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.

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, Kj; De Rocco, D; Bozzi, V; Russo, G; Heller, Pg; Loffredo, G; Ballmaier, M; Fabris, F; Beggiato, E; Kahr, Wh; Pujol-Moix, N; Platokouki, H; Van Geet, C; Noris, P; Yerram, P; Hermans, C; Gerber, B; Economou, M; De Groot, M; Zieger, B; De Candia, E; Fraticelli, V; Kersseboom, R; Piccoli, Gb; Zimmermann, S; Fierro, T; Glembotsky, Ac; Vianello, F; Zaninetti, C; Nicchia, E; Güthner, C; Baronci, C; Seri, M; Knight, Pj; Balduini, Cl; Savoia, A.. - In: HUMAN MUTATION. - ISSN 1059-7794. - STAMPA. - 35:(2014), pp. 236-247. [10.1002/humu.22476]

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

SERI, MARCO;
2014

Abstract

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.
2014
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, Kj; De Rocco, D; Bozzi, V; Russo, G; Heller, Pg; Loffredo, G; Ballmaier, M; Fabris, F; Beggiato, E; Kahr, Wh; Pujol-Moix, N; Platokouki, H; Van Geet, C; Noris, P; Yerram, P; Hermans, C; Gerber, B; Economou, M; De Groot, M; Zieger, B; De Candia, E; Fraticelli, V; Kersseboom, R; Piccoli, Gb; Zimmermann, S; Fierro, T; Glembotsky, Ac; Vianello, F; Zaninetti, C; Nicchia, E; Güthner, C; Baronci, C; Seri, M; Knight, Pj; Balduini, Cl; Savoia, A.. - In: HUMAN MUTATION. - ISSN 1059-7794. - STAMPA. - 35:(2014), pp. 236-247. [10.1002/humu.22476]
Pecci, A; Klersy, C; Gresele, P; Lee, Kj; De Rocco, D; Bozzi, V; Russo, G; Heller, Pg; Loffredo, G; Ballmaier, M; Fabris, F; Beggiato, E; Kahr, Wh; Pujol-Moix, N; Platokouki, H; Van Geet, C; Noris, P; Yerram, P; Hermans, C; Gerber, B; Economou, M; De Groot, M; Zieger, B; De Candia, E; Fraticelli, V; Kersseboom, R; Piccoli, Gb; Zimmermann, S; Fierro, T; Glembotsky, Ac; Vianello, F; Zaninetti, C; Nicchia, E; Güthner, C; Baronci, C; Seri, M; Knight, Pj; Balduini, Cl; Savoia, A.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/454167
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