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

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. Fil: Pecci, Alessandro. University of Pavia; Italia Fil: Klersy, Catherine. IRCCS Policlinico San Matteo Foundation; Italia Fil: Gresele, Paolo. Università di Perugia; Italia Fil: Lee, Kieran J. D.. University of Leeds; Reino Unido Fil: De Rocco, Daniela. Università degli Studi di Trieste; Italia Fil: Bozzi, Valeria. University of Pavia; Italia Fil: Russo, Giovanna. University of Catania; Italia Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Loffredo, Giuseppe. Pausilipon Hospital. Department of Oncology; Italia Fil: Ballmaier, Matthias. Hannover Medical School; Alemania Fil: Fabris, Fabrizio. Università di Padova; Italia Fil: Beggiato, Eloise. Hospital “Città della Salute e Della Scienza”; Italia Fil: Kahr, Walter H. A.. University of Toronto; Canadá. Hospital for Sick Children. Division of Hematology/Oncology; Canadá Fil: Pujol Moix, Nuria. Universitat Autònoma de Barcelona; España Fil: Platokouki, Helen. “Aghia Sophia” Children's Hospital; Grecia Fil: Van Geet, Christel. University of Leuven. Center for Molecular and Vascular Biology; Bélgica Fil: Noris, Patrizia. University of Pavia; Italia Fil: Yerram, Preethi. University of Missouri; Estados Unidos Fil: Hermans, Cedric. St-Luc University Hospital; Bélgica Fil: Gerber, Bernhard. University Hospital Zurich, Division of Hematology; Suiza Fil: Economou, Marina. Aristotle University; Grecia Fil: De Groot, Marco. University of Groningen; Países Bajos Fil: Zieger, Barbara. University Medical Center Freiburg; Alemania Fil: De Candia, Erica. Catholic University of Rome; Italia Fil: Fraticelli, Vincenzo. Giovanni Paolo II Foundation; Italia Fil: Kersseboom, Rogier. Erasmus Medical Centre; Países Bajos Fil: Piccoli, Giorgina B.. Università di Torino; Italia Fil: Zimmermann, Stefanie. Goethe Universitat Frankfurt; Alemania Fil: Fierro, Tiziana. Università di Perugia; Italia Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Vianello, Fabrizio. Università di Padova; Italia Fil: Zaninetti, Carlo. University of Pavia; Italia Fil: Nicchia, Elena. Università degli Studi di Trieste; Italia Fil: Güthner, Christiane. Stadtspital Triemli. Department of Medical Oncology and Hematology; Italia Fil: Baronci, Carlo. Pediatric Hospital "Bambino Gesù"; Italia Fil: Seri, Marco. Università di Bologna; Italia Fil: Knight, Peter J.. University of Leeds; Reino Unido Fil: Balduini, Carlo L.. University of Pavia; Italia Fil: Savoia, Anna. Università degli Studi di Trieste; Italia