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

A Pecci*, C Klersy, P Gresele, Kjd Lee, D De Rocco, V Bozzi, G Russo, Pg Heller, G Loffredo, M Ballmaier, F Fabris, E Beggiato, Wha Kahr, N Pujol Moix, H Platokouki, C Van Geet, P Noris, P Yerram, C Hermans, B GerberM Economou, M De Groot, B Zieger, Erica De Candia, V Fraticelli, R Kersseboom, Gb Piccoli, S Zimmermann, T Fierro, Ac Glembotsky, F Vianello, C Zaninetti, E Nicchia, C Güthner, C Baronci, M Seri, Pj Knight, Cl Balduini, A. Savoia

*Autore corrispondente per questo lavoro

Risultato della ricerca: Contributo in rivistaArticolo

108 Citazioni (Scopus)

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.
Lingua originaleInglese
pagine (da-a)236-247
Numero di pagine12
RivistaHuman Mutation
Volume35
Numero di pubblicazione2
DOI
Stato di pubblicazionePubblicato - 2014

All Science Journal Classification (ASJC) codes

  • Genetica
  • Genetica (clinica)

Keywords

  • MYH9
  • deafness
  • nephropathy
  • nonmuscle myosin
  • thrombocytopenia

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