title: 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.
authors.affiliation: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, Pavia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pecci
authors.forename: Catherine
authors.initials: C
authors.lastname: Klersy
authors.forename: Paolo
authors.initials: P
authors.lastname: Gresele
authors.forename: Kieran J D
authors.initials: KJ
authors.lastname: Lee
authors.forename: Daniela
authors.initials: D
authors.lastname: De Rocco
authors.forename: Valeria
authors.initials: V
authors.lastname: Bozzi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Russo
authors.forename: Paula G
authors.initials: PG
authors.lastname: Heller
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Loffredo
authors.forename: Matthias
authors.initials: M
authors.lastname: Ballmaier
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fabris
authors.forename: Eloise
authors.initials: E
authors.lastname: Beggiato
authors.forename: Walter H A
authors.initials: WH
authors.lastname: Kahr
authors.forename: Nuria
authors.initials: N
authors.lastname: Pujol-Moix
authors.forename: Helen
authors.initials: H
authors.lastname: Platokouki
authors.forename: Christel
authors.initials: C
authors.lastname: Van Geet
authors.forename: Patrizia
authors.initials: P
authors.lastname: Noris
authors.forename: Preethi
authors.initials: P
authors.lastname: Yerram
authors.forename: Cedric
authors.initials: C
authors.lastname: Hermans
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gerber
authors.forename: Marina
authors.initials: M
authors.lastname: Economou
authors.forename: Marco
authors.initials: M
authors.lastname: De Groot
authors.forename: Barbara
authors.initials: B
authors.lastname: Zieger
authors.forename: Erica
authors.initials: E
authors.lastname: De Candia
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Fraticelli
authors.forename: Rogier
authors.initials: R
authors.lastname: Kersseboom
authors.forename: Giorgina B
authors.initials: GB
authors.lastname: Piccoli
authors.forename: Stefanie
authors.initials: S
authors.lastname: Zimmermann
authors.forename: Tiziana
authors.initials: T
authors.lastname: Fierro
authors.forename: Ana C
authors.initials: AC
authors.lastname: Glembotsky
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vianello
authors.forename: Carlo
authors.initials: C
authors.lastname: Zaninetti
authors.forename: Elena
authors.initials: E
authors.lastname: Nicchia
authors.forename: Christiane
authors.initials: C
authors.lastname: Güthner
authors.forename: Carlo
authors.initials: C
authors.lastname: Baronci
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Knight
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Balduini
authors.forename: Anna
authors.initials: A
authors.lastname: Savoia
mesh_terms: D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D002386:Cataract / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007558:Italy; D016014:Linear Models; D008297:Male; D020409:Molecular Motor Proteins / Q000235:genetics*; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D010641:Phenotype; D012307:Risk Factors; D013921:Thrombocytopenia / Q000150:complications / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics
chemical_list: C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains
keywords: MYH9; deafness; nephropathy; nonmuscle myosin; thrombocytopenia