Novel Prognostic Model to Predict the Clinical Evolution of the Disease Based on Genotype–Phenotype Correlations

Alessandro Pecci, Catherine Klersy, Paolo Gresele, Kieran J.D. Lee, Daniela De Rocco, Valeria Bozzi, Giovanna Russo, Paula G. Heller, Giuseppe Loffredo, Matthias Ballmaier, Fabrizio Fabris, Eloise Beggiato, Walter H.A. Kahr, Nuria Pujol‐Moix, Helen Platokouki, Christel Van Geet, Patrizia Noris, Preethi Yerram, Cedric Hermans, Bernhard Gerber, Marina Economou, Marco De Groot, Barbara Zieger, Erica De Candia, Vincenzo Fraticelli, Rogier Kersseboom, Giorgina B. Piccoli, Stefanie Zimmermann, Tiziana Fierro, Ana C. Glembotsky, Fabrizio Vianello, Carlo Zaninetti, Elena Nicchia, Christiane Güthner, Carlo Baronci, Marco Seri, Peter J. Knight, Carlo L. Balduini, Anna Savoia

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.