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

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.

SUBMITTER: Pecci A

PROVIDER: S-EPMC6233870 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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

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

Human mutation 20131212 2

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 cons ...[more]

PMID: 24186861

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Dataset Information

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

Publications

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

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