MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations

PECCI A; KLERSY C ; GRESELE P; LEE K; DE ROCCO D ; BOZZI V; RUSSO G ; HELLER PG; LOFFREDO F ; BALLMAIER M; FABRIS F; BEGGIATO E; KAHR W; PUJOL-MOIX N ; PLATOKOUKI H ; VAN GEET C ; NORIS P; YERRAM P; HERMANS C ; BERNHARD GERBER B; ECONOMOU M; DE GROOT M; ZIEGER B ; DE CANDIA E; FRATICELLI V; KERSSEBOOM R; PICCOLI G; ZIMMERMANN S; FIERRO T; GLEMBOTSKY AC; VIANELLO F; ZANINETTI C; NICCHIA E; GÜTHNER C; BARONCI C; SERI M; KNIGHT P; BALDUINI CL; SAVOIA A

HUMAN MUTATION

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2013 p. 1 - 40

1059-7794

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for non-muscle 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 non-congenital 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 non-congenital 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 non-congenital defects. These findings are essential to patients? clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.