Contributions
Abstract: O10
Type: Oral presentation
Session Topic: Inherited and acquired disorders of platelets
Presentation during EHA Scientific Conference on Bleeding Disorders:
On Thursday, September 15, 2016 from 09:00 - 10:30
Location: Rossini 1
Background
MYH9-related disease (MYH9-RD) is an autosomal-dominant disorder caused by mutations in the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA) and represents the most frequent inherited thrombocytopenia. NMMHC-IIA comprises two distinct domains, the N-terminal globular head domain (HD) and the C-terminal tail domain (TD), and causative mutations hit either the HD or the TD. All patients present at birth with macrothrombocytopenia and only some of them develop during life additional manifestations, including nephropathy often leading to end-stage renal disease (ESRD), sensorineural deafness, and/or cataract. Thus, the search for genotype-phenotype correlations in MYH9-RD has been an important research topic since the identification of the disorder. In 2008, the analysis of 108 patients allowed us to conclude that the mutations affecting the HD were associated with evolution to early-onset ESRD and deafness, whereas the risk of non-hematological manifestations was much lower for patients with TD mutations. In 2014, raising to 255 the number of patients, we suggested that evolution to juvenile ESRD associated only with the most frequent among HD mutations, i.e. substitution of the arginine 702 (R702). Conversely, the other HD mutations, which were almost all localized in a distinct hydrophobic region at the interface between the SH3 subdomain and the motor domain (SH3/MD interface), associated with a less severe evolution.
Aims
To improve prognostic assessment of patients with MYH9-RD.
Methods
All the consecutive patients enrolled in the Italian registry for MYH9-RD until December 2015 were included. The association of MYH9 genotype with phenotype was assessed by a generalized linear regression model (event-free survival analysis).
Results
We enrolled 350 patients belonging to 199 MYH9-RD pedigrees. Mutational screening allowed us to identify 6 novel causative mutations in the HD in 6 different pedigrees. Interestingly, all of these variants were localized in the hydrophobic region at the SH3/MD interface. By raising the number of patients with mutations in this region from 14 to 26 and increasing the observation time, we could demonstrate that mutations in the SH3/MD interface are associated with development of deafness at young-middle age, but low risk of kidney disease and cataract. The other previously identified genotype-phenotype correlations were confirmed. In particular, mutations hitting the R702 in the HD resulted in constant evolution toward juvenile ESRD and severe deafness. Among mutations different from R702 substitutions, the p.D1424H in the TD associated with the highest risk to develop non-congenital manifestations of the disease.
Conclusions
Mutations in the HD of the NMMHC-IIA are almost all localized in a specific region at the SH3/MD interface, which therefore represents a critical region for MYH9-RD pathogenesis. Most importantly, patients with HD mutations can be distinguished into two different prognostic groups: subjects with R702 substitutions are expected to early develop a severe syndromic disorder, whereas mutations in the SH3/MD interface are associated with evolution to a milder phenotype, characterized by development of hearing impairment only (“auditory” phenotype). Our study confirmed a genotype-phenotype model for MYH9-RD that overcomes the previously reported dualism between HD vs. TD mutation.
References
1. Pecci et al, Hum Mutat 2014; 236-47.
2. Pecci et al, Hum Mutat 2008; 409-17.
Abstract: O10
Type: Oral presentation
Session Topic: Inherited and acquired disorders of platelets
Presentation during EHA Scientific Conference on Bleeding Disorders:
On Thursday, September 15, 2016 from 09:00 - 10:30
Location: Rossini 1
Background
MYH9-related disease (MYH9-RD) is an autosomal-dominant disorder caused by mutations in the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA) and represents the most frequent inherited thrombocytopenia. NMMHC-IIA comprises two distinct domains, the N-terminal globular head domain (HD) and the C-terminal tail domain (TD), and causative mutations hit either the HD or the TD. All patients present at birth with macrothrombocytopenia and only some of them develop during life additional manifestations, including nephropathy often leading to end-stage renal disease (ESRD), sensorineural deafness, and/or cataract. Thus, the search for genotype-phenotype correlations in MYH9-RD has been an important research topic since the identification of the disorder. In 2008, the analysis of 108 patients allowed us to conclude that the mutations affecting the HD were associated with evolution to early-onset ESRD and deafness, whereas the risk of non-hematological manifestations was much lower for patients with TD mutations. In 2014, raising to 255 the number of patients, we suggested that evolution to juvenile ESRD associated only with the most frequent among HD mutations, i.e. substitution of the arginine 702 (R702). Conversely, the other HD mutations, which were almost all localized in a distinct hydrophobic region at the interface between the SH3 subdomain and the motor domain (SH3/MD interface), associated with a less severe evolution.
Aims
To improve prognostic assessment of patients with MYH9-RD.
Methods
All the consecutive patients enrolled in the Italian registry for MYH9-RD until December 2015 were included. The association of MYH9 genotype with phenotype was assessed by a generalized linear regression model (event-free survival analysis).
Results
We enrolled 350 patients belonging to 199 MYH9-RD pedigrees. Mutational screening allowed us to identify 6 novel causative mutations in the HD in 6 different pedigrees. Interestingly, all of these variants were localized in the hydrophobic region at the SH3/MD interface. By raising the number of patients with mutations in this region from 14 to 26 and increasing the observation time, we could demonstrate that mutations in the SH3/MD interface are associated with development of deafness at young-middle age, but low risk of kidney disease and cataract. The other previously identified genotype-phenotype correlations were confirmed. In particular, mutations hitting the R702 in the HD resulted in constant evolution toward juvenile ESRD and severe deafness. Among mutations different from R702 substitutions, the p.D1424H in the TD associated with the highest risk to develop non-congenital manifestations of the disease.
Conclusions
Mutations in the HD of the NMMHC-IIA are almost all localized in a specific region at the SH3/MD interface, which therefore represents a critical region for MYH9-RD pathogenesis. Most importantly, patients with HD mutations can be distinguished into two different prognostic groups: subjects with R702 substitutions are expected to early develop a severe syndromic disorder, whereas mutations in the SH3/MD interface are associated with evolution to a milder phenotype, characterized by development of hearing impairment only (“auditory” phenotype). Our study confirmed a genotype-phenotype model for MYH9-RD that overcomes the previously reported dualism between HD vs. TD mutation.
References
1. Pecci et al, Hum Mutat 2014; 236-47.
2. Pecci et al, Hum Mutat 2008; 409-17.