NEW FINDINGS From the FRENCH COHORT of MYH9-RELATED DISORDERS: PHENOTYPE PECULIARITIES and GENOTYPE NOVELTIES on Behalf of the National French Reference Center on Inherited Platelet Disorders (CRPP)

Abstract 1155

MYH9-Related Diseases (RD) are inherited platelet disorders combining thrombocytopenia and giant platelets with various associations of leukocyte inclusions, deafness, nephritis and cataracts. Mutations in the MYH9 gene, that encodes the nonmuscle myosin heavy chain IIA (NMMHC-IIA), are the hallmark of these disorders. Our cohort includes a total of 161 subjects (90 women, 71 men): 76 propositi (37 isolated, 39 family index cases) with MYH9 mutations and 85 family members (45 women, 40 men) belonging to the 39 unrelated families. The cases with an identified mutation were classified according to the location of the mutation either in the motor domain (MD patients (P): “MDP”) or in the tail domain (TD patients (P): “TDP”) of NMMHC-IIA. MYH9 mutations were found in a total of 109 subjects: the 76 propositi (45 women, 31 men) and 33/85 (38.8%) family members (19 women, 14 men, from 22 families). Among the 41 different mutations detected, the majority were missense mutations (33 = 80.5%) and new (25 = 61%). Two substitutions in intron 39 were discovered for the first time: 1 in the donor splice site (corresponding to a classical MYH9-RD phenotype) and the other in position minus 3 of the acceptor splice site (moderate thrombocytopenia only without giant platelets). A total of 15 different exons were identified as having mutations, 4 exons remained unaffected. Mutations were more frequently found in exons 1, 16, 26, 30, 38 and 40, as already published. The majority of patients (102 = 93.6%) were heterozygous for one mutation but 7 patients (6.4%) were compound heterozygous for 2 mutations. Significant differences between MDP and TDP were found for bleeding symptoms (65% of MDP, 33% of TDP, p=0.0037), nephropathy (31.5% of MDP, 11.6% of TDP, p=0.015), age (years, mean) at onset for nephropathy (21 for MDP, 48 for TDP, p=0.0003), deafness (54% of MDP, 23.7% of TDP, p=0.0025), and association bleeding/extra-hematological symptoms (68.2% of MDP, 27.7% of TDP, p=0.01). Patients with bleeding had a lower platelet count than non-bleeders (mean= 42G/L versus 62G/L, p=0.0024) but there were no significant differences in the percentage of giant platelets. ITP (splenectomy for 7) was the initial misdiagnosis for 29/69 (42%), (51.7% of MDP, 35% of TDP, p= 0.165). Cataracts occurred in 4 patients only. Altogether these results showed that the clinical phenotype of MYH9-RD was more severe for MDP than TDP. New mutations were discovered and were widespread along the exons and in some cases two mutations were identified in the same patient. The sequencing of the full gene and all exons-introns boundaries should be mandatory for each patient whatever the initial result.